Clinical trial NCT02791438
Conditions: Pediatric Hypertension
Sponsor: Takeda
Start date: 2016-08-18; Completion date: 2019-06-04
Enrollment: 27 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety of administration of azilsartan in pediatric patients aged 6 to less than 16 years with hypertension.

Detailed description:
The drug being tested in this study is called azilsartan. Azilsartan is being tested to treat pediatric participants with hypertension.

The study enrolled 27 participants. Following a 2-week Placebo Run-in Period, participants were assigned to one of the two treatment groups based on weight:

* Azilsartan 2.5 - 20 mg (Participants \< 50 kg)
* Azilsartan 5 - 40 mg (Participants ≥ 50 kg)

Participants weighing \< 50 kg were asked to take an initial dose azilsartan 2.5 mg (titrated as needed to the highest dose of 20 mg) and participants weighing ≥ 50 kg were asked to take an initial dose of 5 mg azilsartan (titrated as needed to the highest dose of 40 mg).

This multi-centre trial was conducted in Japan. The overall time to participate in this study is 56 weeks. The study consisted of a Run-in Period (Week -2 to Week 0), a 52-week Treatment Period, and a 2-week Follow-up Period (up to Week 54). Participants made multiple visits to the clinic and a final visit 2 weeks after the last dose of study drug for follow-up assessment.

Arms: arm 1: Following a 2-week placebo run-in period, azilsartan 2.5 mg (titrated as needed to the highest dose of 20 mg) was administered orally once daily before or after breakfast, for the participants weighing \< 50 kg. arm 2: Following a 2-week placebo run-in period, azilsartan 5 mg (titrated as needed to the highest dose of 40 mg) was administered orally once daily before or after breakfast, for the participants weighing ≥ 50 kg.
Interventions: intervention 1: Azilsartan intervention 2: Placebo
Intervention descriptions: intervention 1: Azilsartan granules and tablets intervention 2: Placebo-matching azilsartan granules and tablets

Protocol documents:
Prot_000.pdf: 
 
 
Title: A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, 
Efficacy and Pharmacokinetics of TAK-536 in Pediatric Patients 6 to Less Than 16 
Years of Age with Hypertension 
 
NCT Number: NCT02791438 
Protocol Approve Date: 12-APR-2017 
 
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. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
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. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 


PROTOCOL 
A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, Efficacy and 
Pharmacokinetics of TAK-536 in Pediatric Patients 6 to Less Than 16 Years of Age with 
Hypertension 
A Phase 3 Long-term Study of TAK-536 in Pediatric Patients 6 to Less Than 16 Years with 
Hypertension 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka, Japan
Study Number: 
TAK-536/OCT-101 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
TAK-536 
Date: 
12 Apr 2017 
Amendment Number: 02 
Amendment History: 
Date 
Amendment Number 
Region 
16 March 2016 
First version 
All sites 
12 May 2016 
01 
All sites 
12 April 2017 
02 
All sites 
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 AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
See the attachments. 
1.2 
Principles of Clinical Studies 
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 (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
1.3 
Protocol Amendment 02 Summary of Changes 
Reporting items are added to collect the information accurately about the action taken with the 
study drug when AEs occurred. Detailed description of amendments are given in Appendix C.  


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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES ........................................................................................................................ 2 
1.1 
Contacts and Responsibilities of Study-Related Activities .......................................... 2 
1.2 
Principles of Clinical Studies ..................................................................................... 2 
1.3 
Protocol Amendment 02 Summary of Changes .......................................................... 2 
2.0 
STUDY SUMMARY ...................................................................................................... 7 
3.0 
LIST OF ABBREVIATIONS ........................................................................................ 12 
4.0 
INTRODUCTION ......................................................................................................... 14 
4.1 
Background ............................................................................................................. 14 
4.2 
Rationale for the Proposed Study ............................................................................. 15 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 16 
5.1 
Objectives ................................................................................................................ 16 
5.1.1 
Primary Objective .............................................................................................. 16 
5.1.2 
Secondary Objectives ......................................................................................... 16 
5.2 
Endpoints................................................................................................................. 16 
5.2.1 
Primary Endpoints ............................................................................................. 16 
5.2.2 
Secondary Endpoints .......................................................................................... 16 
6.0 
STUDY DESIGN AND DESCRIPTION ....................................................................... 18 
6.1 
Study Design ........................................................................................................... 18 
6.2 
Justification for Study Design, Dose, Regimen, and Endpoints ................................ 20 
6.3 
Premature Termination or Suspension of Study or Study Site ................................... 23 
6.3.1 
Criteria for Premature Termination or Suspension of the Study .......................... 23 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites ....................... 23 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites ................................................................................ 23 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS .............. 24 
7.1 
Inclusion Criteria ..................................................................................................... 24 
7.2 
Exclusion Criteria .................................................................................................... 25 
7.3 
Excluded Medications and Treatments ..................................................................... 27 
7.3.1 
Excluded Medications ........................................................................................ 27 
7.3.2 
Medications Permitted with Conditions .............................................................. 28 
7.4 
Diet, Fluid, and Activity Control .............................................................................. 29 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject ........................................... 31 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject...................................... 32 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT ...................................................... 33 


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8.1 
Study Drug and Materials ........................................................................................ 33 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ..................................... 33 
8.1.1.1 Study Drug ................................................................................................... 33 
8.1.2 
Storage ............................................................................................................... 34 
8.1.3 
Dose and Regimen ............................................................................................. 34 
8.1.4 
Overdose ............................................................................................................ 35 
8.2 
Study Drug Dispensing Procedures .......................................................................... 35 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs ..................................... 35 
9.0 
STUDY PLAN .............................................................................................................. 36 
9.1 
Study Procedures ..................................................................................................... 36 
9.1.1 
Informed Consent Procedure .............................................................................. 36 
9.1.2 
Demographics, Medical History, and Medication History Procedure .................. 36 
9.1.3 
Physical Examination Procedure ........................................................................ 36 
9.1.4 
Weight, Height, and BMI ................................................................................... 36 
9.1.5 
Vital Sign Procedure .......................................................................................... 37 
9.1.6 
Measuring Home Blood Pressure ....................................................................... 38 
9.1.7 
Documentation of Concomitant Medications ...................................................... 39 
9.1.8 
Documentation of Concurrent Medical Conditions ............................................. 39 
9.1.9 
Procedures for Clinical Laboratory Samples ....................................................... 39 
9.1.10 Contraception and Pregnancy Avoidance Procedure ........................................... 41 
9.1.11 Pregnancy .......................................................................................................... 42 
9.1.12 ECG Procedure .................................................................................................. 42 
9.1.13 Pharmacokinetic Sample Collection ................................................................... 42 
9.1.13.1 
Collection of Plasma for Pharmacokinetic Sampling ............................... 43 
9.1.13.2 
Bioanalytical Method ............................................................................. 43 
9.1.14 Documentation of Subjects Failure ..................................................................... 43 
9.1.15 Documentation of Study Entrance ...................................................................... 44 
9.2 
Monitoring Subject Treatment Compliance .............................................................. 44 
9.3 
Schedule of Observations and Procedures ................................................................ 44 
9.3.1 
Screening ........................................................................................................... 44 
9.3.2 
Start of the Run-in Period (Week -2) .................................................................. 44 
9.3.3 
End of the Run-in Period (Week 0) .................................................................... 45 
9.3.4 
Treatment Period (Weeks 2, 4, 8, 12, 16, 20, 24, 32, and 40) .............................. 45 
9.3.5 
Final Visit or Early Termination ......................................................................... 45 
9.3.6 
Follow-up Period: Week 54................................................................................ 46 
9.3.7 
Post Study Care .................................................................................................. 46 


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10.0 
ADVERSE EVENTS .................................................................................................... 47 
10.1 
Definitions ............................................................................................................... 47 
10.1.1 AEs .................................................................................................................... 47 
10.1.2 Additional Points to Consider for AEs................................................................ 47 
10.1.3 SAEs .................................................................................................................. 49 
10.1.4 AEs of Special Interest ....................................................................................... 50 
10.1.5 Severity of AEs .................................................................................................. 50 
10.1.6 Causality of AEs to Study Drugs ........................................................................ 50 
10.1.7 Causality of AEs to Study Procedures ................................................................ 51 
10.1.8 Start Date ........................................................................................................... 51 
10.1.9 End Date ............................................................................................................ 51 
10.1.10 
Pattern of Adverse Event .............................................................................. 51 
10.1.11 
Action Taken with Study Treatment ............................................................. 51 
10.1.12 
Outcome....................................................................................................... 51 
10.2 
Procedures ............................................................................................................... 52 
10.2.1 Collection and Reporting of AEs ........................................................................ 52 
10.2.1.1 
AE Collection Period .............................................................................. 52 
10.2.1.2 
AE Reporting ......................................................................................... 52 
10.2.1.3 
AEs of Special Interest Reporting ........................................................... 53 
10.2.2 Collection and Reporting of SAEs ...................................................................... 53 
10.2.3 Reporting of Abnormal Liver Function Tests ..................................................... 54 
10.3 
Follow-up of SAEs .................................................................................................. 54 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities .................. 54 
11.0 
STUDY-SPECIFIC COMMITTEES ............................................................................. 55 
12.0 
DATA HANDLING AND RECORDKEEPING ............................................................ 56 
12.1 
CRFs (Electronic) .................................................................................................... 56 
12.2 
Record Retention ..................................................................................................... 56 
13.0 
STATISTICAL METHODS .......................................................................................... 58 
13.1 
Statistical and Analytical Plans ................................................................................ 58 
13.1.1 Analysis Sets...................................................................................................... 58 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ........................... 58 
13.1.3 Efficacy Analysis ............................................................................................... 58 
13.1.4 Pharmacokinetic Analysis .................................................................................. 59 
13.1.5 Safety Analysis .................................................................................................. 59 
13.2 
Interim Analysis and Criteria for Early Termination ................................................ 60 
13.3 
Determination of Sample Size .................................................................................. 60 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE............................................... 62 
14.1 
Study-Site Monitoring Visits ................................................................................... 62 
14.2 
Protocol Deviations.................................................................................................. 62 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................ 62 
15.0 
ETHICAL ASPECTS OF THE STUDY ........................................................................ 63 
15.1 
IRB Approval .......................................................................................................... 63 
15.2 
Subject Information, Informed Consent/Assent, and Subject Authorization .............. 63 
15.3 
Subject Confidentiality ............................................................................................ 65 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ................................. 65 
15.4.1 Publication and Disclosure ................................................................................. 65 
15.4.2 Clinical Trial Registration .................................................................................. 65 
15.4.3 Clinical Trial Results Disclosure ........................................................................ 66 
15.5 
Insurance and Compensation for Injury .................................................................... 66 
16.0 
REFERENCES .............................................................................................................. 67 
LIST OF IN-TEXT TABLES 
Table 5.a 
Reference Blood Pressure Values of Children by Gender and Age ..................... 17 
Table 9.a 
Clinical Laboratory Tests ................................................................................... 40 
Table 10.a 
Takeda Medically Significant AE List ................................................................ 50 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ................................................................................ 20 
LIST OF APPENDICES 
Appendix C 
Detailed Description of Amendments to Text ..................................................... 73 
CCI


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2.0 
STUDY SUMMARY 
Clinical Study Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: 
TAK-536 
Study Title: A Phase 3, Open-label, Multicenter, 
Long-term Study to Evaluate the Safety, Efficacy and 
Pharmacokinetics of TAK-536 in Pediatric Patients 6 to 
Less Than 16 Years of Age with Hypertension 
IND No.: 
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Identifier: TAK-536/OCT-101 
Phase: 3 
Study Design: 
This is a phase 3, open-label, multicenter study to evaluate the safety, efficacy, and pharmacokinetics of long-term 
administration of TAK-536 once daily for 52 weeks in pediatric patients aged 6 to less than 16 years with 
hypertension. The study consists of a 2-week Run-in Period, a 52-week Treatment Period (Treatment Period I, 
12-week; Treatment Period II, 40-week), and a 2-week Follow-up Period (56 weeks in total).
Subjects eligible at screening will initiate to receive the placebo in a single-blinded fashion at the start of the Run-in 
Period. 
The duration of the Run-in Period will be 2 weeks. The subjects whose blood pressures meet the inclusion criteria 1 
week (at earliest) after receiving placebo in the Run-in Period can enter the Treatment Period. For the subjects only 
who treated with any antihypertensive drugs as a prior treatment, the Run-in Period could be extended up to 4 weeks if 
blood pressures do not meet the inclusion criteria. Subjects who treated with renin-angiotensin-system (RAS) 
inhibitors (ACE inhibitors, ARB, and DRI) until the start of the Run-in Period should discontinue them at the start of 
the Run-in Period. Subjects who treated with antihypertensive drugs other than RAS inhibitors until the start of the 
Run-in Period can continue to receive a single antihypertensive drug in addition to the study drug if the subjects are 
considered to need the additional treatments for hypertension in the Treatment Period I by the investigator or 
subinvestigator; the antihypertensive drug should be administered under the same dosage at the time of the start of the 
Run-in Period. If subjects have difficulty in discontinuing antihypertensive drugs completely at the start of the Run-in 
Period, the antihypertensive drugs can be down-titrated concurrently with administration of placebo. In the case of the 
down-titration, antihypertensive drugs should be discontinued at least 1 week (7 days) before the start of the Treatment 
Period I. Especially, beta-blockers (BBs) should be tapered off gradually since sudden discontinuation of BBS may 
cause withdrawal syndrome. 
In the Treatment Period I (Week 0 to 12), initial dose of TAK-536 will be 2.5 mg for the subjects weighing < 50 kg or 
5 mg for the subjects weighing ≥ 50 kg. After the initial dose, TAK-536 will be titrated to 5 mg, 10 mg, and 20 mg for 
the subjects weighing < 50 kg or to 10 mg, 20 mg, and 40 mg for the subjects weighing ≥ 50 kg when the subjects do 
not achieve the target blood pressure and there are no concerns in tolerability. TAK-536 will be titrated at any 
scheduled visit of Week 2, 4, or 8 in the Treatment Period I. Between the visits of Week 4 and 8 during the Treatment 
Period I, an additional unscheduled visit of Week 6 may be requested at the investigator’s discretion in order to titrate 
the dose of the study drug in the subjects when the further decrease in blood pressure is needed. TAK-536 can be 
reduced at the investigator’s or subinvestigator’s discretion if there are any concerns in tolerability with titration of 
TAK-536 (i.e., in case of occurring any AEs caused by titration of TAK-536). During the Treatment Period I, change 
in the dosage of the antihypertensive drug is prohibited in the subjects who treated with a single antihypertensive drug 
other than RAS inhibitors at the start of the Treatment Period I. 
During the Treatment Period II (Week 12 to 52), the treatments at the end of the Treatment Period I will be continued. 
TAK-536 can be titrated to the highest dose (20 mg for the subjects weighing < 50 kg or 40 mg for the subjects 
weighing ≥ 50 kg, the same hereinafter) at the investigator’s or subinvestigator’s discretion when the subjects do not 
achieve the target blood pressure and no concerns are found in tolerability. When the subjects do not achieve the target 
blood pressure with the highest dose of TAK-536, the subjects can receive additional antihypertensive drugs (other 
than RAS inhibitors) or can change in dose of the antihypertensive drug in addition to TAK-536. When the 
antihypertensive drugs are required dose reduction or interruption because of the concerns in tolerability with titration 
(i.e., excessive reduction in blood pressure, other AE, etc.) in the Treatment Period II, the antihypertensive drugs other 
than TAK-536 (in case of concomitant use) should be reduced or interrupted first. Thereafter, dose reduction or 


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interruption of TAK-536 should be considered. 
Follow-up Period will be 2 weeks from the next day of the final dose of TAK-536. Safety will be evaluated at Week 54 
after the start of the Treatment Period. At the time when the data from approximately 25 subjects are collected, the data 
until Week 12 in the Treatment Period will be analyzed. In addition, at the time when all subjects complete Week 24 in 
the Treatment Period, the data until Week 24 in the Treatment Period will be analyzed separately after being locked. 
These analyses will not intend to continue or discontinue this study. 
Primary Objectives: 
To evaluate the safety of administration of TAK-536 in pediatric patients aged 6 to less than 16 years with 
hypertension 
Secondary Objectives: 
To evaluate the efficacy and pharmacokinetics of administration of TAK-536 in pediatric patients aged 6 to less than 
16 years with hypertension 
Subject Population: Pediatric patients aged 6 to less than 16 years, with essential or secondary hypertension. 
Planned Number of Subjects: 
Total of 50 subjects (who enter the Treatment Period). 
Planned Number of Sites: 
Approximately 25 sites 
Dose Level(s): 
Regimen: Subjects will orally receive the study drug once 
daily before or after breakfast. 
Dose: Placebo during the Run-in Period. Any of 
TAK-536 2.5 mg, 5 mg, 10 mg, 20 mg tablet for the 
subjects weighing < 50 kg, or any of TAK-536 5 mg, 
10 mg, 20 mg, 40 mg tablet for those weighing ≥ 50 kg 
during the Treatment Period. 
Route of Administration: 
Oral 
Duration of Treatment: 
52 weeks 
Study Length: 
2 weeks of the Run-in Period (acceptable range, 1 to 4 
weeks), 52 weeks of the Treatment Period (12 weeks of 
the Treatment Period I and 40 weeks of the Treatment 
Period II), 2 weeks of the Follow-up Period 


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Main Criteria for Inclusion: 
• 
The Japanese subject who has a diagnosis of hypertension. A subject is eligible if he/she is deemed hypertensive 
according to the reference blood pressure values of children by gender and age; office sitting diastolic or systolic 
blood pressure ≥ 95 percentile for essential hypertension without concomitant hypertensive organ damage, and 
≥ 90 percentile for secondary hypertension with concomitant chronic kidney disease (CKD), diabetes mellitus, 
heart failure or any hypertensive organ damage. 
In addition, subjects need to meet the following criteria: 
(1) If currently treated with any antihypertensive drugs at the start of the Run-in Period: Subject has a 
documented historical diagnosis of hypertension and an office sitting diastolic or systolic blood pressure meeting 
the above criteria at the end of the Run-in Period (Week 0). 
(2) If currently untreated with any antihypertensive drugs at the start of the Run-in Period: Subject who meets the 
above criteria on 3 separate time points including screening and the end of the Run-in Period (Week 0). In 
addition, subject with essential hypertension without concomitant hypertensive organ damage still maintains 
hypertension with non-pharmacotherapy including foods or exercises for at least 3 months within 1 year prior to 
the start of screening. 
• 
The subject is male or female and aged 6 to less than 16 years at the time of informed consent. 
• 
The subject weighs at least 20 kg at screening. 
• 
A subject who has undergone kidney transplantation is eligible if he/she underwent the transplantation at least 6 
months earlier at screening, and the graft has been functionally stable (estimated glomerular filtration rate 
[eGFR] ≥ 30 mL/min/1.73 m2) for at least 6 months with evidence (e.g., Doppler echography, CT scan 
[computed tomography] or MRI [magnetic resonance imaging]) excluding grafted kidney arterial stenosis. A 
subject on immunosuppressive therapy with a stable dose at least 30 days prior to screening is eligible.  
Main Criteria for Exclusion: 
• 
The subject has poorly controlled hypertension indicated by an office sitting systolic blood pressure higher by at 
least 15 mmHg and/or an office sitting diastolic blood pressure higher by at least 10 mmHg than the 99 
percentiles of the reference blood pressure values of children by gender and age. 
• 
The subject has a diagnosis of malignant or accelerated hypertension. 
• 
The subject was noncompliant (< 70% or > 130%) with the study drug during the Run-in Period. 
• 
The subject has severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2), is 
receiving dialysis, has a renovascular disease affecting one or both kidneys, severe nephrotic syndrome not in 
remission, or a serum albumin level < 2.5 g/dL. 
• 
The subject has a history of, or the signs/symptoms of serious cardiovascular, hepatobiliary, gastrointestinal, 
endocrine (eg, hyperthyroidism, Cushing’s syndrome), hematological, immunological, urinogenital, psychiatric 
disease, cancer, or any other disease that adversely affects subject’s health, or, in the opinion of the investigator 
or subinvestigator, potentially confounds the study results. 
• 
The subject has hemodynamically significant left ventricular outflow obstruction due to aortic stenosis or aortic 
valvular disease, or is scheduled to undergo a medical procedure affecting blood pressure during the study (eg, 
correction of arterial anomaly). 
• 
The subject has a history of or concurrent clinically significant abnormality of 12-lead electrocardiogram (ECG) 
that, in the opinion of the investigator or subinvestigator, disqualifies the subject for participation in the study. 
• 
The subject has poorly controlled diabetes mellitus indicated by HbA1c > 9.0% at screening.  
• 
The subject has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥ 2.5 × the upper 
limit of normal (ULN), or a total bilirubin level ≥ 1.5 × ULN at screening, severely impaired hepatic function, 
any active liver disease, or jaundice. 
• 
The subject has hyperkalemia exceeding ULN at screening. 


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Main Criteria for Evaluation and Analyses: 
(1) Primary Endpoint 
<Safety> 
Adverse events (AEs), anthropometric (weight, height and body mass index [BMI]) measurements, laboratory tests, 
resting 12-lead ECG, and vital signs (office standing blood pressure, office sitting pulse rate, office standing pulse 
rate, and home sitting blood pressure) 
(2) Secondary endpoints 
<Efficacy> 
• 
Office trough sitting systolic and diastolic blood pressure 
• 
Proportion of subjects who achieve the target blood pressure* 
*: < 95 percentile shown in a table of the reference blood pressure values of children by gender and age for essential 
hypertension, < 90 percentile shown in the same table for secondary hypertension  
<Pharmacokinetic endpoints> 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) 
Statistical Considerations: 
<Primary endpoints and analytical methods> 
[Primary endpoints] 
AEs, anthropometric (weight, height and BMI) measurements, laboratory tests, resting 12-lead ECG, and vital signs 
(office standing blood pressure, office sitting pulse rate, office standing pulse rate, and home sitting blood pressure) 
[Analytical methods] 
The following analyses will be conducted with the safety analysis set. 
(1) AEs (Treatment-emergent AEs) 
A treatment-emergent AE (TEAE) is defined as any AE occurring after the start of TAK-536 administration of the 
Treatment Period. 
The incidence of TEAEs listed below will be analyzed. TEAEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). The frequency distribution will be provided using the system organ class (SOC) 
and preferred term (PT) using MedDRA as follows: 
• 
TEAEs 
• 
Drug-related TEAEs 
• 
Severity of TEAEs 
• 
Severity of drug-related TEAEs 
• 
TEAEs leading to study drug discontinuation 
• 
Serious TEAEs 
• 
TEAEs overt time 
(2) Anthropometric (weight, height and BMI) measurements, laboratory tests, resting 12-lead ECG, and vital signs 
(office standing blood pressure, office sitting pulse rate, office standing pulse rate, and home sitting blood pressure) 
For continuous variables, the observed values, and the changes from the end of the Run-in Period (Week 0) will be 
summarized for each time point. In addition, individual figures of the observed values will be provided. 
For categorical values, shift tables of the data before and after administration will be provided. 


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Sample Size Justification: 
Total of 50 subjects to enter the Treatment Period was set in consideration of feasibility. 
Assuming the mean change of trough sitting diastolic blood pressure from the end of the Run-in Period (Week 0) to 
the end of the Treatment Period I of -6.5 mmHg and an SD of 10.5 mmHg, and the mean change of trough sitting 
systolic blood pressure from the end of the Run-in Period (Week 0) to the end of the Treatment Period I of -9.5 mmHg 
and an SD of 15.5 mmHg, planned 50 subjects will provide at least 90% power by a 1-sample t-test at the 0.05 
significance level (2-sided). 


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3.0 
LIST OF ABBREVIATIONS 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ARB 
angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
BBs 
beta-blockers 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CKD 
chronic kidney disease 
CRO 
contract research organization 
CT 
computed tomography 
DRI 
direct renin inhibitor 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
eGFR 
estimated glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
hCG 
human chorionic gonadotropin 
HIV 
human immunodeficiency virus 
HPLC/MS/MS 
high-performance liquid chromatography with tandem mass spectrometry 
Ht 
height 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
JCS 2012 
Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular Diseases by the 
Japanese Circulation Society 
JSH 2014 
Guidelines for the Management of Hypertension 2014 
LDH 
lactate dehydrogenase 
LFT 
Liver Function Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
NSAIDs 
non-steroidal anti-inflammatory drugs 
OTC 
over-the-counter 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PT 
preferred term 
PTP 
press through package 


TAK-536 
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QOL 
quality of life 
RAS 
renin-angiotensin-system 
RBC 
red blood cell 
SAE 
serious AE 
SAP 
statistical analysis plan 
SOC 
system organ class 
SUSARs 
suspected unexpected serious adverse reactions 
TEAE 
treatment emergent AE 
TPC 
Takeda Pharmaceutical Company Limited 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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4.0 
INTRODUCTION 
4.1 
Background 
Hypertension develops in not only in adults but also in children and adolescents. While there are 
few epidemiological reports about the number of pediatric patients with hypertension in Japan, it is 
reported that hypertension is detected in 0.1% to 1% among elementary-school and 
junior-high-school students and in approximately 3% among high-school students in health 
checkups for Japanese children [1, 2]. According to the 2013 Population Projection, the number of 
pediatric patients with hypertension is estimated to be approximately 11 million in 
elementary-school and junior-high-school students (6 to 15 years) and approximately 3.6 million 
in high-school students (16 to 18 years). Therefore, on the basis of the morbidity rate of 
hypertension in health checkups above, the number of pediatric patients with hypertension is 
estimated to be 100 to 200 thousand (10 to 110 thousand in elementary-school and 
junior-high-school students and 110 thousand in high-school students). 
Pediatric hypertension is classified into essential hypertension and secondary hypertension as 
described for adults. Although essential hypertension in children is generally mild, such patients 
are at a high risk of cardiovascular disease including left ventricular hypertrophy and carotid 
intima-media wall thickening as well as organ damage, eg, renal dysfunction [3, 4]. Furthermore, 
essential hypertension in children can track into adult essential hypertension with patients’ growth 
[5]. The possibility of secondary hypertension, in contrast, increases with a younger age and the 
majority cases are severe. Hypertension caused by renal diseases (renal hypertension) accounts for 
60% to 80% of children with secondary hypertension, and chronic renal failure requires particular 
attention. Therefore, it is necessary to prevent deterioration of renal function and progression of 
organ damage. 
Moreover, hypertension persisting from childhood is likely to cause cardiovascular diseases and 
organ damage including renal dysfunction, thereby markedly affecting the patient’s quality of life 
(QOL) and prognosis not only in childhood but also in future. Therefore, it is highly important to 
manage blood pressure in the early stage. 
The Japanese Society of Hypertension Guidelines for the Management of Hypertension 2014 (JSH 
2014) [6] recommends that drug therapy should be considered after non-pharmacological 
interventions (dietary and exercise therapy) are primarily performed since essential hypertension 
in children is often mild. For patients with secondary hypertension and patients with target organ 
damage, diabetes mellitus, or chronic kidney disease (CKD), drug therapy is highly recommended 
to prevent the development and progression of organ damage. 
JSH 2014 [6] and the Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular 
Diseases by the Japanese Circulation Society (JCS 2012) [7] recommend angiotensin II receptor 
blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers 
as the first-choice drugs for pediatric patients. In particular, more strict blood pressure 
management is recommended for hypertension with CKD or diabetes mellitus than that for 
hypertension without complications. Hypertension with such complications is recommended to be 
treated with ARBs having antiproteinuric effects and inhibitory effects of CKD progression in 
addition to ACE inhibitors. 


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While a number of antihypertensive drugs for adults are available in Japan, only 4 drugs are 
indicated for hypertension in children, valsartan being the only ARB among them. Therefore, the 
treatment options for pediatric patients with hypertension are not sufficient. 
TAK-536 (azilsartan) is a novel ARB produced by Takeda Pharmaceutical Company Limited 
(TPC) and was approved for the treatment of adult hypertension under the product name of Azilva 
tablets 20 mg and 40 mg in January 2012. A supplementary new drug application was filed for the 
additional registration of Azilva tablet 10 mg, which was approved in March 2014. TAK-536 is 
superior to the existing ARBs (candesartan) in the antihypertensive effect as well as its persistence , 
while being safe and well tolerated. It is now widely used by adult patients with hypertension. 
Thus, to resolve the unmet needs in the present treatment of pediatric hypertension, it is important 
to provide TAK-536 for pediatric patients with hypertension, whose clinical usefulness for adult 
patients is established. 
Findings from a Clinical Study of TAK-536 
Upon the development of TAK-536 as an antihypertensive drug for pediatric patients with 
hypertension, single-dose study (TAK-536/CPH-103) was conducted to evaluate the 
pharmacokinetics and safety of TAK-536 in 6 pediatric patients aged 6 to less than 16 years with 
hypertension. The dose of TAK-536 was 5 mg for subjects weighing less than 50 kg, and 10 mg 
for those weighing at least 50 kg. 
TAK-536 was rapidly absorbed after a single oral administration of a TAK-536 5 mg tablet or 
10 mg tablet and was detectable in the plasma of all subjects at 1 hour after administration. The 
mean Cmax of TAK-536 was 888.3 ng/mL in the 5 mg group and 831.3 ng/mL in the 10 mg group, 
and the mean AUC(0-inf) of TAK-536 was 6635.7 ng·hr/mL and 7433.3 ng·hr/mL, respectively. 
Only 1 subject who received a TAK-536 5 mg tablet experienced a TEAE (gastroenteritis), which 
was mild in intensity and considered to be unrelated to the study drug. The outcome of 
gastroenteritis was “recovered/resolved.” No safety concerns were found in the study, and 
TAK-536 was well tolerated. 
4.2 
Rationale for the Proposed Study 
TAK-536 is developed to be approved for the pediatric patients aged 1 to less than 16 years with 
hypertension. In the field of the pediatrics, the efficacy and safety should be evaluated in 
schoolchildren (6 to 16 years) first, and thereafter, the efficacy and safety should be evaluated in 
the lower aged pediatric patients [8]. Since no clinical studies have been conducted to evaluate 
safety and efficacy of TAK-536 in pediatric patients with hypertension, this study is planned to 
evaluate the safety, efficacy, and pharmacokinetics of long-term administration of TAK-536 in 
pediatric patients with hypertension aged 6 to less than 16 years before evaluating those in 
pediatric patients with hypertension aged 1 to less than 6 years. 
 
CONFIDENTIAL 
CCI


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
To evaluate the safety of administration of TAK-536 in pediatric patients aged 6 to less than 16 
years with hypertension 
5.1.2 
Secondary Objectives 
To evaluate the efficacy and pharmacokinetics of administration of TAK-536 in pediatric patients 
aged 6 to less than 16 years with hypertension 
5.2 
Endpoints 
5.2.1 
Primary Endpoints 
Safety: 
AEs, anthropometric (weight, height, and body mass index [BMI]) measurements, laboratory tests, 
resting 12-lead electrocardiogram (ECG), and vital signs (office standing blood pressure, office 
sitting pulse rate, office standing pulse rate, and home sitting blood pressure) 
5.2.2 
Secondary Endpoints 
Efficacy: 
• Office trough* sitting diastolic and systolic blood pressure 
*The time point immediately before the next dosing, when the blood drug concentration is assumed to be lowest 
• Proportion of subjects who achieve the target blood pressure** 
** < 95 percentile shown in Table 5.a for essential hypertension 
< 90 percentile shown in Table 5.a for secondary hypertension 


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Table 5.a 
Reference Blood Pressure Values of Children by Gender and Age 
Age 
Boy 
Girl 
(years) 
90th 
95th 
99th 
90th 
95th 
99th 
6 
110/70 
114/74 
121/82 
108/70 
111/74 
119/81 
7 
111/72 
115/76 
122/84 
109/71 
113/75 
120/82 
8 
112/73 
116/78 
123/86 
111/72 
115/76 
122/83 
9 
114/75 
118/79 
125/87 
113/73 
117/77 
124/84 
10 
115/75 
119/80 
127/88 
115/74 
119/78 
126/86 
11 
117/76 
121/80 
129/88 
117/75 
121/79 
128/87 
12 
120/76 
123/81 
131/89 
119/76 
123/80 
130/88 
13 
122/77 
126/81 
133/89 
121/77 
124/81 
132/89 
14 
125/78 
128/82 
136/90 
122/78 
126/82 
133/90 
15 
127/79 
131/83 
138/91 
123/79 
127/83 
134/91 
16 
130/80 
134/84 
141/92 
124/80 
128/84 
135/91 
Systolic/diastolic blood pressures (mmHg, JCS2012 [7]) 
The 90th, 95th, and 99th indicate 90, 95, and 99 percentile, respectively. 
 
Pharmacokinetics: 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a Phase 3, open-label, multicenter study to evaluate the safety, efficacy, and 
pharmacokinetics of long-term administration of TAK-536 once daily for 52 weeks in pediatric 
patients aged 6 to less than 16 years with hypertension. 
The study consists of a 2-week Run-in Period, a 52-week Treatment Period (Treatment Period I, 
12-week; Treatment Period II, 40-week), and a 2-week Follow-up Period (56 weeks in total). 
(1) Screening and Run-in Period 
Subjects eligible at screening will initiate to receive the placebo in a single-blinded fashion at the 
start of the Run-in Period. 
The duration of the Run-in Period will be 2 weeks. The subjects whose blood pressures meet the 
inclusion criteria 1 week (at earliest) after receiving placebo in the Run-in Period can enter the 
Treatment Period. For the subjects only who treated with any antihypertensive drugs as a prior 
treatment, the Run-in Period could be extended up to 4 weeks if blood pressures do not meet the 
inclusion criteria. 
Subjects who treated with renin-angiotensin-system (RAS) inhibitors (ACE inhibitors, ARB, and 
DRI) until the start of the Run-in Period should discontinue them at the start of the Run-in Period. 
Subjects who treated with antihypertensive drugs other than RAS inhibitors until the start of the 
Run-in Period can continue to receive a single antihypertensive drug in addition to the study drug 
if the subjects are considered to need the additional treatment for hypertension in the Treatment 
Period I by the investigator or subinvestigator; the antihypertensive drug should be administered 
under the same dosage at the time of the start of the Run-in Period. If subjects have difficulty in 
discontinuing antihypertensive drugs completely at the start of the Run-in Period, the 
antihypertensive drugs can be down-titrated concurrently with administration of placebo. In the 
case of the down-titration, antihypertensive drugs should be discontinued at least 1 week (7 days) 
before the start of the Treatment Period I. Especially, beta-blockers (BBs) should be tapered off 
gradually since sudden discontinuation of BBs may cause withdrawal syndrome. 
(2) Treatment Period I 
In the Treatment Period I (Week 0 to 12), initial dose of TAK-536 will be 2.5 mg for the subjects 
weighing < 50 kg or 5 mg for the subjects weighing ≥ 50 kg. After the initial dose, TAK-536 will 
be titrated to 5 mg, 10 mg, and 20 mg for the subjects weighing < 50 kg or to 10 mg, 20 mg, and 
40 mg for the subjects weighing ≥ 50 kg when the subjects do not achieve the target blood 
pressure* and no concerns are found in tolerability. TAK-536 will be titrated at any scheduled visit 
of Week 2, 4, or 8 in the Treatment Period I. Between the visits of Week 4 and 8 during the 
Treatment Period I, an additional unscheduled visit of Week 6 may be requested at the 
investigator’s or subinvestigator’s discretion in order to titrate the dose of the study drug in the 
subjects when the further decrease in blood pressure is needed. TAK-536 can be reduced at the 
investigator’s or subinvestigator’s discretion if there are any concerns in tolerability with titration 
of TAK-536 (i.e., in case of occurring any AEs caused by titration of TAK-536). During the 


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Treatment Period I, change in the dosage of the antihypertensive drug is prohibited in the subjects 
who treated with a single antihypertensive drug other than RAS inhibitors at the start of the 
Treatment Period I. 
* target blood pressure: 
< 95 percentile shown in Table 5.a for essential hypertension, < 90 percentile shown in Table 5.a for secondary 
hypertension 
(3) Treatment Period II 
During the Treatment Period II (Week 12 to 52), the treatments at the end of the Treatment Period 
I will be continued. TAK-536 can be titrated to the highest dose (20 mg for the subjects weighing 
< 50 kg or 40 mg for the subjects weighing ≥ 50 kg, the same hereinafter) at the investigator’s or 
subinvestigator’s discretion when the subjects do not achieve the target blood pressure and no 
concerns are found in tolerability. When the subjects do not achieve the target blood pressure with 
the highest dose of TAK-536, the subjects can receive additional antihypertensive drugs (other 
than RAS inhibitors) or can change in dose of the antihypertensive drug in addition to TAK-536 at 
the investigator’s or subinvestigator’s discretion. 
When the antihypertensive drugs are required dose reduction or interruption because of the 
concerns in tolerability with titration (i.e., excessive reduction in blood pressure, other AE, etc.) in 
the Treatment Period II, the antihypertensive drugs other than TAK-536 (in case of concomitant 
use) should be reduced or interrupted first. Thereafter, dose reduction or interruption of TAK-536 
should be considered. 
(4) Follow-up Period 
Follow-up Period will be 2 weeks from the next day of the final dose of TAK-536. Safety will be 
evaluated at Week 54 after the start of the Treatment Period. 
At the time when the data from approximately 25 subjects are collected, the data until Week 12 in 
the Treatment Period will be analyzed. In addition, at the time when all subjects complete Week 24 
in the Treatment Period, the data until Week 24 in the Treatment Period will be analyzed 
separately after being locked. These analyses will not intend to continue or discontinue this study. 
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A. 


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Figure 6.a 
Schematic of Study Design 
 
 
 
Run-in 
Period 1),2) 
Treatment Period I* 
Treatment Period II 
Follow-up 
Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 mg (< 50 kg) or 40 mg (≥ 50 kg) 3),4) 
 
 
 
 
 
 
 
 
 
 
 
10 mg (< 50 kg) or 20 mg (≥50 kg) 3),4) 
 
 
 
 
 
 
 
 
 
5 mg (< 50 kg) or 10 mg (≥ 50 kg) 3),4) 
 
 
 
 
 
Placebo 
2.5 mg (< 50 kg) or 5 mg(≥ 50 kg) 3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-2W 
0W 
2W 
4W 
8W 
 
12W 
 
52W 
54W 
Concomitan
t use of 
antihyperten
sive drugs. 
RAS inhibitors are prohibited. 
 
 
 
Subjects who treated with antihypertensive drugs other than RAS inhibitors until the start of 
the Run-in Period can continue to receive a single antihypertensive drug in addition to the 
study drug (Change in the dosage of the antihypertensive drug is prohibited.）2),5) 
Subjects can receive antihypertensive 
drugs (other than RAS inhibitors) or 
can change the dosage of the 
antihypertensive drug in addition to 
TAK-536.6) 
 
 
 
1) The subjects whose blood pressures meet the inclusion criteria 1 (at earliest) week after receiving placebo in the Run-in Period can enter the Treatment Period. For the 
subjects only who treated with any antihypertensive drugs as a prior treatment only, the Run-in Period could be extended up to 4 weeks if blood pressures do not meet 
the inclusion criteria. 
2) If subjects have difficulty in discontinuing antihypertensive drugs completely at the start of the Run-in Period, the antihypertensive drugs can be down-titrated 
concurrently with administration of placebo. In the case of the down-titration, antihypertensive drugs should be discontinued at least 1 week (7 days) before the start 
of the Treatment Period I. Especially, beta-blockers (BBs) should be tapered off gradually since sudden discontinuation of BBs may cause withdrawal syndrome. 
3) In the Treatment Period I, TAK-536 can be titrated biweekly when the subjects do not achieve the target blood pressure while evaluation of safety and tolerability. 
TAK-536 can be reduced at the investigator’s or subinvestigator’s discretion if there are any concerns in tolerability with titration of TAK-536 (i.e., in case of 
occurring any AEs caused by titration of TAK-536). 
4) When the antihypertensive drugs are required dose reduction or interruption because of the concerns in tolerability with titration (i.e., excessive reduction in blood 
pressure, other AE, etc.) in the Treatment Period II, the antihypertensive drugs other than TAK-536 (in case of concomitant use) should be reduced or interrupted first. 
Thereafter, dose reduction or interruption of TAK-536 should be considered. 
5) Subjects who treated with antihypertensive drugs other than RAS inhibitors until the start of the Run-in Period can continue to receive a single antihypertensive drug 
in addition to the study drug if the subjects are considered to need the additional treatments for hypertension in the Treatment Period I by the investigator or 
subinvestigator. Change in the dosage of the antihypertensive drug at the start of the Run-in Period I is prohibited until the end of the Treatment Period I. 
6) When the subjects do not achieve the target blood pressure with the highest dose of TAK-536, the subjects can receive antihypertensive drugs (other than RAS 
inhibitors) or can change in dosage of the antihypertensive drug in addition to TAK-536 at the investigator’s or subinvestigator’s discretion. 
* Between the visits of Week 4 and 8, an additional unscheduled visit of Week 6 may be requested at the investigator’s or subinvestigator’s discretion in order to titrate 
the dose of the study drug in the subjects when the further decrease in blood pressure is needed. 
6.2 
Justification for Study Design, Dose, Regimen, and Endpoints 
[Justification for the Study Design] 
Many pediatric patients with renal dysfunction are assumed to be entered this study since the 
proportion of pediatric patients with secondary hypertension caused by renal disease is high in 
pediatric patients with hypertension. Evidence-based Clinical Practice Guideline for CKD 2013 
(JSN2013) [9] indicates that treatment with ARB should be start at a low dose in patients with 
renal dysfunction and the dose should be increased with caution by confirming the hypotensive 
effect of ARB and renal function. On the basis of above indication, an open-label, optional titration 
Screening 


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design was selected in this study, in which TAK-536 can be titrated with monitoring subject 
condition. 
Co-administration of RAS inhibitors, which is similar to TAK-536, is prohibited in order to 
evaluate appropriately the efficacy of TAK-536 in the pediatric patients throughout the Run-in 
Period and the Treatment Period I. In consideration of the safety for vulnerable pediatric 
population, subjects can continue to receive a single antihypertensive drug other than RAS 
inhibitors in the same dosage after the start of the Run-in Period, if the subjects are considered to 
need the additional treatment for hypertension by the investigator or subinvestigator. In the 
Treatment Period II, the subjects whose blood pressure is not reduced sufficiently by TAK-536 can 
receive additional antihypertensive drugs other than RAS inhibitors concomitantly in order to 
evaluate the efficacy and safety of the long-term administration of TAK-536 in pediatric patients 
under the condition of being closer to the routine medical care. 
The Run-in Period with placebo was selected to wash out the placebo effect of the study drug and 
the influence of antihypertensive drugs as a prior treatment in subjects who were treated with any 
prior antihypertensive drugs. In addition, the Run-in Period allows the opportunity to assess 
subject compliance with the study drug (i.e., placebo) and subjects who are not sufficiently 
compliant with placebo will be excluded. 
The Follow-up Period was selected to evaluate the subject safety after the study drug 
administration. 
[Justification for the Doses] 
The population pharmacokinetic model was developed based on data from a total of 58 subjects (6 
for pediatric patients and 52 for healthy adult subjects). Also a population of subjects whose 
weights were uniformly distributed within the specified weight range between 20-80 kg by 1 kg 
(100 subjects for each body weight range and 6100 subjects in total) were generated and equally 
allocated to fixed TAK-536 doses of 2.5, 5, 10, 20, and 40 mg. Then, the population 
pharmacokinetic model was used to simulate the Cmax and AUC of TAK-536 following a single 
oral dose of each dose for each body weight category for virtual pediatric population, and 
distributions of simulated Cmax and AUC (median and 90% CI) of TAK-536 in pediatric patients 
weighing ≥ 20 kg and < 50 kg and those weighing ≥ 50 kg and < 80 kg were compared with actual 
parameters of Cmax and AUC (minimum and maximum) following TAK-536 10, 20, 40 and 
80 mg in healthy adults. 
Based on the simulation, estimated exposures to TAK-536 in pediatric patients weighing ≥ 50 kg 
and < 80 kg and those weighing ≥ 20 kg and < 50 kg after receiving TAK-536 2.5, 5, 10, 20, or 
40 mg are similar to and a little below double of that in healthy adults receiving the same fixed 
dose, respectively. These findings indicate that exposures to TAK-536 in pediatric patients with 
doses up to 20 mg do not exceed the exposure in adults with the approved maximum dose of 
40 mg. 
Therefore, the initial dose was set at 5 mg, a half the typical adult half dose of 10 mg, for the 
subjects weighing ≥ 50 kg and at 2.5 mg for those weighing < 50 kg by further reducing the dose 
by half in consideration of subject safety. 


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On the basis of the results of the population pharmacokinetic model, 40 mg or 20 mg was selected 
as the highest dose of TAK-536 by weight for the subjects weighing ≥ 50 kg or < 50 kg, 
respectively. In the population pharmacokinetic model, estimated exposures to TAK-536 in 
pediatric patients weighing ≥ 50 kg after receiving TAK-536 40 mg as the highest clinical dose in 
adults or those in the patients weighing < 50 kg after receiving TAK-536 20 mg does not exceed 
the exposure to TAK-536 in adults after receiving TAK-536 40 mg as the approved maximum 
dose in adults. In addition, titrating from the lower dose while evaluation of safety and tolerability 
sufficiently were selected in consideration of subject safety. 
TAK-536 has not been administered to the pediatric patients with hypertension with renal 
dysfunction. In addition, TAK-536 should be administered initially in lower dose to the adult 
patients with serious renal dysfunction and gradual titration is required for them in careful with 
monitoring subject condition in case of titration. The design of this study fulfills the above 
requirements. 
[Justification for the Regimen] 
Since meals do not affect the pharmacokinetics of TAK-536 in adults, the subjects receive the 
study drug before or after breakfast in the study. 
[Justification of Endpoints] 
Variables commonly used to evaluate the safety were selected as the primary endpoints because 
the primary objective of this study is to evaluate the long-term safety of TAK-536. 
Office trough sitting diastolic and systolic blood pressure were selected as secondary endpoints to 
evaluate the efficacy and persistence of effect in reference to Principles for Clinical Evaluation of 
New Antihypertensive Drugs [10] and JSH2014 [6]. 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) will be measured in order to 
evaluate the pharmacokinetics of TAK-536 in pediatric patients with hypertension. 
[Justification for Study Duration] 
(1) Run-in Period 
Two weeks were set as the Run-in Period with placebo to wash out the placebo effect of the study 
drug or the influence of the antihypertensive drugs as a prior treatment. The subjects whose blood 
pressures meet the inclusion criteria 1 week (at earliest) after receiving placebo during the Run-in 
Period can enter the Treatment Period in consideration of subject safety. For the subjects only who 
treated with any antihypertensive drugs as a prior treatment, the Run-in Period could be extended 
up to 4 weeks while considering of subject safety if the blood pressures do not meet the inclusion 
criteria. 
(2) Treatment Period 
JSH2014 [6] recommends that low-dose therapy with a single antihypertensive drug should be 
initiated first for the treatment of the hypertensive patients, and the dose should be increased to a 
standard dose in 4 to 8 weeks while evaluating the effects. On the basis of above recommendation, 
8 weeks were set as a titration period with 3 titration point and 2 weeks for each titration point for 
evaluating the tolerability. In addition, a phase 3 confirmatory study (TAK-536/CCT-005) 


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demonstrated that maximum decline of blood pressure was observed 4 weeks after the titration of 
TAK-536 in Japanese adult patients with hypertension. On the basis of the results, 4 weeks were 
set as the duration of administration with the highest dose in case of the titration of TAK-536 to the 
highest dose (20 mg or 40 mg). Therefore, 12 weeks in total were set as the Treatment Period I in 
this study. 
Forty weeks was set as the Treatment Period II in reference to the Extent of Population Exposure 
to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening 
Conditions [11], so that duration of administration would be 52 weeks in total with the Treatment 
Period I. 
(3) Follow-up Period 
The elimination half-life was 12.8 hours following the single administration of TAK-536 40 mg in 
healthy adult subjects. In reference to the amendment of the Guideline for Bioequivalence Studies 
of Generic Products [12], 2 weeks were set as Follow-up Period of 5 times or more the elimination 
half-life. 
6.3 
Premature Termination or Suspension of Study or Study Site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 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 drug 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 GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety. 
6.3.2 
Criteria for Premature Termination or Suspension of Study 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 Study Sites 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable study 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 first dose. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator or subinvestigator, the subject’s parent or the subject’s legal 
guardian is capable of understanding and complying with protocol requirements. 
2. The subject’s parent or the subject’s legal guardian is capable of signing and dating a written, 
informed consent form on behalf of the subject prior to the initiation of any study procedures. 
Written informed assent is also obtained from the subject as much as possible. 
3. The Japanese subject who has a diagnosis of hypertension. A subject is eligible if he/she is 
deemed hypertensive according to the reference blood pressure values of children by gender 
and age (Table 5.a); office sitting diastolic or systolic blood pressure ≥ 95 percentile for 
essential hypertension without concomitant hypertensive organ damage, and ≥ 90 percentile 
for secondary hypertension with concomitant CKD, diabetes mellitus, heart failure or any 
hypertensive organ damage. 
In addition, subjects need to meet the following criteria: 
(1) If currently treated with any antihypertensive drugs at the start of the Run-in Period: 
Subject has a documented historical diagnosis of hypertension and an office sitting diastolic or 
systolic blood pressure meeting the above criteria at the end of the Run-in Period (Week 0). 
(2) If currently untreated with any antihypertensive drugs at the start of the Run-in Period: 
Subject who meets the above criteria on 3 separate time points including screening and the end 
of the Run-in Period (Week 0). In addition, subject with essential hypertension without 
concomitant hypertensive organ damage still maintains hypertension with 
non-pharmacotherapy including foods or exercises for at least 3 months within 1 year prior to 
the start of screening. 
4. The subject is male or female and aged 6 to less than 16 years at the time of informed consent. 
5. The subject weighs at least 20 kg at screening. 
6. The subject is capable of taking the tablets or granules supplied as the study drug. 
7. A subject who has undergone kidney transplantation is eligible if he/she underwent the 
transplantation at least 6 months earlier at screening, and the graft has been functionally stable 
(estimated glomerular filtration rate [eGFR] ≥ 30 mL/min/1.73 m2) for at least 6 months with 
evidence (eg, Doppler echography, CT scan [computed tomography] or MRI [magnetic 
resonance imaging]) excluding grafted kidney arterial stenosis. A subject on 
immunosuppressive therapy with a stable dose at least 30 days prior to screening is eligible. 
8. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
through 1 month after the completion of the study, and proves negative in the pregnancy test at 
screening. 


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*Definitions and acceptable methods of contraception are defined in 
Section 9.1.10 and reporting responsibilities are defined in Section 9.1.11. 
9. The subjects judged by the investigator or subinvestigator that he/she can discontinue the 
therapy with RAS inhibitors for 2 weeks (acceptable range, 1 to 4 weeks) in safe prior to the 
Treatment Period. 
[Justification of Inclusion Criteria] 
1.2.6. These were set as the standard requirements for clinical studies in pediatric patients. 
3. The patients with hypertension who can be candidates for pharmacotherapy was set in 
reference to JCS2012 [7]. Reference blood pressure value of hypertension in the US 
guideline’s criteria for children of 50 percentile height categorized by age and gender was 
selected since which was also the diagnosing criteria for hypertension adopted by JCS2012 [7]. 
For patients untreated with any antihypertensive drugs at the start of the Run-in Period, blood 
pressure values of 3 separate time points were adopted since hypertension would be diagnosed 
with above criteria 3 times or more in separate day or week. 
4. The subject can be male or female, since evaluation in boys and girls is needed. The subjects of 
this study will be school children. Since children aged 6 to 16 years are categorized as school 
children in the final report on the Guidelines for Clinical Evaluation of Antihypertensive Drugs 
in Children [8], 6 to 16 years will be an acceptable age range in this study. 
5. According to the physical status survey (Part 2 of the National Health and Nutrition Survey 
2011 [13]), the average weight of 6-year-old children was 20.2 kg for girls and 20.9 kg for 
boys. This study will therefore enroll children weighing at least 20 kg. 
7. In consideration of possible effects on the evaluation of TAK-536 and the subject safety, the 
subject who has undergone kidney transplantation will be eligible only if his/her clinical 
course has been stable. 
8. RAS inhibitors are contraindicated in pregnant women based on the disorders and deaths in 
fetuses and new-born children reported for women using them during pregnancy. 
9. These were set in consideration of subject safety. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received any investigational compound within 30 days prior to screening or is 
participating in another clinical study or a post-marketing clinical study. 
Note: This does not apply to subjects participating in observational studies without 
interventional or invasive therapy. 
2. The subject previously received therapy with azilsartan. 
Note: This does not apply to subjects participating in single dose pharmacokinetic studies of 
TAK-536. 


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3. The subject has poorly controlled hypertension indicated by an office sitting systolic blood 
pressure higher by at least 15 mmHg and/or an office sitting diastolic blood pressure higher by 
at least 10 mmHg than the 99 percentiles of the reference blood pressure values of children by 
gender and age (Table 5.a). 
4. The subject has a diagnosis of malignant or accelerated hypertension. 
5. The subject was noncompliant (< 70% or > 130%)* with the study drug during the Run-in 
Period. 
*: The proportion of the number of the received the study drug to the number of the study drug which the subjects 
should receive. 
6. The subject has severe renal dysfunction (eGFR < 30 mL/min/1.73 m2), is receiving dialysis, 
has a renovascular disease affecting one or both kidneys, severe nephrotic syndrome not in 
remission, or a serum albumin level < 2.5 g/dL. 
7. The subject has a history of, or the signs/symptoms of serious cardiovascular, hepatobiliary, 
gastrointestinal, endocrine (eg, hyperthyroidism, Cushing’s syndrome), hematological, 
immunological, urinogenital, psychiatric disease, cancer, or any other disease that adversely 
affects subject’s health, or, in the opinion of the investigator or subinvestigator, potentially 
confounds the study results. 
8. The subject has hemodynamically significant left ventricular outflow obstruction due to aortic 
stenosis or aortic valvular disease, or is scheduled to undergo a medical procedure affecting 
blood pressure during the study (eg, correction of arterial anomaly). 
9. The subject has a history of or concurrent clinically significant abnormality of 12-lead ECG 
that, in the opinion of the investigator or subinvestigator, disqualifies the subject for 
participation in the study. 
10. The subject has poorly controlled diabetes mellitus indicated by HbA1c > 9.0% at screening. 
11. The subject has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level 
≥ 2.5 × the upper limit of normal (ULN), or a total bilirubin level ≥ 1.5 × ULN at screening, 
severely impaired hepatic function, any active liver disease (regardless of the cause), or 
jaundice. 
12. The subject has hyperkalemia exceeding ULN at screening. 
13. The subject has a history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) 
infection at screening. 
14. The subject has a known hypersensitivity or allergy to any ARBs. 
15. The subject needs treatment with any of the excluded medication. 
16. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after the completion of this study. 
[Justification of Exclusion Criteria] 
1, 15. These were set as the standard exclusion criteria used for clinical studies. 


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2. This was set because of the potential for bias in evaluation of the safety and the efficacy. 
3,4, 6-11, 13,14. These were set in consideration of the subject safety. 
5. This was set to assure the appropriateness of the evaluation in this study. 
12. This was set in consideration of the subject safety; hyperkalemia may develop after the 
administration of RAS inhibitors. 
16. This was set as a standard requirement used for clinical studies. It was also due to a 
contraindication for pregnant females, because RAS inhibitors have caused fetal and neonatal 
disorders and death when used during pregnancy, and were transferred in the milk and affected 
nursing neonates when administered to lactating animals in nonclinical studies. 
7.3 
Excluded Medications and Treatments 
7.3.1 
Excluded Medications 
The following medications including over-the-counter (OTC) drugs will be prohibited at the 
specified period during the study (Run-in Period and Treatment Period). 
Subjects and subjects’ parent or the subjects’ legal guardian must be instructed not to take any 
medications including OTC products, without first consulting with the investigator or 
subinvestigator. 
Other medications that are listed in the precautions for co-administration section of the package 
inserts of TAK-536 must be administered with caution. 
<Run-in Period and Treatment Period I> 
The following medications will be prohibited during the Run-in Period and Treatment Period I. A 
subject can continue the conventional therapy for the concurrent medical conditions without 
changing daily dosage except the excluded medications. 
(1) RAS inhibitors (ACE inhibitors, ARB, and DRI) 
(2) Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) excluding acetaminophen (4 
days or more per week) 
(3) Lithium 
(4) Monoamine oxidase inhibitors 
(5) Tricyclic antidepressants 
(6) Amphetamine or it-derived materials (exception for the materials shown in the section of 
Medications Permitted with Conditions) 
(7) Dopamine agonist 
(8) Atypical antipsychotics 
(9) Anticonvulsants 
(10) Trazodone 


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(11) Nitrates  
(12) Estrogen preparations 
<Treatment Period II> 
The following medications will be prohibited during the Treatment Period II. 
(1) RAS inhibitors (ACE inhibitors, ARB, and DRI) 
(2) Chronic use of NSAIDs excluding acetaminophen (4 days or more per week) 
(3) Lithium 
(4) Monoamine oxidase inhibitors 
(5) Nitrates 
(6) Estrogen preparations 
[Justification for Excluded Medications] 
<Run-in Period and Treatment Period I> 
(1) 
These similar drugs are excluded because they could influence the evaluation of 
TAK-536 efficacy. 
(2), (4)-(12) 
These drugs are excluded because they could increase or decrease blood pressure 
and influence the evaluation of TAK-536 efficacy. 
(3) 
This drug is prohibited because their concomitant use with ARBs could cause 
poisoning. 
<Treatment Period II> 
(1) 
These similar drugs are excluded because they could influence the evaluation of 
TAK-536 efficacy. 
(2), (4)-(6) 
These drugs will be supposed to be used chronically and are excluded because they 
could increase or decrease blood pressure and influence the evaluation of TAK-536 
efficacy when these are used chronically. 
(3) 
This drug is prohibited because their concomitant use with ARBs could cause 
poisoning. 
7.3.2 
Medications Permitted with Conditions 
Following medications will be permitted with conditions in consideration of subject safety during 
the Run-in Period and Treatment Period I. 
(1) Antihypertensive drugs other than RAS inhibitors: Subjects who treated with antihypertensive 
drugs other than RAS inhibitors until the start of the Run-in Period can continue to receive a 
single antihypertensive drug in addition to the study drug if the subjects are considered to need 
the additional treatment for hypertension in the Treatment Period I by the investigator or 
subinvestigator; the antihypertensive drug should be administered under the same dosage at 


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the time of the start of the Run-in Period. If subjects have difficulty in discontinuing 
antihypertensive drugs completely at the start of the Run-in Period, the antihypertensive drugs 
can be down-titrated concurrently with administration of placebo. In the case of the 
down-titration, antihypertensive drugs should be discontinued at least 1 week (7 days) before 
the start of the Treatment Period I. Especially, beta-blockers (BBs) should be tapered off 
gradually since sudden discontinuation of BBs may cause withdrawal syndrome. 
(2) Steroids: Systemic steroid is permitted as an alternative therapy on a stable low dose/ 
maintenance dose in subjects with adrenal insufficiency. The highest dose per day is 
12 mg/m2 for hydrocortisone or equivalent dose to hydrocortisone for other steroids. 
Prednisolone or other steroids can be administered up to 15 mg/m2 per day or equivalent dose 
to prednisolone for other steroids as an immunosuppressive therapy in subjects after renal 
transplantation or with glomerular disease. The steroids are permitted on a stable dose from 30 
days or more prior to the screening to the end of the Treatment Period I (alternate-day 
administration is also permitted). Topical or inhaled steroid is permitted but the dose cannot 
be changed unless there are no medical needs. 
(3) Central nervous system stimulants, non-central nervous system stimulants: Use for treatment 
of attention deficit/hyperactivity disorder is permitted on a stable dose from 30 days prior or 
more to the screening to the end of the Treatment Period I. 
7.4 
Diet, Fluid, and Activity Control 
The investigator, the subinvestigator, and the study collaborator should instruct the subject, the 
subject’s parent or the subject’s legal guardian to adhere the following study requirements. 
1. Subjects will be instructed to ask the investigator, the subinvestigator, or the study collaborator 
by telephone for their instructions or visit the study site, as soon as they experience vomiting or 
diarrhea frequently throughout the study. 
2. Subjects will be fully explained about the possibility of excessive reduction in the blood 
pressure associated with TAK-536 treatment. Subjects will be instructed to rest in a supine 
position, as soon as they experience any symptoms suggesting decreased blood pressure (eg, 
dizziness, lightheadedness, etc.) outside the study site on days other than the scheduled visit. 
Subjects were instructed to ask the investigator, subinvestigator, or the study collaborator by 
telephone for further instructions, or to visit the study site, if the symptoms did not subside. 
3. Subjects will be instructed to ask the investigator, subinvestigator, or the study collaborator by 
telephone for their instructions, or to visit the study site, as soon as they experience any 
symptoms associated with increased blood pressure (eg, headache, palpitations, hot flushes, 
perspiration, etc.) outside the study site on days other than the scheduled visit. 
4. Subjects will be instructed to take the study drugs as directed (1 tablet or 1 sachet once daily) 
without fail and continue receiving the study drug at the same timing (before or after breakfast) 
throughout the study. Subjects will be instructed to take the study drug at the same time every 
day except for scheduled visit day. Subjects will be instructed to take the study drug by AM 
9:00 at the latest, setting ±3-hours for acceptable range. Subjects will be instructed that they 
will be allowed to take the study drug when they realize it in case of failing to take the study 


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drug, but will not be allowed to take the study drugs for 2 days at once. On the day before 
scheduled visit, subjects must take the study drug 24 hours (acceptable range, 21 to 27 hours) 
before office blood pressure measurement on the following day. TAK-536 2.5 mg granules 
should be administered immediately after the sachet (aluminum strip) is torn off. TAK-536 
2.5 mg granules sachet should not be administered if the sachet is torn off at least 1 hour before 
the administration. 
5. Subjects will be fully explained about how to adequately measure home blood pressure. 
Subjects will be instructed to measure the home blood pressure, preferably consecutive 2 times 
daily immediately before the study drug administration for 1 week each before and after the 
visit at the start of the Treatment Period I, for 1 week after the following day of a visit of each 
time point between Week 2 and Week 8 of the Treatment Period I, and for 1 week from the day 
before the visit at Week 12 of the Treatment Period I. Subjects will be instructed to inform the 
study site if a home sitting systolic blood pressure which is higher by at least 15 mmHg and/or 
a home sitting diastolic blood pressure which is higher by at least 10 mmHg than the 99 
percentiles of the reference blood pressure values of children by gender and age in Table 5.a 
(See Section 9.1.6). 
6. Subjects will be instructed not to eat or bathe within 1 hour before office blood pressure 
measurement, not to intake any caffeine containing product within 30 minutes before the 
measurement. 
7. Subjects will be instructed to comply with and not to change a fixed diet (eg, caloric and salt 
intake) and/or exercise therapies, if performed, throughout the study. 
8. Subjects will be instructed to avoid food with a high salt and to take adequate hydration and to 
maintain a routine sleep, behavior and caffeine intake. In addition, subjects will be instructed 
to avoid excessive drinking/eating, significant change of diet (eg, excessively high-fat diet), 
excessive exercise, and staying up late. Especially, subjects will be instructed to maintain a 
regular lifestyle on the day before visit days. 
9. Subjects will be instructed to inform the investigator, subinvestigator before receiving 
treatment from another doctor, or to provide details of treatment the subject received in case of 
reporting afterwards. Subjects receiving treatment by another doctor will be instructed to 
inform another doctor of their participation in this study before the participation, as far as 
possible. 
10. Subjects will be instructed to consult the investigator or subinvestigator before using or 
changing the dosage of any drug not prescribed by the investigator or subinvestigator 
(including vitamins supplements, OTC drugs, and herbal preparations). Subjects will be 
instructed to promptly provide the details when they use any such drug. 
11. Subjects will be instructed to visit the study site at the scheduled times to undergo 
examinations and tests by the investigator or subinvestigator. Subjects will be instructed to 
promptly inform the investigator or subinvestigator when they are unable to visit the study site 
as scheduled. 


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12. Female subjects of childbearing potential (eg, a female subject of childbearing potential is 
defined by the investigator’s or subinvestigator’s positive opinion about the subject’s 
reproductive potential) will be instructed to use appropriate contraception from signing of 
informed consent to 1 month after completing the study (see Section 9.1.10). 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the case report form (eCRF) using the following categories. For subject 
failure, refer to Section 9.1.14. 
1. Death. The subject died on study. 
Note: If the subject dies on study, the event will be considered as SAE. See Section 10.2.2 for 
the reporting procedures. 
2. AE. The subject has experienced an 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 AE. 
• Acute deterioration of renal function 
Acute deterioration of renal function or increase in potassium value should be monitored 
carefully. If 50% reduction in estimated glomerular filtration rate [eGFR] or less than 
30 mL/min/1.73 m2, or serum potassium value over 5.5 mEq/L is seen at consecutive 2 time 
points, discontinuation should be considered. Appropriate follow-up should be performed 
for all subjects who discontinue the study until the subjects have been recovered or 
stabilized (see Section 9.1.9). 
• Liver Function Test (LFT) Abnormalities 
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.9), if the following circumstances occur at any time 
during study drug treatment: 
– ALT or AST > 8 ×ULN, or 
– ALT or AST > 5 × ULN and persists for more than 2 weeks, or 
– ALT or AST > 3 × ULN in conjunction with elevated total bilirubin > 2 × ULN or 
international normalized ratio (INR) > 1.5, or 
– ALT or AST > 3 × ULN with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
3. Protocol deviation. The discovery after the start of the Treatment Period 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. 
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject, 
the subject’s parent or the subject’s legal guardian were unsuccessful. Attempts to contact the 


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subject, the subject’s parent or the subject’s legal guardian must be documented in the 
subject’s source documents. 
5. Withdrawal by subject. The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (i.e., withdrawal due to an 
AE). 
6. Withdrawal by parent or guardian. The subject’s parent or the subject’s legal guardian wishes 
to withdraw the subject from the study. The reason for withdrawal, if provided, should be 
recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (i.e., withdrawal due to an 
AE). 
7. Study terminated by sponsor. The sponsor terminates the study. 
8. 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 9.1.11. 
9. Lack of efficacy. The investigator or subinvestigator has determined that the subject is not 
benefiting from study treatment; and, continued participation would pose an unacceptable risk 
to the subject. For example, discontinuation should be considered in the following case; on 
consecutive visits, an office sitting systolic blood pressure is persistently higher by at least 
15 mmHg and/or an office sitting diastolic blood pressure is persistently higher by at least 
10 mmHg than the 99 percentiles of the reference blood pressure values of children by gender 
and age in Table 5.a, or, subjective symptoms or findings deemed associated with poorly 
controlled blood pressure do not improve with titration of TAK-536 during the Treatment 
Period I or with the addition of any other antihypertensive drugs other than RAS inhibitors 
during the Treatment Period II. 
10. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator or subinvestigator may discontinue 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 by the investigator or subinvestigator. In addition, efforts should be 
made to perform all procedures scheduled for the Early Termination Visit. 


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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 Drug and Materials 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study drug refers to all or any of the drugs defined below. 
8.1.1.1 
Study Drug 
(1) Dosage form and manufacturing 
Code name: TAK-536 
Chemical name: 2-Ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) 
biphenyl-4-yl]methyl}-1H-benzo[d]imidazole-7-carboxylic acid 
Generic name: Azilsartan (JAN) 
Formulation and Strength: 
Study drug 
Formulation 
Strength 
TAK-536 2.5 mg granules 
(placebo for the Run-in 
Period) 
White to nearly white granules 
Contains no TAK-536 in 250 mg 
TAK-536 2.5 mg granules 
(active drug for the 
Treatment Period) 
White to nearly white granules 
Contains 2.5 mg of TAK-536 in 250 mg 
TAK-536 5 mg tablet 
(placebo for the Run-in 
Period) 
Pale pink film-coated tablet 
Contains no TAK-536 in 1 tablet 
TAK-536 5 mg tablet 
(active drug for the 
Treatment Period) 
Pale pink film-coated tablet 
Contains 5 mg of TAK-536 in 1 tablet 
TAK-536 10 mg tablet 
Pale yellow to red film-coated 
tablet 
Contains 10 mg of TAK-536 in 1 tablet 
TAK-536 20 mg tablet 
Pale-red film-coated tablet 
Contains 20 mg of TAK-536 in 1 tablet 
TAK-536 40 mg tablet 
Yellow film-coated tablet 
Contains 40 mg of TAK-536 in 1 tablet 
 
Manufacturing: TPC 
(2) Package and labeling 
1) Package 
– TAK-536 2.5 mg granules (placebo for the Run-in Period, active drug for the Treatment 
Period): For placebo for the Run-in Period, each aluminum strip sachet contains 250 mg of 


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TAK-536 granules containing no TAK-536. Forty two sachets are packaged in a box. For 
active drug for the Treatment Period, each aluminum strip sachet contains 250 mg of 
TAK-536 granules containing 2.5 mg of TAK-536. Seventy sachets are packaged in a box. 
– TAK-536 5 mg tablet (placebo for the Run-in Period, active drug for the Treatment 
Period): For placebo for the Run-in Period, each press through package (PTP) sheet 
contains 14 tablets of TAK-536. Three sheets are packaged in a box. For active drug for the 
Treatment Period, each PTP sheet contains 14 tablets of TAK-536. Ten sheets are 
packaged in a box. 
– TAK-536 10 mg, 20 mg, and 40 mg tablets: Each PTP sheet contains 14 tablets of 
TAK-536. Ten sheets are packaged in a box. 
2) Labeling 
Each outer box indicates the following information: the drug is for the study use only, study drug 
name, amount, the sponsor’s name and address, batch number, and storage condition. 
8.1.2 
Storage 
The study drugs are to be stored at room temperature (1 to 30°C). 
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. Study drug 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 
During the Run-in Period, subjects will orally receive TAK-536 2.5 mg granules (placebo for the 
Run-in Period) if subjects weighing < 50 kg, or TAK-536 5 mg tablet (placebo for the Run-in 
Period) if subjects weighing ≥ 50 kg, once daily, before or after breakfast. During the Treatment 
Period, the same dose of the selected placebo during the Run-in Period will be the initial dose. 
After the initial dose, subjects will orally receive any of TAK-536 2.5 mg granules, TAK-536 
5 mg, 10 mg, 20 mg tablet, once daily, before or after breakfast, if subjects weighing < 50 kg, or 
any of TAK-536 5 mg, 10 mg, 20 mg, 40 mg tablet, if subjects weighing ≥ 50 kg. For dose titration 
method, see Section 6.1 Study Design. 
Because weight is likely to change during the study, the highest dose for the subjects is allowed to 
be changed if dose adjustment by changing of weight is required during the Treatment Period II.  
The investigator or subinvestigator may select the timing of the study drug administration (i.e., 
before or after breakfast) in consideration of subject lifestyle but should not change this timing 
throughout the study. The investigator or its designee will record the guidance provided about the 
timing of the study drug administration (before or after breakfast) at the start of the Run-in Period 
(Week -2) in the eCRF. 
At the start of the Run-in Period (Week -2), the study drug for the Run-in Period will be 
administered on the same day after completing all tests, observations, and evaluations. In case that 


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subjects take RAS inhibitors in the morning of the visit day, the administration of the study drug  
for the Run-in Period will be started from the next day. 
Except for Week 16, subjects will visit the study site on each visit day without taking the study 
drugs, and receive them only after completing all tests, observations, and evaluations. 
On the visit of Week 16, subjects, the subjects’ parent or the subjects’ legal guardian will be 
instructed to visit the study site after taking the study drug and the tests, observations, and 
evaluations 2 hour (acceptable time window, 1 to 3 hours) after taking the study drug will be 
performed. 
Regular doses on days except for the visits will be administered no later than 9:00 AM, regardless 
of the specified dosing timing (i.e., before or after breakfast). The study drug should be 
administered at the almost same time every day throughout the study (acceptable range is ± 3 
hours) except the visit day. The investigator or subinvestigator will confirm whether the subject 
has taken the study drug or not in the morning of each visit. 
8.1.4 
Overdose 
An overdose is defined as a known deliberate or accidental administration of study 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 AEs) about TAK-536 active drug for the 
Treatment Period, will be documented on an Overdose page of the eCRF, in order to capture this 
important safety information consistently in the database. Cases of overdose without manifested 
signs or symptoms are not considered AEs. AEs associated with an overdose will be documented 
on AE CRFs according to Section 10.0. 
SAEs associated with overdose should be reported according to the procedure outlined in Section 
10.2.2. 
In the event of drug overdose, the subject should be treated symptomatically. 
8.2 
Study Drug Dispensing Procedures 
The investigator or subinvestigator will dispense the study drug to subjects according to the study 
procedure. 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs 
The site designee will receive the procedures for handling, storage and management of study drugs 
created by the sponsor, according to which the site designee will appropriately manage the 
sponsor-supplied drug. The investigator will also receive those procedures from the sponsor. The 
procedures include those for ensuring appropriate receipt, handling, storage, management, 
dispensation of the sponsor-supplied drug, and collection of unused medications from the subject 
as well as return of them to the sponsor or destruction of them. 
The site designee will immediately return unused medications to the sponsor after the study is 
closed at the site. 


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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 and assent are described in Section 15.2. 
Informed assent of the subject, if deemed possible by the investigator or subinvestigator, and 
informed consent of the subject’s parent or the subject’s legal guardian must be obtained prior to 
the subject entering into the study, and before any protocol-directed procedures are performed. 
Assent and consent to participate in the study will be obtained from any subject before 
discontinuing the prior treatment (antihypertensive drugs). 
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is explained; 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, diagnosis timing and 
type of hypertension, and underlying diseases in case of secondary hypertension at screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the diseases under study that stopped within 1 year prior to 
informed consent. Any history of kidney transplantation should be documented regardless of the 
time elapsed. Ongoing conditions are considered concurrent medical conditions (see Section 
9.1.8). 
Medication history information to be obtained includes any medication stopped at or within 4 
weeks prior to VISIT 2. 
9.1.3 
Physical Examination Procedure 
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; 
(11) other. All subsequent physical examinations should assess clinically significant changes from 
the assessment performed before the study drug administration. 
9.1.4 
Weight, Height, and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below: The Takeda 
standard for collecting height is centimeters without decimal places and for weight it is kilograms 
(kg) with 1 decimal place. BMI should be derived as: 


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Metric: BMI = weight (kg)/height (m)2 
Height in centimeters (cm) will be rounded to integers and weight in kilograms (kg) will be 
rounded to 1 decimal place. BMI will be rounded to 1 decimal place. 
9.1.5 
Vital Sign Procedure 
Vital signs will include office sitting blood pressure (systolic and diastolic), office standing blood 
pressure (systolic and diastolic), office sitting pulse rate, and office standing pulse rate (pulse rate 
per 1 minute). All office blood pressure will be measured with a blood pressure meter specified by 
the sponsor. 
Office blood pressure should be measured at the time of trough (approximately 21 to 27 hours after 
the latest dose, i.e., in the morning of that day) with the subject without taking the study drug in the 
morning of the scheduled visit except for Week 16. The subject, the subject’s parent, or legal 
guardian will be instructed strongly not to take the study drug at home on the scheduled visit day 
except for Week 16. The subject, the subject’s parent, or the subject’s legal guardian will be 
instructed again if the subject receives the study drug before the measurements of vital signs on the 
scheduled visit day by mistake. 
When vital signs are scheduled at the same time as blood draws, vital signs will be obtained before 
the scheduled blood draw. 
Office sitting blood pressure after taking the study drug will be also measured only at Week 16 of 
the Treatment Period; the time point which the pharmacokinetics after receiving the study drug is 
evaluated.  
Subjects will be instructed not to eat or bathe within 1 hour before office blood pressure 
measurement, not to intake any caffeine containing product 30 minutes before the measurement. 
<Determining difference in blood pressure between right and left arm> 
At screening, sitting blood pressure in the right and left arms will be measured once after sitting at 
rest for ≥ 5 minutes to determine the difference in blood pressure between the arms. The arm with 
a higher systolic blood pressure will be used to measure office blood pressure during the study. 
The right arm will be used if systolic blood pressure is the same on both sides. Change of the arm 
for measurement will not be allowed during the study. 
<Measuring sitting blood pressure and sitting pulse rate> 
Sitting blood pressure will be repeatedly measured 3 times at 1 to 2 minute intervals after the 
subject has been sitting at rest for at least 5 minutes and recorded in the subject source documents 
and eCRF. However, if 2 of the 3 systolic blood pressure measurements differ by more than 
8 mmHg or diastolic blood pressure measurements differ by more than 5 mmHg, a second set of 3 
sitting blood pressure measurements should be obtained and only the second set of readings should 
be recorded in the eCRF (even if these still differ by > 8 mmHg for systolic blood pressure or 
5 mmHg for diastolic blood pressure). Original and repeat readings must all be recorded in the 
source documents with an explanation. 


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The arithmetic mean (rounded to integers) of 3 measurements of a session will be used for 
determination of the subject eligibility. 
The pulse rate measured at the last measurement of the sitting blood pressure will be used as the 
sitting pulse rate value. 
Sitting blood pressure must be measured after resting in a sitting position for at least 5 minutes. An 
appropriately sized cuff (40% of the arm’s perimeter) should be used, and applied to an upper arm 
held at the heart level. All measurements must be made on the same arm using the same-sized cuff. 
Every effort should be made to standardize the condition of office blood pressure measurements as 
possible, such as measurement time, the same blood pressure device should be used, whenever 
possible, by the same investigator, subinvestigator, or the study collaborator. 
<Measuring standing blood pressure and standing pulse rate> 
Standing blood pressure will be measured to evaluate the orthostatic vital signs at the scheduled 
visit of Week 0, 12, 24 and 52. After measuring the sitting blood pressure, standing blood pressure 
will be measured once after the subject has been standing for 2 minutes. Standing systolic and 
diastolic blood pressure will be also measured with the same device which measures sitting blood 
pressure on the same arm. For standing blood pressure measurements, the arm should be supported 
and extended such that the cuff is at heart level. Standing pulse rate will be measured once during 
the subject maintains a standing position. 
9.1.6 
Measuring Home Blood Pressure 
Each subject, the subject’s parent, or the subject’s legal guardian will be provided a home blood 
pressure meter and adequately informed of the measurement procedures at the start of the Run-in 
Period (Week -2) by the sponsor through the study site. 
The subject, the subject’s parent, or the subject’s legal guardian will be instructed to measure home 
blood pressure (systolic and diastolic), preferably consecutive 2 times daily immediately before 
the study drug administration for 1 week each before and after the visit at the start of the Treatment 
Period I, and for 1 week after the following day of a visit of each time point between Week 2 and 
Week 8 of the Treatment Period I (including visit at Week 6, when performed), and for 1 week 
from the day before the visit at Week 12 of the Treatment Period I. 
The subject should measure blood pressure 2 times in a row after having been sitting for at least 5 
minutes with the blood pressure cuff applied to the same arm as used to measure blood pressure at 
the visits. The blood pressure measurements should be recorded in patient diary and reviewed by 
the investigator or subinvestigator at each visit. The blood pressure measured twice immediately 
before the study drug administration should be recorded in CRFs. The subject, the subject’s parent, 
or the subject’s legal guardian will be instructed to inform the study site if a home sitting systolic 
blood pressure which is higher by at least 15 mmHg and/or a home sitting diastolic blood pressure 
which is higher by at least 10 mmHg than the 99 percentiles of the reference blood pressure values 
of children by gender and age in Table 5.a. The subject, the subject’s parent, or the subject’s legal 
guardian will be instructed by the investigators to visit the study site to measure blood pressure 
again if needed. If the elevated blood pressure is confirmed by repeat measurements at the study 
site, the subject is to be considered to discontinue the study. 


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9.1.7 
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. 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 drug (used from the start of the Run-in Period [Week 2] through the end of the 
study), and all medication including vitamin supplements, OTC medications, and oral herbal 
preparations, must be recorded in the eCRF. 
If the concomitant medications are antihypertensive drugs, the daily dosage and unit of 
concomitant medications must be recorded in the eCRF as well. 
9.1.8 
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, ECG, or physical 
examination abnormalities noted at the first test after signing of informed consent. The condition 
(i.e., diagnosis) should be described. 
9.1.9 
Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 8 mL. 


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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Red blood cell count 
White blood cell count with 
differential (neutrophils, 
basophils, eosinophils, 
lymphocytes, monocytes) 
Hemoglobin 
Hematocrit 
Platelets 
Hemoglobin A1C/Hemoglobin (a) 
ALT 
Albumin 
Alkaline phosphatase (ALP) 
AST 
Bilirubin (Total bilirubin) 
Blood urea nitrogen (BUN) (b) 
Calcium 
Chloride (b) 
Creatinine (b) 
Creatine kinase 
Cystatin C 
Glomerular Filtration Rate (b) 
Gamma-glutamyl transferase (GGT) 
Glucose 
Cholesterol (Total cholesterol) 
Triglyceride 
Phosphate 
Potassium (b) 
Sodium (b) 
Protein (Total protein) 
Lactate dehydrogenase (LDH) 
Qualitative tests for 
glucose, pH, protein, 
occult blood, Ketones 
Quantitative tests for 
protein, creatinine, 
Albumin 
Protein/creatinine ratio, 
albumin/creatinine ratio, 
specific gravity 
Other 
Urine qualitative human chorionic gonadotropin (hCG) pregnancy test (only female subjects of childbearing potential) 
(a) Only patients with diabetes mellitus 
(b) Only the laboratory tests associated with renal function. The local laboratory will perform the laboratory tests 
associated with renal function in addition to measuring at the central laboratory to confirm the tolerability when 
TAK-536 is titrating (including unscheduled visit), if needed at the investigator’s discretion. 
 
The central laboratory will perform laboratory tests for hematology, chemistries, and urinalysis 
(acceptable under the fed condition). 
The local laboratory will perform the laboratory tests associated with renal function (BUN, 
chloride, creatinine, eGFR, potassium, and sodium) in addition to measuring at the central 
laboratory to confirm the tolerability when TAK-536 is titrating (including unscheduled visit), if 
needed at the investigator’s discretion. The results of the local measurements will not be required 
recording in the eCRF. 
The following formula proposed by the Committee for Pediatric Chronic Kidney Disease will be 
used to deduce eGFR in Japanese children. 


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eGFR in children (mL/min/1.73 m2) 
=110.2 × standard serum Cr (mg/dL)/serum Cr (mg/dL) + 2.93, 
where, the standard serum Cr (mg/dL) is calculated from the height (Ht, in meter; Ht measured 
most recently will be used) as follows: 
For a boy, -1.259 Ht5 + 7.815 Ht4 - 18.57 Ht3 + 21.39 Ht2 - 11.71 Ht + 2.628 
For a girl, -4.536 Ht5 + 27.16 Ht4 - 63.47 Ht3 + 72.43 Ht2 - 40.06 Ht + 8.778 
Uemura O, et al. Clin Exp Nephrol. 2014 [14] 
Follow-up laboratory tests should be performed to determine whether the subject continue the 
study or not, in case of acute deterioration of renal function (eg, ≥50% reduction in eGFR or less 
than 30 mL/min/1.73 m2 or serum potassium value over 5.5 mEq/L) (See Section 7.5). 
If subjects experience ALT or AST > 3 ×ULN after the start of the Run-in Period (Week -2), 
follow-up laboratory tests (at a minimum, ALP [serum], ALT, AST, bilirubin [total bilirubin], 
GGT, and INR) should be performed within a maximum of 7 days and preferably within 48-72 
hours after the abnormality was noted (Please refer to Section 7.5 for discontinuation criteria, and 
Section 10.2.3 for the appropriate guidance on Reporting of Abnormal Liver Function Tests in 
relation to ALT or AST >3 ×ULN in conjunction with total bilirubin >2 ×ULN.). 
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study drug, discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.3 
Reporting of Abnormal Liver Function Tests for reporting requirements). 
Only female subjects of childbearing potential, defined by the investigator’s or subinvestigator’s 
positive opinion about the subject’s reproductive potential, will undergo a qualitative hCG 
pregnancy test. The local laboratory will perform the test. 
The investigator or subinvestigator is reviewing and filing the laboratory results. The investigator 
will maintain a copy of the normal reference ranges including the archival records for the 
laboratory used. 
9.1.10 
Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, throughout the duration of the study, and for 1 month after the 
end of the study, 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 preserve or 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), who are postmenopausal (defined as at 
least 5 years since last regular menses, confirmed before any study drug is implemented), or who 
have no possibility of childbearing in the opinion of investigator or subinvestigator. 
**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, female subjects of childbearing potential must use copper intrauterine devices 
(IUDs) combined with male condom or female condom. Medications and devices containing 
hormones are excluded. 
The subject and the subject’s parent, or the subject’s legal guardian will be provided with 
information on acceptable methods of contraception as part of the subject informed consent/assent 
process and will be asked to sign a consent/assent form stating that they understand the 
requirements for avoidance of pregnancy, preservation or donation of ova from providing the 
consent/assent until 1 month has passed from the end of the study. 
During the course of the study, regular urine hCG pregnancy tests will be performed only for 
female subjects of childbearing potential and subjects will receive continued guidance with respect 
to the avoidance of pregnancy as part of the study procedures (Appendix A). 
This protocol does not condone or endorse under-age sexual activity. 
9.1.11 
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 drug, or within 1 month of the last 
dose of active study drug, the pregnancy should be reported immediately, using a pregnancy 
notification form, to the contact listed in attachment 1. 
If the female subject and her parent, or the subject’s legal guardian agree to the primary care 
physician being informed, the investigator or subinvestigator 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 (blinded or unblinded, as applicable). 
All pregnancies in subjects on active study drug 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. 
9.1.12 
ECG Procedure 
A resting 12-lead ECG will be recorded. The investigator (or a qualified observer at the study site) 
will interpret the ECG using 1 of the following categories: normal or abnormal. The investigator 
(or a qualified observer at the study site) will judge if it is clinically significant. The following 
parameters will be recorded on the eCRF from the subject’s ECG trace: heart rate, RR interval, PR 
interval, QT interval, and QRS interval. 
QTc will be calculated by the sponsor using the Fredericia’s formula (QT/RR0.33). 
9.1.13 
Pharmacokinetic Sample Collection 
According to the study schedule (Appendix A), all pharmacokinetic samples should be collected 
on each visit except for Week 16, at the same time of blood sample collection for laboratory tests 


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to evaluate the trough values (approximately 21 to 27 hours after the latest dose) without taking the 
study drugs. 
In addition to collection of the pharmacokinetic samples at trough, pharmacokinetic samples will 
be also collected once (total twice before and after the administration of the study drug) 2 hour 
(acceptable time window, 1 to 3 hours) after taking the study drug from the available subjects to 
evaluate the pharmacokinetics after taking the study drug at each visit by Week 12 of the 
Treatment Period. 
On the visit of Week 16, subjects should visit the study site after taking the study drug to collect 
pharmacokinetic samples 2 hour (acceptable time window, 1 to 3 hours) after taking the study drug 
at the same time as the blood sample collection for laboratory tests. 
9.1.13.1 Collection of Plasma for Pharmacokinetic Sampling 
Blood samples (one 2-mL sample per scheduled time) for pharmacokinetic analysis of TAK-536 
and its metabolites (M-I and M-II) will be collected into vacutainers containing 
ethylenediaminetetraacetic acid dipotassium salt dihydrate (EDTA-2K). After mixing the 
vacutainers 5 to 6 times by inversion immediately, vacutainers will be centrifuged at 4°C and 
3000 rpm for 10 minutes. The plasma will be dispensed from the vacutainers to polypropylene 
tube and be stored frozen below -20°C in a freezer until being shipped to the analytical institute. 
For each sample, the date and time of the latest study drug administration and the actual time of 
blood sample collection will be recorded in the eCRF. 
9.1.13.2 Bioanalytical Method 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) will be measured by 
HPLC/MS/MS (high-performance liquid chromatography with tandem mass spectrometry) at 
 
9.1.14 
Documentation of Subjects Failure 
An eCRF must be created for all subjects giving informed consent who withdrawn before the start 
of the Treatment Period. 
The primary reason for subject failure is recorded in the eCRF using the following categories: 
•
Death
•
Adverse Event
•
Screen Failure (failed inclusion criteria or did meet exclusion criteria)
•
Protocol deviation.
•
Lost to follow-up.
•
Withdrawal by subject <specify reason>.
•
Withdrawal by parent or guardian <specify reason>.
PPD


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• Study terminated by sponsor. 
• Pregnancy 
• Other <specify reason>. 
Subject numbers assigned to subjects who fail screening should not be reused. 
9.1.15 
Documentation of Study Entrance 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the Treatment Period. 
If the subject is found to be not eligible for the Treatment Period, the investigator or 
subinvestigator should record the primary reason for failure on the applicable eCRF. 
9.2 
 Monitoring Subject Treatment Compliance 
Compliance with study drug (amount of dispense and return) between the visits, timing of the 
study dose (before or after breakfast) and the latest dosing date and time before collecting sample 
for pharmacokinetic evaluation will be confirmed and recorded in the eCRF. 
Subjects, the subjects’ parent, or the subjects’ legal guardian will be instructed to be compliant 
with the study drug throughout the study. If a subject is noncompliant (< 70% or > 130%) with the 
study medication (TAK-536 placebo) during the Run-in Period, the subject will be excluded 
before the start of the Treatment Period, as indicated in the exclusion criteria No. 5. If a subject is 
noncompliant with the study medication (TAK-536) (eg, failure to take < 50% of the scheduled 
dosed after the last visit) after the start of the Treatment Period, 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. 
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 points. 
9.3.1 
Screening 
Subjects will be screened within 14 days prior to the start of the Run-in Period. Subjects will be 
screened in accordance with predefined inclusion and exclusion criteria as described in 
Section 7.0. 
9.3.2 
Start of the Run-in Period (Week -2) 
The study drug (TAK-536 placebo) for the Run-in Period will be administered on the same day 
after the tests, observations and evaluations specified for each visit are performed. In case that 
subjects take RAS inhibitors in the morning of the visit day, the administration of the study drug 
(TAK-536 placebo) for the Run-in Period will be started from the next day. 


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Two weeks will be set as the Run-in Period. The subjects whose blood pressures meet the 
inclusion criteria 1 week (at earliest) after receiving placebo during the Run-in Period can enter the 
Treatment Period. For the subjects only who treated with any antihypertensive drugs as a prior 
treatment, the Run-in Period could be extended up to 4 weeks if blood pressures do not meet the 
inclusion criteria. 
9.3.3 
End of the Run-in Period (Week 0) 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will be entered after 
performing the tests and observations specified for each visit and will be initiated to receive the 
study drug for the Treatment Period on the same day. 
The first and the last date of the study drugs administration for the Run-in Period will be recorded 
in the eCRF for those receiving the study drugs for the Run-in Period and subsequently received 
the study drug for the Treatment Period. 
See Section 9.1.14 for procedures for documenting subjects withdrawn before the start of the 
Treatment Period. 
9.3.4 
Treatment Period (Weeks 2, 4, 8, 12, 16, 20, 24, 32, and 40) 
The tests and observations specified for each visit will be performed. 
Between the visits of Week 4 and 8 during the Treatment Period I, an additional unscheduled visit 
of Week 6 may be requested at the investigator’s discretion in order to titrate the dose of the study 
drug in the subjects when the further decrease in blood pressure is needed. 
On the visit of Week 16, subjects should visit the study site after taking the study drug and the tests 
and observations specified will be performed. 
9.3.5 
Final Visit or Early Termination 
The Final Visit will be performed on Week 52 or at the Early Termination Visit. 
The tests and observations specified for each visit will be performed. 
For subjects early terminate the study after the start of the Treatment Period, if possible, the same 
tests, observations, and evaluations as those scheduled at Week 52 should be performed. 
Whenever possible, office sitting blood pressure should be determined within 3 days after early 
termination and the other tests, observations, and evaluations should be performed within 14 days 
after early termination (the next day of the final dose should be calculated as the first day). 
For all subjects who entered the Treatment Period, the investigator or subinvestigator must 
complete the Subject Status on eCRF page with the first day when the subjects received the study 
drug for the Treatment Period and study completion or early termination status until Week 24 and 
study completion status at Week 52 for subjects who continuingly received the study drug beyond 
Week 24. 


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9.3.6 
Follow-up Period: Week 54 
Follow-up Period will begin the first day after the final administration of TAK-536 for the 
Treatment Period and will continue until 2 weeks. The tests and observations specified for each 
visit will be performed. If subjects terminate the study drug in the Run-in Period or at an early 
stage of the Treatment Period, no tests, observations, and evaluations will be required but care 
should be taken for subject safety. 
9.3.7 
Post Study Care 
The study drug 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 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with this treatment or study participation. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the study participation 
whether or not it is considered related to the drug or study procedures. 
10.1.2 
Additional Points to Consider for AEs 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.) 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in dose of study drug or a concomitant medication. 
• Be considered unfavorable by the investigator or subinvestigator for any reason. 
• AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as an AE. 
Diagnoses vs signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s). 
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG parameters are only considered to be AEs if they are 
judged to be clinically significant (i.e., if some action or intervention is required or if the 
investigator or subinvestigator 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. 
• 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 an AE. 


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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 AEs. Baseline evaluations (eg, 
laboratory tests, ECG, X-rays etc.) should NOT be recorded as AEs unless related to study 
procedures. However, if the subject experiences a worsening or complication of such a 
concurrent medical condition after informed consent is signed, the worsening or complication 
should be recorded appropriately as an AE. The investigator or subnvestigator 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 an AE if the episodes become more frequent, serious or 
severe in nature, that is, the investigator or subinvestigator 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 medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be captured as an AE if occurring to a greater 
extent to that which would be expected. Again, the investigator or subinvestigator should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of …”). 
Worsening of AEs: 
• If the subject experiences a worsening or complication of an AE after starting administration of 
the study drug, or if a sign or a symptom appears secondarily due to an AE, the worsening or 
complication should be recorded appropriately as a new AE. The investigator or 
subinvestigator 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 the study 
drug, or if a sign or a symptom appears secondarily due to an AE, the worsening or 
complication should be recorded as a new AE. The investigator or subinvestigator should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”). 
Changes in severity of AEs: 
• If the subject experiences changes in severity of an AE that are not related to starting the study 
drug or changing in the dose or regimen, 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 AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs. 


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Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator or subinvestigator 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 
AEs, but instead will be documented on an Overdose page of the eCRF. Any manifested side 
effects will be considered AEs and will be recorded on the AE page of the eCRF. 
10.1.3 
SAEs 
An SAE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study: 
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. Leads to 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 seizure 
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 
 
10.1.4 
AEs of Special Interest 
An AEs of Special Interest (treatment-emergent only, serious or non-serious) is one of scientific 
and medical concern specific to the compound or program, for which ongoing monitoring and 
rapid communication by the investigator or subinvestigator to Takeda may be appropriate. Such 
events may require further investigation in order to characterize and understand them and would 
be described in protocols and instructions provided for the investigator or subinvestigator as to 
how and when they should be reported to Takeda. 
10.1.5 
Severity of AEs 
The different categories of 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 to Study Drugs 
The causality of each AE to study drugs will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including the course 
after withdrawal of the drug), or for which a causal relationship is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be responsible. 
Not 
related: 
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. 


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10.1.7 
Causality of AEs to Study Procedures 
The causality of each AE to study procedures will be assessed. 
The causality should be assessed as Related if the investigator or subinvestigator considers that 
there is reasonable possibility that an event is due to a study procedure. Otherwise, the causality 
should be assessed as Not Related. 
10.1.8 
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
the investigator or subinvestigator. 
10.1.9 
End Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
10.1.10 Pattern of Adverse Event 
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous. 
10.1.11 Action Taken with Study Treatment 
• Drug withdrawn – a study drug is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study drug. 
• Unknown – only to be used if it has not been possible to determine what action has been taken. 
• Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE, the AE that occurred before the study drug administration. 
• Dose Reduced – the dose was reduced due to the particular AE. 
• Dose Increased – the dose was increased due to the particular AE. 
• Drug 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. 
• 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 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 


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study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved”. 
• Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis. 
• Fatal – the AEs which are considered as the cause of death. 
• Unknown – the course of the AE 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 AE Collection Period 
Collection of AEs will commence from the time the subject signs the informed consent. Routine 
collection of AEs will continue until the end of the Follow-up Period (or the tests performed at 
early termination). 
10.2.1.2 AE Reporting 
At each study visit, the investigator or subinvestigator 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 AE that occurs prior to the first exposure to study drug 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 AEs that occur prior to 
the first exposure to study drug, related or unrelated to the study procedure, need not to be 
followed-up for the purposes of the protocol. 
All subjects experiencing AEs after the first exposure to study drug, whether considered associated 
with the use of the study drug 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 AEs will be documented in the AE page of 
the eCRF, whether or not the investigator or subinvestigator concludes that the event is related to 
the drug treatment. The following information will be documented for each event: 
1. Event term. 
2. Start and end date. 
3. Pattern. 
4. Severity. 
5. Investigator’s opinion of the causality between the event and administration of study drug(s). 


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6. Investigator’s opinion of the causality to study procedure(s), including the details of the 
suspected procedure. 
7. Action taken with study treatment (not applicable for the AE that occurred before the study 
drug administration). 
8. Outcome of event. 
9. Seriousness. 
10. After administration of study drug. 
11. Treatment emergent. 
10.2.1.3 AEs of Special Interest Reporting 
Pediatric subjects, the subject population of this study, are vulnerable, and as such need special 
attention with regard to the risk of the over decrease in blood pressure accompanying the use of 
antihypertensive drugs. Furthermore, kidney function is often impaired in pediatric subjects with 
secondary hypertension. Administration of RAS inhibitors to such patients may reduce GFR, 
deteriorating the kidney function. Hence, the following adverse events related to hypotension or 
renal impairment will be investigated as special interest AEs in this study. 
[Hypotension-related AE] 
Hypotension, blood pressure decreased, orthostatic hypotension, blood pressure orthostatic 
decreased, dizziness, dizziness postural, vertigo, circulatory collapse, shock, loss of consciousness, 
syncope, and presyncope. 
[Renal dysfunction-related AE] 
Renal failure, acute renal failure, renal impairment, prerenal failure, acute prerenal failure, anuria, 
oliguria, nephropathy toxic, acute phosphate nephropathy, and azotaemia. 
If this AE of special interest occurs during the Run-in Period, the Treatment Period or the 
Follow-up Period, it should be reported to the sponsor (described in the separate contact 
information list) immediately or within 1 business day of first onset or subject’s notification of the 
event. Hypotension-related AE or renal dysfunction-related AE Form or an SAE Form should be 
completed, signed and/or sealed by the principal investigator, and reported to appropriate 
personnel in the separate contact information list within 10 business days. 
The AE of special interest have to be recorded as AEs in the eCRF. An evaluation form along with 
all other required documentation must be submitted to the sponsor. 
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: 
An SAE should be reported to the sponsor (described in the separate contact information list) 
within 1 business day of first onset or subject’s, the subject’s parent’s, or the subject’s legal 
guardian’s notification of the event. The principal investigator should submit the completed SAE 


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form within 10 calendar days. The information should be completed as fully as possible but 
contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s or subinvestigator’s name. 
• Name of the study drugs 
• Causality assessment. 
Any SAE spontaneously reported to the investigator or subinvestigator following the AE 
collection period should be reported to the sponsor if considered related to study participation. 
10.2.3 
Reporting of Abnormal Liver Function Tests 
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 or subinvestigator must contact the sponsor for discussion 
of the relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or 
B or other acute liver disease or medical history/concurrent medical conditions. Follow-up 
laboratory tests as described in Section 9.1.9 must also be performed. 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator or subinvestigator should complete a follow-up SAE form or provide other written 
documentation and fax it immediately. Copies of any relevant data from the hospital notes (eg, 
ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the addressee, if 
requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 
Safety Reporting to Investigators, IRBs, 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, and 
the head of the study site, as applicable. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee , SUSARs will be submitted to the regulatory 
authorities as expedited report 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 a study drug/sponsor supplied drug or that would be sufficient to 
consider changes in the study drug/sponsor supplied drug administration or in the overall conduct 
of the trial. The study site also will forward a copy of all expedited reports to his or her IRB. 


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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 and medical history including 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 eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs. 
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 eCRFs 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. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs. 
The following data will not be recorded into the eCRFs: 
• 
Results of clinical laboratory tests conducted at the central laboratory 
• 
Results of pharmacokinetics conducted at the analytical institute 
After the lock of the clinical study database, any change of, modification of or addition to the data 
on the eCRFs should be made by the investigator or subinvestigator with use of change and 
modification records of the eCRFs (Data Clarification Form) provided by the sponsor. The 
principal investigator must review the data change for completeness and accuracy, and must sign, 
or sign and seal, and date. 
eCRFs 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 eCRFs. The completed eCRFs 
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 and the head of the study site agree to keep the records stipulated in Section 12.1 
and those documents that include (but are not limited to) the study-specific documents, the 


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identification log of all participating subjects, medical records, source worksheets, all original 
signed and dated informed consent forms, electronic copy of eCRFs, including the audit trail, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities, the 
sponsor or its designees. Any source documentation printed on degradable thermal sensitive paper 
should be photocopied by the site and filed with the original in the subject’s chart to ensure long 
term legibility. Furthermore, the investigator and the head of the site are required to retain essential 
relevant documents until the day specified as 1) or 2) below, whichever comes later. However, if 
the sponsor requests a longer time period for retention, the head of the site should discuss how long 
and how to retain those documents with the sponsor. 
1. The day on which marketing approval of the study drug is obtained (or the day 3 years after the 
date of notification in the case that the investigation is discontinued.) 
2. The day 3 years after the date of early termination or completion of the clinical study. 
In addition, the investigator and the head of the site should retain the essential relevant documents 
until the receipt of a sponsor-issued notification to state the retention is no longer required. 


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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 database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. 
A data review will be conducted prior to database lock. This review will assess the accuracy and 
completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods. 
At the time when the data of approximately 25 subjects are collected, the data until Week 12 in the 
Treatment Period will be analyzed. In addition, at the time when all subjects complete Week 24 or 
52 in the Treatment Period, the data until Week 24 or 52 in the Treatment Period will be analyzed 
separately after being locked. 
13.1.1 
Analysis Sets 
In this study, 2 kinds of analysis sets are defined: a full analysis set (FAS) and a safety analysis set. 
The safety analysis set used for safety analysis will be defined as “all subjects who received at least 
1 dose of the study drug for the Treatment Period.” The definition of each analysis set will be 
described in the Handling Rule for Analysis. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. The Handling Rule for Analysis must be 
finalized prior to database lock. 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Demographics will be summarized using the safety analysis set. 
13.1.3 
Efficacy Analysis 
(1) Secondary endpoints and analytical methods 
[Secondary endpoints] 
Office trough sitting systolic and diastolic blood pressure, proportion of subjects who achieve the 
target blood pressure 
[Analytical methods] 
The analyses discussed below will be conducted with the FAS. 
Summary statistics (number of subjects, mean, standard deviation, maximum, minimum, and 
quartiles; hereinafter the same) and 2-sided 95% confidence intervals for mean values will be 
calculated for the office trough sitting systolic and diastolic blood pressure at each time point 
(including the end of the Treatment Period I and the end of the Treatment Period II; hereinafter the 
same). 


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Summary statistics and 2-sided 95% confidence intervals for mean values will be calculated 
referring to a 1-sample t-test for the change of office trough sitting systolic and diastolic blood 
pressure from the end of the Run-in Period (Week 0) to each time point during the Treatment 
Period. 
The proportion of subjects who achieve the target blood pressure at each time point during the 
Treatment Period will be summarized. 
(2) Data conversion methods and handling of missing data 
Details of data conversion methods and handling of missing data will be defined in the Handling 
Rule for Analysis and SAP. 
(3) Significant level and confidence coefficient 
Significant level: 5% (2-sided test) 
Confidence coefficient: 95% (2-sided estimates) 
13.1.4 
Pharmacokinetic Analysis 
Pharmacokinetic endpoints and analytical methods 
[Secondary endpoints] 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) 
[Analytical methods] 
The following analyses will be conducted with the subjects who have adequately measured plasma 
concentration of TAK-536 in the FAS. 
Concentration of TAK-536 and its metabolites (M-I and M-II) in plasma will be summarized at 
each time point. 
A population pharmacokinetic analysis will be conducted with the subjects who have adequately 
measured plasma concentration of TAK-536 in the FAS. Population pharmacokinetic parameters 
in pediatric patients with hypertension will be estimated and the effect of weight on the 
pharmacokinetics of TAK-536 will be assessed quantitatively. In addition, other factors which 
affect the pharmacokinetics of TAK-536 will be explored. When the above analyses are conducted, 
an integrated analysis will be also performed with the data of the prior pharmacological study in 
pediatric patients with hypertension (TAK-536/CPH-103) as needed, and a SAP and an analysis 
results will be provided separately from those of this study. 
13.1.5 
Safety Analysis 
[Primary endpoints] 
AEs, anthropometric (weight, height and BMI) measurements, laboratory tests, resting 12-lead 
ECG, and vital signs (office standing blood pressure, office sitting pulse rate, office standing pulse 
rate, and home sitting blood pressure) 


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[Analytical methods] 
The following analyses will be conducted with the safety analysis set. 
1) AEs (Treatment-emergent AEs) 
A treatment-emergent AE (TEAE) is defined as any AE occurring after the start of TAK-536 
administration of the Treatment Period. 
The incidence of TEAEs listed below will be analyzed. TEAEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). The frequency distribution will be provided 
using the system organ class (SOC) and preferred term (PT) using MedDRA as follows: 
• TEAEs 
• Drug-related TEAEs 
• Severity of TEAEs 
• Severity of drug-related TEAEs 
• TEAEs leading to study drug discontinuation 
• Serious TEAEs 
• TEAEs over time 
2) Anthropometric (weight, height and BMI) measurements, laboratory tests, resting 12-lead 
ECG, and vital signs (office standing blood pressure, office sitting pulse rate, office standing 
pulse rate, and home sitting blood pressure) 
For continuous variables, the observed values and the changes from the end of the Run-in Period 
(Week 0) will be summarized for each time point. In addition, individual figures of the observed 
values will be provided. 
For categorical values, shift tables of the data before and after administration will be provided. 
13.2 
Interim Analysis and Criteria for Early Termination 
At the time when the data of approximately 25 subjects are collected, the data until Week 12 in the 
Treatment Period will be analyzed. In addition, at the time when all subjects complete Week 24 in 
the Treatment Period, the data until Week 24 in the Treatment Period will be analyzed separately 
after being locked. These analyses will not intend to continue or discontinue this study. 
13.3 
Determination of Sample Size 
Total of 50 subjects (who enter the Treatment Period). 
[Justification for Determination of Sample Size] 
Total of 50 subjects to enter the Treatment Period was set in consideration of feasibility. 
Assuming the mean change of trough sitting diastolic blood pressure from the end of the Run-in 
Period (Week 0) to the end of the Treatment Period I of -6.5 mmHg and an SD of 10.5 mmHg, and 


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the mean change of trough sitting systolic blood pressure from the end of the Run-in Period 
(Week 0) to the end of the Treatment Period I of -9.5 mmHg and an SD of 15.5 mmHg, planned 50 
subjects will provide at least 90% power by a 1-sample t-test at the 0.05 significance level 
(2-sided). 


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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 eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and site guarantee access to source documents by the sponsor or its designee 
(CRO) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the Investigator’s Binder, study drug, subject medical records, 
informed consent documentation, and review of eCRFs and associated source documents. It is 
important that the investigator, subinvestigator 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 or subinvestigator can deviate and change from the protocol for any medically 
unavoidable reason, for example, to eliminate an immediate hazard to study subjects, without a 
prior written agreement with the sponsor or a prior approval from IRB. In the event of a deviation 
or change, the principal investigator should notify the sponsor and the head of the site of the 
deviation or change as well as its reason in a written form, and then retain a copy of the written 
form. When necessary, the principal investigator may consult and agree with the sponsor on a 
protocol amendment. If the protocol amendment is appropriate, the amendment proposal should be 
submitted to the head of the site as soon as possible and an approval from IRB should be obtained. 
The investigator or subinvestigator should document all protocol deviations. Significant protocol 
deviations will be entered into the eCRF, which is reviewed by the study sponsor or designee. 
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
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 Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency [MHRA], PMDA). If the study site is 
contacted for an inspection by a regulatory body, the sponsor should be notified immediately. The 
investigator and site 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 (i.e., 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 Approval 
IRBs 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. If any member of the IRB 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 for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent/assent 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 for approval. The IRB’s written approval of the protocol and 
subject informed consent/assent must be obtained and submitted to the sponsor or designee before 
commencement of the study (i.e., before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB approval must refer to the study by exact protocol title, number, and 
version date; identify versions of other documents (eg, informed consent/assent form) reviewed; 
and state the approval date. The sponsor will notify site once the sponsor has confirmed the 
adequacy of site regulatory documentation. Until the site receives notification no protocol 
activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent/assent 
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, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee. 
Subject/parent/legal guardian incentives should not exert undue influence for participation. 
Payments to subjects, the subjects’ parent, or the subjects’ legal guardian must be approved by the 
IRB and sponsor. 
15.2 
Subject Information, Informed Consent/Assent, 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. An assent document describes the study, using a language 
appropriate to the subject’s age and development, to potential subjects with enough mental 
capacity to understand what it means to participate in a clinical study, and is used to obtain the 


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subject’s assent (a pediatric subject’s consent, which is not a regulatory requirement) separately 
from the subject’s parent’s, or the subject’s legal guardian’s consent. The informed consent form 
describes 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 
further explains 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 approval of the informed 
consent and assent forms. The informed consent and assent forms must be approved by both of the 
IRB and sponsor prior to use. 
The subject assent form must be written in a language appropriate to the subject’s age and 
development to the prospective subject. The informed consent form must be written in a language 
fully comprehensible to a subject’s parent or the subjects’ legal guardian. It is the responsibility of 
the investigator or subinvestigator to explain the subject assent form to the subject using a 
language and terms comprehensible and to explain the detailed elements of the informed consent 
form to a subject. Information should be given in both oral and written form whenever possible 
and in the manner deemed appropriate by the IRB. 
The subject and the subject’s parent, or the subject’s legal guardian 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’s parent or the subject’s legal guardian determines the subject will 
participate in the study, then the informed consent form must be signed and dated by the subject’s 
parent or the subject’s legal guardian at the time of consent and prior to the subject entering into 
the study. 
Whenever possible, the subject’s own assent should be obtained in addition to the subject’s 
parent’s or the subject’s legal guardian’s consent. The subject’s assent will be preferably obtained 
in writing, if he/she is a junior high school student or of a higher age. Whenever a written assent is 
not provided, though preferable also for subjects aged below junior high school students, the 
subject’s oral assent must be documented in the informed consent form signed by the subject’s 
parent or the subject’s legal guardian. The subject’s parent or the subject’s legal guardian should 
be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. 
Once signed, the original informed consent form, and the subject assent form (if applicable, the 
same hereinafter) will be stored in the investigator’s site file. The investigator or subinvestigator 
must document and the dates the subject’s parent or the subject’s legal guardian signs the informed 
consent form and the date the subject signs the informed assent form in the subject’s medical 
record. Copies of the signed informed consent form and the signed subject assent form shall be 
given to the subject, the subject’s parent, or the subject’s legal guardian. 
All revised informed consent/assent forms must be reviewed and signed by relevant subjects, the 
relevant subject’s parent or the subject’s legal guardian in the same manner as the original 
informed consent/assent. The date the revised consent/assent was obtained should be recorded in 


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the subject’s medical record, and the subject, the subject’s parent, or legal guardian should receive 
a copy of the revised informed consent/assent 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 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, MHRA, PMDA), the sponsor’s designated auditors, and the 
appropriate IRBs 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 and the subject’s parent, or the subject’s legal guardian as part of the informed 
consent/assent (if deemed appropriate by the investigator or subinvestigator) process (see Section 
15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
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 and after 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 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. 
The investigator and subinvestigator need to obtain a prior written approval from the sponsor to 
publish any information from the study externally such as to a professional association. 
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 laws, regulations and guidance, Takeda will, at a minimum register 


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interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, 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 and subinvestigator have questions 
regarding this policy, he or she should contact the sponsor or sponsor’s designee. 


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16.0 
REFERENCES 
1. Uchiyama M, Sakai K. Studies of blood pressures in school children in northern Japan. Public 
Health. 1985;99:18-22. 
2. Tochikubo O, Sasaki O, Umemura S, Kaneko Y. Management of hypertension in high school 
students by using new salt titrator tape. J Hypertension. 1986;8:1164-71. 
3. Stabouli S, Kotsis V, Zakopoulos N. Ambulatory blood pressure monitoring and target organ 
damage in pediatrics. J Hypertens. 2007;25(10):1979-86. 
4. Lurbe E, Cifkova R, Cruickshank JK, Dillon MJ, Ferreira I, Invitti C, et al. Management of 
high blood pressure in children and adolescents: recommendations of the European Society of 
Hypertension. J Hypertens. 2009;27:1719-42. 
5. Bao W, Threefoot SA, Srinivasan SR, Berenson GS. Essential hypertension predicted by 
tracking of elevated blood pressure from childhood to adulthood: the Bogalusa Heart Study. 
Am J Hypertens. 1995;8:657-65. 
6. The Japanese Society of Hypertension Committee for Guidelines for the Management of 
Hypertension. The Japanese Society of Hypertension Guidelines for the Management of 
Hypertension (JSH 2014). Tokyo: The Japanese Society of Hypertension; 2014. 
7. The Japanese Circulation Society. The Guidelines for Drug Therapy in Pediatric Patients with 
Cardiovascular Diseases: V. Antihypertensive Drugs. In: The Guidelines for Diagnosis and 
Therapy of Cardiovascular Diseases (JCS 2012: The 2010-2011 Report of the Joint Working 
Group). 2013. [cited 2014 Sep]. 184 pages. Available from: 
http://www.j-circ.or.jp/guideline/index.htm. Accessed September 2014. 
8. The final report on the Guidelines for Clinical Evaluation of Antihypertensive Drugs in 
Children, a part of MHLW-commissioned research enterprise on the Guidelines for Clinical 
Evaluation of New Drugs for Pediatric Disease. 
9. Japanese Society of Nephrology. Evidence-based Clinical Practice Guideline for CKD 2013. 
Tokyo Igakusha; 2013. 
10. Principles for Clinical Evaluation of New Antihypertensive Drugs. (Notification No. 0128001 
of the Evaluation and Licensing Division, PFSB dated January 28, 2002) 
11. “The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for 
Long-Term Treatment of Non-Life-Threatening Conditions” (PAB/ELD Notification No. 592, 
Evaluation and Licensing Division, Pharmaceutical Affairs Bureau, Ministry of Health, 
Labour and Welfare; May 24, 1995). 
12. Partial Revision of the Guideline on Bioequivalence Studies of Generic Drugs: Pharmaceutical 
and Food Safety Bureau Notification No.0229-10, February 29, 2012. 
13. MHLW. The physical status survey: Part 2 of the National Health and Nutrition Survey 2011. 
2013. [cited 2014 Sep]. 46 pages. Available from: 
http://www.mhlw.go.jp/bunya/kenkou/eiyou/h23-houkoku.html. Accessed September 2014. 


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14. Uemura O, Nagai T, Ishikura K, Ito S, Hataya H, Gotoh Y, et al. Creatinine-based equation to 
estimate the glomerular filtration rate in Japanese children and adolescents with chronic 
kidney disease. Clin Exp Nephrol. 2014;18:626-33. 


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Appendix C Detailed Description of Amendments to Text 
This document describes changes in reference to Protocol Amendment 02. 
 
Page 51, Section 10.1.11 Action Taken with Study Treatment 
Existing Text: 
• Drug withdrawn – a study drug is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study drug. 
• Unknown – only to be used if it has not been possible to determine what action has been taken. 
• Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE, the AE that occurred before the study drug administration. 
• Drug Interrupted – the dose was interrupted due to the particular AE. 
Revised Text: 
• Drug withdrawn – a study drug is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study drug. 
• Unknown – only to be used if it has not been possible to determine what action has been taken. 
• Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE, the AE that occurred before the study drug administration. 
• Dose Reduced – the dose was reduced due to the particular AE. 
• Dose Increased – the dose was increased due to the particular AE. 
• Drug Interrupted – the dose was interrupted due to the particular AE. 
 
Rationale for Amendment: 
It was revised to collect the information accurately about the action taken with the study drug when 
AEs occurred. 
 


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Page 71, Appendix A Schedule of Study Procedures<Acceptable Time Windows for Study 
Procedures> 
Existing Text: 
Open Label Treatment 
Follow-up 
Week 32 
(Day 225) 
Week 40 
(Day 281) 
Week 52 
(Day 365) 
Early 
termination 
Week 54 
(Day 379) 
212 to 239 
268 to 295 
359 to 372 
(b) 
373 to 386 
Note: The first day of the study drug administration for the Treatment Period is counted as Day 1. (Day X) indicates the reference 
day of each time point. 
(a) 
Within 3 days after early termination for office sitting blood pressure, within 14 days after early termination for the other tests, 
observations, and evaluations (The day after the last study drug administration day is accounted as 1.). 
Revised Text: 
Open Label Treatment 
Follow-up 
Week 32 
(Day 225) 
Week 40 
(Day 281) 
Week 52 
(Day 365) 
Early 
termination 
Week 54 
(Week 52+14) 
212 to 239 
268 to 295 
352 to 372 
(b) 
±7 
Note: The first day of the study drug administration for the Treatment Period is counted as Day 1. (Day X) indicates the reference 
day of each time point. 
(b) 
Within 3 days after early termination for office sitting blood pressure, within 14 days after early termination for the other tests, 
observations, and evaluations (The day after the last study drug administration day is accounted as 1.). 
Rationale for Amendment: 
Correction of misdescription. 


PROTOCOL 
A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, Efficacy and 
Pharmacokinetics of TAK-536 in Pediatric Patients 6 to Less Than 16 Years of Age with 
Hypertension 
A Phase 3 Long-term Study of TAK-536 in Pediatric Patients 6 to Less Than 16 Years with 
Hypertension 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka, Japan
Study Number: 
TAK-536/OCT-101 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
TAK-536 
Date: 
12 May 2016 
Amendment Number: 01 
Amendment History: 
Date
Amendment Number
Region 
16 March 2016 
First version
All sites 
12 May 2016 
01
All sites 
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 AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
See the attachments. 
1.2 
Principles of Clinical Studies 
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 (ICH) E6 Good Clinical Practice (GCP):
Consolidated Guideline.
•
All applicable laws and regulations, including, without limitation, data privacy laws, clinical
trial disclosure laws, and regulations.
1.3 
Protocol Amendment 01 Summary of Changes 
The primary purpose of this amendment is to clarify examples of contraceptive methods. Some 
part are modified to clarify the contents. Detailed description of amendments are given in 
Appendix C.  


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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES ........................................................................................................................ 2 
1.1 
Contacts and Responsibilities of Study-Related Activities .......................................... 2 
1.2 
Principles of Clinical Studies ..................................................................................... 2 
1.3 
Protocol Amendment 01 Summary of Changes .......................................................... 2 
2.0 
STUDY SUMMARY ...................................................................................................... 7 
3.0 
LIST OF ABBREVIATIONS ........................................................................................ 12 
4.0 
INTRODUCTION ......................................................................................................... 14 
4.1 
Background ............................................................................................................. 14 
4.2 
Rationale for the Proposed Study ............................................................................. 15 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 16 
5.1 
Objectives ................................................................................................................ 16 
5.1.1 
Primary Objective .............................................................................................. 16 
5.1.2 
Secondary Objectives ......................................................................................... 16 
5.2 
Endpoints................................................................................................................. 16 
5.2.1 
Primary Endpoints ............................................................................................. 16 
5.2.2 
Secondary Endpoints .......................................................................................... 16 
6.0 
STUDY DESIGN AND DESCRIPTION ....................................................................... 18 
6.1 
Study Design ........................................................................................................... 18 
6.2 
Justification for Study Design, Dose, Regimen, and Endpoints ................................ 20 
6.3 
Premature Termination or Suspension of Study or Study Site ................................... 23 
6.3.1 
Criteria for Premature Termination or Suspension of the Study .......................... 23 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites ....................... 23 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites ................................................................................ 23 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS .............. 24 
7.1 
Inclusion Criteria ..................................................................................................... 24 
7.2 
Exclusion Criteria .................................................................................................... 25 
7.3 
Excluded Medications and Treatments ..................................................................... 27 
7.3.1 
Excluded Medications ........................................................................................ 27 
7.3.2 
Medications Permitted with Conditions .............................................................. 28 
7.4 
Diet, Fluid, and Activity Control .............................................................................. 29 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject ........................................... 31 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject...................................... 32 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT ...................................................... 33 


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8.1 
Study Drug and Materials ........................................................................................ 33 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ..................................... 33 
8.1.1.1 Study Drug ................................................................................................... 33 
8.1.2 
Storage ............................................................................................................... 34 
8.1.3 
Dose and Regimen ............................................................................................. 34 
8.1.4 
Overdose ............................................................................................................ 35 
8.2 
Study Drug Dispensing Procedures .......................................................................... 35 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs ..................................... 35 
9.0 
STUDY PLAN .............................................................................................................. 36 
9.1 
Study Procedures ..................................................................................................... 36 
9.1.1 
Informed Consent Procedure .............................................................................. 36 
9.1.2 
Demographics, Medical History, and Medication History Procedure .................. 36 
9.1.3 
Physical Examination Procedure ........................................................................ 36 
9.1.4 
Weight, Height, and BMI ................................................................................... 36 
9.1.5 
Vital Sign Procedure .......................................................................................... 37 
9.1.6 
Measuring Home Blood Pressure ....................................................................... 38 
9.1.7 
Documentation of Concomitant Medications ...................................................... 39 
9.1.8 
Documentation of Concurrent Medical Conditions ............................................. 39 
9.1.9 
Procedures for Clinical Laboratory Samples ....................................................... 39 
9.1.10 Contraception and Pregnancy Avoidance Procedure ........................................... 41 
9.1.11 Pregnancy .......................................................................................................... 42 
9.1.12 ECG Procedure .................................................................................................. 42 
9.1.13 Pharmacokinetic Sample Collection ................................................................... 42 
9.1.13.1 
Collection of Plasma for Pharmacokinetic Sampling ............................... 43 
9.1.13.2 
Bioanalytical Method ............................................................................. 43 
9.1.14 Documentation of Subjects Failure ..................................................................... 43 
9.1.15 Documentation of Study Entrance ...................................................................... 44 
9.2 
Monitoring Subject Treatment Compliance .............................................................. 44 
9.3 
Schedule of Observations and Procedures ................................................................ 44 
9.3.1 
Screening ........................................................................................................... 44 
9.3.2 
Start of the Run-in Period (Week -2) .................................................................. 44 
9.3.3 
End of the Run-in Period (Week 0) .................................................................... 45 
9.3.4 
Treatment Period (Weeks 2, 4, 8, 12, 16, 20, 24, 32, and 40) .............................. 45 
9.3.5 
Final Visit or Early Termination ......................................................................... 45 
9.3.6 
Follow-up Period: Week 54................................................................................ 46 
9.3.7 
Post Study Care .................................................................................................. 46 


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10.0 
ADVERSE EVENTS .................................................................................................... 47 
10.1 
Definitions ............................................................................................................... 47 
10.1.1 AEs .................................................................................................................... 47 
10.1.2 Additional Points to Consider for AEs................................................................ 47 
10.1.3 SAEs .................................................................................................................. 49 
10.1.4 AEs of Special Interest ....................................................................................... 50 
10.1.5 Severity of AEs .................................................................................................. 50 
10.1.6 Causality of AEs to Study Drugs ........................................................................ 50 
10.1.7 Causality of AEs to Study Procedures ................................................................ 51 
10.1.8 Start Date ........................................................................................................... 51 
10.1.9 End Date ............................................................................................................ 51 
10.1.10 
Pattern of Adverse Event .............................................................................. 51 
10.1.11 
Action Taken with Study Treatment ............................................................. 51 
10.1.12 
Outcome....................................................................................................... 51 
10.2 
Procedures ............................................................................................................... 52 
10.2.1 Collection and Reporting of AEs ........................................................................ 52 
10.2.1.1 
AE Collection Period .............................................................................. 52 
10.2.1.2 
AE Reporting ......................................................................................... 52 
10.2.1.3 
AEs of Special Interest Reporting ........................................................... 53 
10.2.2 Collection and Reporting of SAEs ...................................................................... 53 
10.2.3 Reporting of Abnormal Liver Function Tests ..................................................... 54 
10.3 
Follow-up of SAEs .................................................................................................. 54 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities .................. 54 
11.0 
STUDY-SPECIFIC COMMITTEES ............................................................................. 55 
12.0 
DATA HANDLING AND RECORDKEEPING ............................................................ 56 
12.1 
CRFs (Electronic) .................................................................................................... 56 
12.2 
Record Retention ..................................................................................................... 56 
13.0 
STATISTICAL METHODS .......................................................................................... 58 
13.1 
Statistical and Analytical Plans ................................................................................ 58 
13.1.1 Analysis Sets...................................................................................................... 58 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ........................... 58 
13.1.3 Efficacy Analysis ............................................................................................... 58 
13.1.4 Pharmacokinetic Analysis .................................................................................. 59 
13.1.5 Safety Analysis .................................................................................................. 59 
13.2 
Interim Analysis and Criteria for Early Termination ................................................ 60 
13.3 
Determination of Sample Size .................................................................................. 60 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE............................................... 62 
14.1 
Study-Site Monitoring Visits ................................................................................... 62 
14.2 
Protocol Deviations.................................................................................................. 62 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................ 62 
15.0 
ETHICAL ASPECTS OF THE STUDY ........................................................................ 63 
15.1 
IRB Approval .......................................................................................................... 63 
15.2 
Subject Information, Informed Consent/Assent, and Subject Authorization .............. 63 
15.3 
Subject Confidentiality ............................................................................................ 65 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ................................. 65 
15.4.1 Publication and Disclosure ................................................................................. 65 
15.4.2 Clinical Trial Registration .................................................................................. 65 
15.4.3 Clinical Trial Results Disclosure ........................................................................ 66 
15.5 
Insurance and Compensation for Injury .................................................................... 66 
16.0 
REFERENCES .............................................................................................................. 67 
LIST OF IN-TEXT TABLES 
Table 5.a 
Reference Blood Pressure Values of Children by Gender and Age ..................... 17 
Table 9.a 
Clinical Laboratory Tests ................................................................................... 40 
Table 10.a 
Takeda Medically Significant AE List ................................................................ 50 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ................................................................................ 20 
LIST OF APPENDICES 
Appendix C 
Detailed Description of Amendments to Text ..................................................... 73 
CCI


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2.0 
STUDY SUMMARY 
Clinical Study Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound:
TAK-536 
Study Title: A Phase 3, Open-label, Multicenter, 
Long-term Study to Evaluate the Safety, Efficacy and 
Pharmacokinetics of TAK-536 in Pediatric Patients 6 to 
Less Than 16 Years of Age with Hypertension 
IND No.: 
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Identifier: TAK-536/OCT-101 
Phase: 3
Study Design: 
This is a phase 3, open-label, multicenter study to evaluate the safety, efficacy, and pharmacokinetics of long-term 
administration of TAK-536 once daily for 52 weeks in pediatric patients aged 6 to less than 16 years with 
hypertension. The study consists of a 2-week Run-in Period, a 52-week Treatment Period (Treatment Period I, 
12-week; Treatment Period II, 40-week), and a 2-week Follow-up Period (56 weeks in total).
Subjects eligible at screening will initiate to receive the placebo in a single-blinded fashion at the start of the Run-in 
Period. 
The duration of the Run-in Period will be 2 weeks. The subjects whose blood pressures meet the inclusion criteria 1 
week (at earliest) after receiving placebo in the Run-in Period can enter the Treatment Period. For the subjects only 
who treated with any antihypertensive drugs as a prior treatment, the Run-in Period could be extended up to 4 weeks if 
blood pressures do not meet the inclusion criteria. Subjects who treated with renin-angiotensin-system (RAS) 
inhibitors (ACE inhibitors, ARB, and DRI) until the start of the Run-in Period should discontinue them at the start of 
the Run-in Period. Subjects who treated with antihypertensive drugs other than RAS inhibitors until the start of the 
Run-in Period can continue to receive a single antihypertensive drug in addition to the study drug if the subjects are 
considered to need the additional treatments for hypertension in the Treatment Period I by the investigator or 
subinvestigator; the antihypertensive drug should be administered under the same dosage at the time of the start of the 
Run-in Period. If subjects have difficulty in discontinuing antihypertensive drugs completely at the start of the Run-in 
Period, the antihypertensive drugs can be down-titrated concurrently with administration of placebo. In the case of the 
down-titration, antihypertensive drugs should be discontinued at least 1 week (7 days) before the start of the Treatment 
Period I. Especially, beta-blockers (BBs) should be tapered off gradually since sudden discontinuation of BBS may 
cause withdrawal syndrome. 
In the Treatment Period I (Week 0 to 12), initial dose of TAK-536 will be 2.5 mg for the subjects weighing < 50 kg or 
5 mg for the subjects weighing ≥ 50 kg. After the initial dose, TAK-536 will be titrated to 5 mg, 10 mg, and 20 mg for 
the subjects weighing < 50 kg or to 10 mg, 20 mg, and 40 mg for the subjects weighing ≥ 50 kg when the subjects do 
not achieve the target blood pressure and there are no concerns in tolerability. TAK-536 will be titrated at any 
scheduled visit of Week 2, 4, or 8 in the Treatment Period I. Between the visits of Week 4 and 8 during the Treatment 
Period I, an additional unscheduled visit of Week 6 may be requested at the investigator’s discretion in order to titrate 
the dose of the study drug in the subjects when the further decrease in blood pressure is needed. TAK-536 can be 
reduced at the investigator’s or subinvestigator’s discretion if there are any concerns in tolerability with titration of 
TAK-536 (i.e., in case of occurring any AEs caused by titration of TAK-536). During the Treatment Period I, change 
in the dosage of the antihypertensive drug is prohibited in the subjects who treated with a single antihypertensive drug 
other than RAS inhibitors at the start of the Treatment Period I. 
During the Treatment Period II (Week 12 to 52), the treatments at the end of the Treatment Period I will be continued. 
TAK-536 can be titrated to the highest dose (20 mg for the subjects weighing < 50 kg or 40 mg for the subjects 
weighing ≥ 50 kg, the same hereinafter) at the investigator’s or subinvestigator’s discretion when the subjects do not 
achieve the target blood pressure and no concerns are found in tolerability. When the subjects do not achieve the target 
blood pressure with the highest dose of TAK-536, the subjects can receive additional antihypertensive drugs (other 
than RAS inhibitors) or can change in dose of the antihypertensive drug in addition to TAK-536. When the 
antihypertensive drugs are required dose reduction or interruption because of the concerns in tolerability with titration 
(i.e., excessive reduction in blood pressure, other AE, etc.) in the Treatment Period II, the antihypertensive drugs other 
than TAK-536 (in case of concomitant use) should be reduced or interrupted first. Thereafter, dose reduction or 


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interruption of TAK-536 should be considered.
Follow-up Period will be 2 weeks from the next day of the final dose of TAK-536. Safety will be evaluated at Week 54 
after the start of the Treatment Period. At the time when the data from approximately 25 subjects are collected, the data 
until Week 12 in the Treatment Period will be analyzed. In addition, at the time when all subjects complete Week 24 in 
the Treatment Period, the data until Week 24 in the Treatment Period will be analyzed separately after being locked. 
These analyses will not intend to continue or discontinue this study. 
Primary Objectives: 
To evaluate the safety of administration of TAK-536 in pediatric patients aged 6 to less than 16 years with 
hypertension 
Secondary Objectives: 
To evaluate the efficacy and pharmacokinetics of administration of TAK-536 in pediatric patients aged 6 to less than 
16 years with hypertension 
Subject Population: Pediatric patients aged 6 to less than 16 years, with essential or secondary hypertension.
Planned Number of Subjects: 
Total of 50 subjects (who enter the Treatment Period). 
Planned Number of Sites:
Approximately 25 sites 
Dose Level(s): 
Regimen: Subjects will orally receive the study drug once 
daily before or after breakfast. 
Dose: Placebo during the Run-in Period. Any of 
TAK-536 2.5 mg, 5 mg, 10 mg, 20 mg tablet for the 
subjects weighing < 50 kg, or any of TAK-536 5 mg, 
10 mg, 20 mg, 40 mg tablet for those weighing ≥ 50 kg 
during the Treatment Period. 
Route of Administration:
Oral 
Duration of Treatment: 
52 weeks 
Study Length:
2 weeks of the Run-in Period (acceptable range, 1 to 4 
weeks), 52 weeks of the Treatment Period (12 weeks of 
the Treatment Period I and 40 weeks of the Treatment 
Period II), 2 weeks of the Follow-up Period 


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Main Criteria for Inclusion: 
•
The Japanese subject who has a diagnosis of hypertension. A subject is eligible if he/she is deemed hypertensive
according to the reference blood pressure values of children by gender and age; office sitting diastolic or systolic
blood pressure ≥ 95 percentile for essential hypertension without concomitant hypertensive organ damage, and
≥ 90 percentile for secondary hypertension with concomitant chronic kidney disease (CKD), diabetes mellitus,
heart failure or any hypertensive organ damage.
In addition, subjects need to meet the following criteria:
(1) If currently treated with any antihypertensive drugs at the start of the Run-in Period: Subject has a
documented historical diagnosis of hypertension and an office sitting diastolic or systolic blood pressure meeting 
the above criteria at the end of the Run-in Period (Week 0).
(2) If currently untreated with any antihypertensive drugs at the start of the Run-in Period: Subject who meets the 
above criteria on 3 separate time points including screening and the end of the Run-in Period (Week 0). In
addition, subject with essential hypertension without concomitant hypertensive organ damage still maintains
hypertension with non-pharmacotherapy including foods or exercises for at least 3 months within 1 year prior to
the start of screening.
•
The subject is male or female and aged 6 to less than 16 years at the time of informed consent.
•
The subject weighs at least 20 kg at screening.
•
A subject who has undergone kidney transplantation is eligible if he/she underwent the transplantation at least 6
months earlier at screening, and the graft has been functionally stable (estimated glomerular filtration rate
[eGFR] ≥ 30 mL/min/1.73 m2) for at least 6 months with evidence (e.g., Doppler echography, CT scan
[computed tomography] or MRI [magnetic resonance imaging]) excluding grafted kidney arterial stenosis. A
subject on immunosuppressive therapy with a stable dose at least 30 days prior to screening is eligible.
Main Criteria for Exclusion: 
•
The subject has poorly controlled hypertension indicated by an office sitting systolic blood pressure higher by at
least 15 mmHg and/or an office sitting diastolic blood pressure higher by at least 10 mmHg than the 99
percentiles of the reference blood pressure values of children by gender and age.
•
The subject has a diagnosis of malignant or accelerated hypertension.
•
The subject was noncompliant (< 70% or > 130%) with the study drug during the Run-in Period.
•
The subject has severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2), is
receiving dialysis, has a renovascular disease affecting one or both kidneys, severe nephrotic syndrome not in
remission, or a serum albumin level < 2.5 g/dL.
•
The subject has a history of, or the signs/symptoms of serious cardiovascular, hepatobiliary, gastrointestinal,
endocrine (eg, hyperthyroidism, Cushing’s syndrome), hematological, immunological, urinogenital, psychiatric
disease, cancer, or any other disease that adversely affects subject’s health, or, in the opinion of the investigator
or subinvestigator, potentially confounds the study results.
•
The subject has hemodynamically significant left ventricular outflow obstruction due to aortic stenosis or aortic
valvular disease, or is scheduled to undergo a medical procedure affecting blood pressure during the study (eg,
correction of arterial anomaly).
•
The subject has a history of or concurrent clinically significant abnormality of 12-lead electrocardiogram (ECG)
that, in the opinion of the investigator or subinvestigator, disqualifies the subject for participation in the study.
•
The subject has poorly controlled diabetes mellitus indicated by HbA1c > 9.0% at screening.
•
The subject has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥ 2.5 × the upper
limit of normal (ULN), or a total bilirubin level ≥ 1.5 × ULN at screening, severely impaired hepatic function,
any active liver disease, or jaundice.
•
The subject has hyperkalemia exceeding ULN at screening.


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Main Criteria for Evaluation and Analyses:
(1) Primary Endpoint
<Safety>
Adverse events (AEs), anthropometric (weight, height and body mass index [BMI]) measurements, laboratory tests, 
resting 12-lead ECG, and vital signs (office standing blood pressure, office sitting pulse rate, office standing pulse 
rate, and home sitting blood pressure) 
(2) Secondary endpoints
<Efficacy>
•
Office trough sitting systolic and diastolic blood pressure
•
Proportion of subjects who achieve the target blood pressure*
*: < 95 percentile shown in a table of the reference blood pressure values of children by gender and age for essential 
hypertension, < 90 percentile shown in the same table for secondary hypertension  
<Pharmacokinetic endpoints> 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) 
Statistical Considerations: 
<Primary endpoints and analytical methods> 
[Primary endpoints] 
AEs, anthropometric (weight, height and BMI) measurements, laboratory tests, resting 12-lead ECG, and vital signs 
(office standing blood pressure, office sitting pulse rate, office standing pulse rate, and home sitting blood pressure)
[Analytical methods] 
The following analyses will be conducted with the safety analysis set. 
(1) AEs (Treatment-emergent AEs)
A treatment-emergent AE (TEAE) is defined as any AE occurring after the start of TAK-536 administration of the 
Treatment Period. 
The incidence of TEAEs listed below will be analyzed. TEAEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). The frequency distribution will be provided using the system organ class (SOC) 
and preferred term (PT) using MedDRA as follows: 
•
TEAEs
•
Drug-related TEAEs
•
Severity of TEAEs
•
Severity of drug-related TEAEs
•
TEAEs leading to study drug discontinuation
•
Serious TEAEs
•
TEAEs overt time
(2) Anthropometric (weight, height and BMI) measurements, laboratory tests, resting 12-lead ECG, and vital signs
(office standing blood pressure, office sitting pulse rate, office standing pulse rate, and home sitting blood pressure)
For continuous variables, the observed values, and the changes from the end of the Run-in Period (Week 0) will be 
summarized for each time point. In addition, individual figures of the observed values will be provided. 
For categorical values, shift tables of the data before and after administration will be provided. 


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Sample Size Justification: 
Total of 50 subjects to enter the Treatment Period was set in consideration of feasibility. 
Assuming the mean change of trough sitting diastolic blood pressure from the end of the Run-in Period (Week 0) to 
the end of the Treatment Period I of -6.5 mmHg and an SD of 10.5 mmHg, and the mean change of trough sitting 
systolic blood pressure from the end of the Run-in Period (Week 0) to the end of the Treatment Period I of -9.5 mmHg 
and an SD of 15.5 mmHg, planned 50 subjects will provide at least 90% power by a 1-sample t-test at the 0.05 
significance level (2-sided). 


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3.0 
LIST OF ABBREVIATIONS 
ACE
angiotensin-converting enzyme
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ARB 
angiotensin II receptor blocker
AST
aspartate aminotransferase
BBs 
beta-blockers 
BMI 
body mass index
BUN 
blood urea nitrogen
CKD 
chronic kidney disease
CRO
contract research organization
CT
computed tomography
DRI
direct renin inhibitor
ECG
electrocardiogram
eCRF 
electronic case report form
eGFR 
estimated glomerular filtration rate
FAS 
full analysis set 
FDA 
Food and Drug Administration
GCP 
Good Clinical Practice
eGFR 
estimated glomerular filtration rate
GGT 
Gamma glutamyl transferase
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HPLC/MS/MS
high-performance liquid chromatography with tandem mass spectrometry 
Ht
height
ICH 
International Conference on Harmonisation
INR 
international normalized ratio
IRB
institutional review board
JCS 2012 
Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular Diseases by the 
Japanese Circulation Society 
JSH 2014 
Guidelines for the Management of Hypertension 2014
LDH
lactate dehydrogenase
LFT 
Liver Function Test
MedDRA 
Medical Dictionary for Regulatory Activities
MHRA 
Medicines and Healthcare products Regulatory Agency
MRI
magnetic resonance imaging
NSAIDs 
non-steroidal anti-inflammatory drugs
OTC
over-the-counter
PMDA 
Pharmaceuticals and Medical Devices Agency
PT 
preferred term 
PTP 
press through package


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QOL
quality of life 
RAS
renin-angiotensin-system
RBC 
red blood cell 
SAE
serious AE
SAP
statistical analysis plan
SOC 
system organ class
SUSARs 
suspected unexpected serious adverse reactions
TEAE 
treatment emergent AE
TPC 
Takeda Pharmaceutical Company Limited
ULN 
upper limit of normal
WBC 
white blood cell
WHO 
World Health Organization


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4.0 
INTRODUCTION 
4.1 
Background 
Hypertension develops in not only in adults but also in children and adolescents. While there are 
few epidemiological reports about the number of pediatric patients with hypertension in Japan, it is 
reported that hypertension is detected in 0.1% to 1% among elementary-school and 
junior-high-school students and in approximately 3% among high-school students in health 
checkups for Japanese children [1, 2]. According to the 2013 Population Projection, the number of 
pediatric patients with hypertension is estimated to be approximately 11 million in 
elementary-school and junior-high-school students (6 to 15 years) and approximately 3.6 million 
in high-school students (16 to 18 years). Therefore, on the basis of the morbidity rate of 
hypertension in health checkups above, the number of pediatric patients with hypertension is 
estimated to be 100 to 200 thousand (10 to 110 thousand in elementary-school and 
junior-high-school students and 110 thousand in high-school students). 
Pediatric hypertension is classified into essential hypertension and secondary hypertension as 
described for adults. Although essential hypertension in children is generally mild, such patients 
are at a high risk of cardiovascular disease including left ventricular hypertrophy and carotid 
intima-media wall thickening as well as organ damage, eg, renal dysfunction [3, 4]. Furthermore, 
essential hypertension in children can track into adult essential hypertension with patients’ growth 
[5]. The possibility of secondary hypertension, in contrast, increases with a younger age and the 
majority cases are severe. Hypertension caused by renal diseases (renal hypertension) accounts for 
60% to 80% of children with secondary hypertension, and chronic renal failure requires particular 
attention. Therefore, it is necessary to prevent deterioration of renal function and progression of 
organ damage. 
Moreover, hypertension persisting from childhood is likely to cause cardiovascular diseases and 
organ damage including renal dysfunction, thereby markedly affecting the patient’s quality of life 
(QOL) and prognosis not only in childhood but also in future. Therefore, it is highly important to 
manage blood pressure in the early stage. 
The Japanese Society of Hypertension Guidelines for the Management of Hypertension 2014 (JSH 
2014) [6] recommends that drug therapy should be considered after non-pharmacological 
interventions (dietary and exercise therapy) are primarily performed since essential hypertension 
in children is often mild. For patients with secondary hypertension and patients with target organ 
damage, diabetes mellitus, or chronic kidney disease (CKD), drug therapy is highly recommended 
to prevent the development and progression of organ damage. 
JSH 2014 [6] and the Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular 
Diseases by the Japanese Circulation Society (JCS 2012) [7] recommend angiotensin II receptor 
blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers 
as the first-choice drugs for pediatric patients. In particular, more strict blood pressure 
management is recommended for hypertension with CKD or diabetes mellitus than that for 
hypertension without complications. Hypertension with such complications is recommended to be 
treated with ARBs having antiproteinuric effects and inhibitory effects of CKD progression in 
addition to ACE inhibitors. 


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While a number of antihypertensive drugs for adults are available in Japan, only 4 drugs are 
indicated for hypertension in children, valsartan being the only ARB among them. Therefore, the 
treatment options for pediatric patients with hypertension are not sufficient. 
TAK-536 (azilsartan) is a novel ARB produced by Takeda Pharmaceutical Company Limited 
(TPC) and was approved for the treatment of adult hypertension under the product name of Azilva 
tablets 20 mg and 40 mg in January 2012. A supplementary new drug application was filed for the 
additional registration of Azilva tablet 10 mg, which was approved in March 2014. TAK-536 is 
superior to the existing ARBs (candesartan) in the antihypertensive effect as well as its persistence , 
while being safe and well tolerated. It is now widely used by adult patients with hypertension. 
Thus, to resolve the unmet needs in the present treatment of pediatric hypertension, it is important 
to provide TAK-536 for pediatric patients with hypertension, whose clinical usefulness for adult 
patients is established. 
Findings from a Clinical Study of TAK-536 
Upon the development of TAK-536 as an antihypertensive drug for pediatric patients with 
hypertension, single-dose study (TAK-536/CPH-103) was conducted to evaluate the 
pharmacokinetics and safety of TAK-536 in 6 pediatric patients aged 6 to less than 16 years with 
hypertension. The dose of TAK-536 was 5 mg for subjects weighing less than 50 kg, and 10 mg 
for those weighing at least 50 kg. 
TAK-536 was rapidly absorbed after a single oral administration of a TAK-536 5 mg tablet or 
10 mg tablet and was detectable in the plasma of all subjects at 1 hour after administration. The 
mean Cmax of TAK-536 was 888.3 ng/mL in the 5 mg group and 831.3 ng/mL in the 10 mg group, 
and the mean AUC(0-inf) of TAK-536 was 6635.7 ng·hr/mL and 7433.3 ng·hr/mL, respectively. 
Only 1 subject who received a TAK-536 5 mg tablet experienced a TEAE (gastroenteritis), which 
was mild in intensity and considered to be unrelated to the study drug. The outcome of 
gastroenteritis was “recovered/resolved.” No safety concerns were found in the study, and 
TAK-536 was well tolerated. 
4.2 
Rationale for the Proposed Study 
TAK-536 is developed to be approved for the pediatric patients aged 1 to less than 16 years with 
hypertension. In the field of the pediatrics, the efficacy and safety should be evaluated in 
schoolchildren (6 to 16 years) first, and thereafter, the efficacy and safety should be evaluated in 
the lower aged pediatric patients [8]. Since no clinical studies have been conducted to evaluate 
safety and efficacy of TAK-536 in pediatric patients with hypertension, this study is planned to 
evaluate the safety, efficacy, and pharmacokinetics of long-term administration of TAK-536 in 
pediatric patients with hypertension aged 6 to less than 16 years before evaluating those in 
pediatric patients with hypertension aged 1 to less than 6 years. 
 
CONFIDENTIAL 
CCI


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
To evaluate the safety of administration of TAK-536 in pediatric patients aged 6 to less than 16 
years with hypertension 
5.1.2 
Secondary Objectives 
To evaluate the efficacy and pharmacokinetics of administration of TAK-536 in pediatric patients 
aged 6 to less than 16 years with hypertension 
5.2 
Endpoints 
5.2.1 
Primary Endpoints 
Safety: 
AEs, anthropometric (weight, height, and body mass index [BMI]) measurements, laboratory tests, 
resting 12-lead electrocardiogram (ECG), and vital signs (office standing blood pressure, office 
sitting pulse rate, office standing pulse rate, and home sitting blood pressure) 
5.2.2 
Secondary Endpoints 
Efficacy: 
•
Office trough* sitting diastolic and systolic blood pressure
*The time point immediately before the next dosing, when the blood drug concentration is assumed to be lowest
•
Proportion of subjects who achieve the target blood pressure**
** < 95 percentile shown in Table 5.a for essential hypertension
< 90 percentile shown in Table 5.a for secondary hypertension 


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Table 5.a 
Reference Blood Pressure Values of Children by Gender and Age 
Age
Boy
Girl 
(years)
90th
95th
99th
90th
95th
99th
6
110/70
114/74
121/82
108/70
111/74
119/81
7
111/72
115/76
122/84
109/71
113/75
120/82
8
112/73
116/78
123/86
111/72
115/76
122/83
9
114/75
118/79
125/87
113/73
117/77
124/84
10
115/75
119/80
127/88
115/74
119/78
126/86
11
117/76
121/80
129/88
117/75
121/79
128/87
12
120/76
123/81
131/89
119/76
123/80
130/88
13
122/77
126/81
133/89
121/77
124/81
132/89
14
125/78
128/82
136/90
122/78
126/82
133/90
15
127/79
131/83
138/91
123/79
127/83
134/91
16
130/80
134/84
141/92
124/80
128/84
135/91
Systolic/diastolic blood pressures (mmHg, JCS2012 [7]) 
The 90th, 95th, and 99th indicate 90, 95, and 99 percentile, respectively. 
Pharmacokinetics: 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a Phase 3, open-label, multicenter study to evaluate the safety, efficacy, and 
pharmacokinetics of long-term administration of TAK-536 once daily for 52 weeks in pediatric 
patients aged 6 to less than 16 years with hypertension. 
The study consists of a 2-week Run-in Period, a 52-week Treatment Period (Treatment Period I, 
12-week; Treatment Period II, 40-week), and a 2-week Follow-up Period (56 weeks in total).
(1) Screening and Run-in Period
Subjects eligible at screening will initiate to receive the placebo in a single-blinded fashion at the 
start of the Run-in Period. 
The duration of the Run-in Period will be 2 weeks. The subjects whose blood pressures meet the 
inclusion criteria 1 week (at earliest) after receiving placebo in the Run-in Period can enter the 
Treatment Period. For the subjects only who treated with any antihypertensive drugs as a prior 
treatment, the Run-in Period could be extended up to 4 weeks if blood pressures do not meet the 
inclusion criteria. 
Subjects who treated with renin-angiotensin-system (RAS) inhibitors (ACE inhibitors, ARB, and 
DRI) until the start of the Run-in Period should discontinue them at the start of the Run-in Period. 
Subjects who treated with antihypertensive drugs other than RAS inhibitors until the start of the 
Run-in Period can continue to receive a single antihypertensive drug in addition to the study drug 
if the subjects are considered to need the additional treatment for hypertension in the Treatment 
Period I by the investigator or subinvestigator; the antihypertensive drug should be administered 
under the same dosage at the time of the start of the Run-in Period. If subjects have difficulty in 
discontinuing antihypertensive drugs completely at the start of the Run-in Period, the 
antihypertensive drugs can be down-titrated concurrently with administration of placebo. In the 
case of the down-titration, antihypertensive drugs should be discontinued at least 1 week (7 days) 
before the start of the Treatment Period I. Especially, beta-blockers (BBs) should be tapered off 
gradually since sudden discontinuation of BBs may cause withdrawal syndrome. 
(2) Treatment Period I
In the Treatment Period I (Week 0 to 12), initial dose of TAK-536 will be 2.5 mg for the subjects 
weighing < 50 kg or 5 mg for the subjects weighing ≥ 50 kg. After the initial dose, TAK-536 will 
be titrated to 5 mg, 10 mg, and 20 mg for the subjects weighing < 50 kg or to 10 mg, 20 mg, and 
40 mg for the subjects weighing ≥ 50 kg when the subjects do not achieve the target blood 
pressure* and no concerns are found in tolerability. TAK-536 will be titrated at any scheduled visit 
of Week 2, 4, or 8 in the Treatment Period I. Between the visits of Week 4 and 8 during the 
Treatment Period I, an additional unscheduled visit of Week 6 may be requested at the 
investigator’s or subinvestigator’s discretion in order to titrate the dose of the study drug in the 
subjects when the further decrease in blood pressure is needed. TAK-536 can be reduced at the 
investigator’s or subinvestigator’s discretion if there are any concerns in tolerability with titration 
of TAK-536 (i.e., in case of occurring any AEs caused by titration of TAK-536). During the 


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Treatment Period I, change in the dosage of the antihypertensive drug is prohibited in the subjects 
who treated with a single antihypertensive drug other than RAS inhibitors at the start of the 
Treatment Period I. 
* target blood pressure:
< 95 percentile shown in Table 5.a for essential hypertension, < 90 percentile shown in Table 5.a for secondary 
hypertension 
(3) Treatment Period II
During the Treatment Period II (Week 12 to 52), the treatments at the end of the Treatment Period 
I will be continued. TAK-536 can be titrated to the highest dose (20 mg for the subjects weighing 
< 50 kg or 40 mg for the subjects weighing ≥ 50 kg, the same hereinafter) at the investigator’s or 
subinvestigator’s discretion when the subjects do not achieve the target blood pressure and no 
concerns are found in tolerability. When the subjects do not achieve the target blood pressure with 
the highest dose of TAK-536, the subjects can receive additional antihypertensive drugs (other 
than RAS inhibitors) or can change in dose of the antihypertensive drug in addition to TAK-536 at 
the investigator’s or subinvestigator’s discretion. 
When the antihypertensive drugs are required dose reduction or interruption because of the 
concerns in tolerability with titration (i.e., excessive reduction in blood pressure, other AE, etc.) in 
the Treatment Period II, the antihypertensive drugs other than TAK-536 (in case of concomitant 
use) should be reduced or interrupted first. Thereafter, dose reduction or interruption of TAK-536 
should be considered. 
(4) Follow-up Period
Follow-up Period will be 2 weeks from the next day of the final dose of TAK-536. Safety will be 
evaluated at Week 54 after the start of the Treatment Period. 
At the time when the data from approximately 25 subjects are collected, the data until Week 12 in 
the Treatment Period will be analyzed. In addition, at the time when all subjects complete Week 24 
in the Treatment Period, the data until Week 24 in the Treatment Period will be analyzed 
separately after being locked. These analyses will not intend to continue or discontinue this study. 
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A. 


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Figure 6.a 
Schematic of Study Design 
Run-in 
Period 1),2) 
Treatment Period I* 
Treatment Period II 
Follow-up
Period 
20 mg (< 50 kg) or 40 mg (≥ 50 kg) 3),4) 
10 mg (< 50 kg) or 20 mg (≥50 kg) 3),4) 
5 mg (< 50 kg) or 10 mg (≥ 50 kg) 3),4) 
Placebo 
2.5 mg (< 50 kg) or 5 mg(≥ 50 kg) 3) 
-2W
0W
2W
4W
8W
12W
52W
54W
Concomitan
t use of 
antihyperten
sive drugs. 
RAS inhibitors are prohibited. 
Subjects who treated with antihypertensive drugs other than RAS inhibitors until the start of 
the Run-in Period can continue to receive a single antihypertensive drug in addition to the 
study drug (Change in the dosage of the antihypertensive drug is prohibited.）2),5) 
Subjects can receive antihypertensive 
drugs (other than RAS inhibitors) or 
can change the dosage of the 
antihypertensive drug in addition to 
TAK-536.6) 
1) The subjects whose blood pressures meet the inclusion criteria 1 (at earliest) week after receiving placebo in the Run-in Period can enter the Treatment Period. For the
subjects only who treated with any antihypertensive drugs as a prior treatment only, the Run-in Period could be extended up to 4 weeks if blood pressures do not meet
the inclusion criteria. 
2) If subjects have difficulty in discontinuing antihypertensive drugs completely at the start of the Run-in Period, the antihypertensive drugs can be down-titrated
concurrently with administration of placebo. In the case of the down-titration, antihypertensive drugs should be discontinued at least 1 week (7 days) before the start
of the Treatment Period I. Especially, beta-blockers (BBs) should be tapered off gradually since sudden discontinuation of BBs may cause withdrawal syndrome.
3) In the Treatment Period I, TAK-536 can be titrated biweekly when the subjects do not achieve the target blood pressure while evaluation of safety and tolerability. 
TAK-536 can be reduced at the investigator’s or subinvestigator’s discretion if there are any concerns in tolerability with titration of TAK-536 (i.e., in case of 
occurring any AEs caused by titration of TAK-536). 
4) When the antihypertensive drugs are required dose reduction or interruption because of the concerns in tolerability with titration (i.e., excessive reduction in blood 
pressure, other AE, etc.) in the Treatment Period II, the antihypertensive drugs other than TAK-536 (in case of concomitant use) should be reduced or interrupted first.
Thereafter, dose reduction or interruption of TAK-536 should be considered. 
5) Subjects who treated with antihypertensive drugs other than RAS inhibitors until the start of the Run-in Period can continue to receive a single antihypertensive drug 
in addition to the study drug if the subjects are considered to need the additional treatments for hypertension in the Treatment Period I by the investigator or 
subinvestigator. Change in the dosage of the antihypertensive drug at the start of the Run-in Period I is prohibited until the end of the Treatment Period I. 
6) When the subjects do not achieve the target blood pressure with the highest dose of TAK-536, the subjects can receive antihypertensive drugs (other than RAS 
inhibitors) or can change in dosage of the antihypertensive drug in addition to TAK-536 at the investigator’s or subinvestigator’s discretion.
*
Between the visits of Week 4 and 8, an additional unscheduled visit of Week 6 may be requested at the investigator’s or subinvestigator’s discretion in order to titrate
the dose of the study drug in the subjects when the further decrease in blood pressure is needed. 
6.2 
Justification for Study Design, Dose, Regimen, and Endpoints 
[Justification for the Study Design] 
Many pediatric patients with renal dysfunction are assumed to be entered this study since the 
proportion of pediatric patients with secondary hypertension caused by renal disease is high in 
pediatric patients with hypertension. Evidence-based Clinical Practice Guideline for CKD 2013 
(JSN2013) [9] indicates that treatment with ARB should be start at a low dose in patients with 
renal dysfunction and the dose should be increased with caution by confirming the hypotensive 
effect of ARB and renal function. On the basis of above indication, an open-label, optional titration 
Screening 


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design was selected in this study, in which TAK-536 can be titrated with monitoring subject 
condition. 
Co-administration of RAS inhibitors, which is similar to TAK-536, is prohibited in order to 
evaluate appropriately the efficacy of TAK-536 in the pediatric patients throughout the Run-in 
Period and the Treatment Period I. In consideration of the safety for vulnerable pediatric 
population, subjects can continue to receive a single antihypertensive drug other than RAS 
inhibitors in the same dosage after the start of the Run-in Period, if the subjects are considered to 
need the additional treatment for hypertension by the investigator or subinvestigator. In the 
Treatment Period II, the subjects whose blood pressure is not reduced sufficiently by TAK-536 can 
receive additional antihypertensive drugs other than RAS inhibitors concomitantly in order to 
evaluate the efficacy and safety of the long-term administration of TAK-536 in pediatric patients 
under the condition of being closer to the routine medical care. 
The Run-in Period with placebo was selected to wash out the placebo effect of the study drug and 
the influence of antihypertensive drugs as a prior treatment in subjects who were treated with any 
prior antihypertensive drugs. In addition, the Run-in Period allows the opportunity to assess 
subject compliance with the study drug (i.e., placebo) and subjects who are not sufficiently 
compliant with placebo will be excluded. 
The Follow-up Period was selected to evaluate the subject safety after the study drug 
administration. 
[Justification for the Doses] 
The population pharmacokinetic model was developed based on data from a total of 58 subjects (6 
for pediatric patients and 52 for healthy adult subjects). Also a population of subjects whose 
weights were uniformly distributed within the specified weight range between 20-80 kg by 1 kg 
(100 subjects for each body weight range and 6100 subjects in total) were generated and equally 
allocated to fixed TAK-536 doses of 2.5, 5, 10, 20, and 40 mg. Then, the population 
pharmacokinetic model was used to simulate the Cmax and AUC of TAK-536 following a single 
oral dose of each dose for each body weight category for virtual pediatric population, and 
distributions of simulated Cmax and AUC (median and 90% CI) of TAK-536 in pediatric patients 
weighing ≥ 20 kg and < 50 kg and those weighing ≥ 50 kg and < 80 kg were compared with actual 
parameters of Cmax and AUC (minimum and maximum) following TAK-536 10, 20, 40 and 
80 mg in healthy adults. 
Based on the simulation, estimated exposures to TAK-536 in pediatric patients weighing ≥ 50 kg 
and < 80 kg and those weighing ≥ 20 kg and < 50 kg after receiving TAK-536 2.5, 5, 10, 20, or 
40 mg are similar to and a little below double of that in healthy adults receiving the same fixed 
dose, respectively. These findings indicate that exposures to TAK-536 in pediatric patients with 
doses up to 20 mg do not exceed the exposure in adults with the approved maximum dose of 
40 mg. 
Therefore, the initial dose was set at 5 mg, a half the typical adult half dose of 10 mg, for the 
subjects weighing ≥ 50 kg and at 2.5 mg for those weighing < 50 kg by further reducing the dose 
by half in consideration of subject safety. 


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On the basis of the results of the population pharmacokinetic model, 40 mg or 20 mg was selected 
as the highest dose of TAK-536 by weight for the subjects weighing ≥ 50 kg or < 50 kg, 
respectively. In the population pharmacokinetic model, estimated exposures to TAK-536 in 
pediatric patients weighing ≥ 50 kg after receiving TAK-536 40 mg as the highest clinical dose in 
adults or those in the patients weighing < 50 kg after receiving TAK-536 20 mg does not exceed 
the exposure to TAK-536 in adults after receiving TAK-536 40 mg as the approved maximum 
dose in adults. In addition, titrating from the lower dose while evaluation of safety and tolerability 
sufficiently were selected in consideration of subject safety. 
TAK-536 has not been administered to the pediatric patients with hypertension with renal 
dysfunction. In addition, TAK-536 should be administered initially in lower dose to the adult 
patients with serious renal dysfunction and gradual titration is required for them in careful with 
monitoring subject condition in case of titration. The design of this study fulfills the above 
requirements. 
[Justification for the Regimen] 
Since meals do not affect the pharmacokinetics of TAK-536 in adults, the subjects receive the 
study drug before or after breakfast in the study. 
[Justification of Endpoints] 
Variables commonly used to evaluate the safety were selected as the primary endpoints because 
the primary objective of this study is to evaluate the long-term safety of TAK-536. 
Office trough sitting diastolic and systolic blood pressure were selected as secondary endpoints to 
evaluate the efficacy and persistence of effect in reference to Principles for Clinical Evaluation of 
New Antihypertensive Drugs [10] and JSH2014 [6]. 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) will be measured in order to 
evaluate the pharmacokinetics of TAK-536 in pediatric patients with hypertension. 
[Justification for Study Duration] 
(1) Run-in Period
Two weeks were set as the Run-in Period with placebo to wash out the placebo effect of the study 
drug or the influence of the antihypertensive drugs as a prior treatment. The subjects whose blood 
pressures meet the inclusion criteria 1 week (at earliest) after receiving placebo during the Run-in 
Period can enter the Treatment Period in consideration of subject safety. For the subjects only who 
treated with any antihypertensive drugs as a prior treatment, the Run-in Period could be extended 
up to 4 weeks while considering of subject safety if the blood pressures do not meet the inclusion 
criteria. 
(2) Treatment Period
JSH2014 [6] recommends that low-dose therapy with a single antihypertensive drug should be 
initiated first for the treatment of the hypertensive patients, and the dose should be increased to a 
standard dose in 4 to 8 weeks while evaluating the effects. On the basis of above recommendation, 
8 weeks were set as a titration period with 3 titration point and 2 weeks for each titration point for 
evaluating the tolerability. In addition, a phase 3 confirmatory study (TAK-536/CCT-005) 


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demonstrated that maximum decline of blood pressure was observed 4 weeks after the titration of 
TAK-536 in Japanese adult patients with hypertension. On the basis of the results, 4 weeks were 
set as the duration of administration with the highest dose in case of the titration of TAK-536 to the 
highest dose (20 mg or 40 mg). Therefore, 12 weeks in total were set as the Treatment Period I in 
this study. 
Forty weeks was set as the Treatment Period II in reference to the Extent of Population Exposure 
to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening 
Conditions [11], so that duration of administration would be 52 weeks in total with the Treatment 
Period I. 
(3) Follow-up Period
The elimination half-life was 12.8 hours following the single administration of TAK-536 40 mg in 
healthy adult subjects. In reference to the amendment of the Guideline for Bioequivalence Studies 
of Generic Products [12], 2 weeks were set as Follow-up Period of 5 times or more the elimination 
half-life. 
6.3 
Premature Termination or Suspension of Study or Study Site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 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 drug 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 GCP that compromises the ability to achieve the primary study
objectives or compromises subject safety.
6.3.2 
Criteria for Premature Termination or Suspension of Study 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 Study Sites 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable study 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 first dose. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator or subinvestigator, the subject’s parent or the subject’s legal
guardian is capable of understanding and complying with protocol requirements.
2. The subject’s parent or the subject’s legal guardian is capable of signing and dating a written,
informed consent form on behalf of the subject prior to the initiation of any study procedures.
Written informed assent is also obtained from the subject as much as possible.
3. The Japanese subject who has a diagnosis of hypertension. A subject is eligible if he/she is
deemed hypertensive according to the reference blood pressure values of children by gender
and age (Table 5.a); office sitting diastolic or systolic blood pressure ≥ 95 percentile for
essential hypertension without concomitant hypertensive organ damage, and ≥ 90 percentile
for secondary hypertension with concomitant CKD, diabetes mellitus, heart failure or any
hypertensive organ damage.
In addition, subjects need to meet the following criteria:
(1) If currently treated with any antihypertensive drugs at the start of the Run-in Period:
Subject has a documented historical diagnosis of hypertension and an office sitting diastolic or
systolic blood pressure meeting the above criteria at the end of the Run-in Period (Week 0).
(2) If currently untreated with any antihypertensive drugs at the start of the Run-in Period:
Subject who meets the above criteria on 3 separate time points including screening and the end
of the Run-in Period (Week 0). In addition, subject with essential hypertension without
concomitant hypertensive organ damage still maintains hypertension with
non-pharmacotherapy including foods or exercises for at least 3 months within 1 year prior to
the start of screening.
4. The subject is male or female and aged 6 to less than 16 years at the time of informed consent.
5. The subject weighs at least 20 kg at screening.
6. The subject is capable of taking the tablets or granules supplied as the study drug.
7. A subject who has undergone kidney transplantation is eligible if he/she underwent the
transplantation at least 6 months earlier at screening, and the graft has been functionally stable
(estimated glomerular filtration rate [eGFR] ≥ 30 mL/min/1.73 m2) for at least 6 months with
evidence (eg, Doppler echography, CT scan [computed tomography] or MRI [magnetic
resonance imaging]) excluding grafted kidney arterial stenosis. A subject on
immunosuppressive therapy with a stable dose at least 30 days prior to screening is eligible.
8. A female subject of childbearing potential* who is sexually active with a nonsterilized* male
partner agrees to use routinely adequate contraception* from signing of informed consent
through 1 month after the completion of the study, and proves negative in the pregnancy test at
screening.


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*Definitions and acceptable methods of contraception are defined in
Section 9.1.10 and reporting responsibilities are defined in Section 9.1.11.
9. The subjects judged by the investigator or subinvestigator that he/she can discontinue the
therapy with RAS inhibitors for 2 weeks (acceptable range, 1 to 4 weeks) in safe prior to the
Treatment Period.
[Justification of Inclusion Criteria] 
1.2.6. These were set as the standard requirements for clinical studies in pediatric patients. 
3. The patients with hypertension who can be candidates for pharmacotherapy was set in
reference to JCS2012 [7]. Reference blood pressure value of hypertension in the US
guideline’s criteria for children of 50 percentile height categorized by age and gender was
selected since which was also the diagnosing criteria for hypertension adopted by JCS2012 [7].
For patients untreated with any antihypertensive drugs at the start of the Run-in Period, blood
pressure values of 3 separate time points were adopted since hypertension would be diagnosed
with above criteria 3 times or more in separate day or week.
4. The subject can be male or female, since evaluation in boys and girls is needed. The subjects of
this study will be school children. Since children aged 6 to 16 years are categorized as school
children in the final report on the Guidelines for Clinical Evaluation of Antihypertensive Drugs
in Children [8], 6 to 16 years will be an acceptable age range in this study.
5. According to the physical status survey (Part 2 of the National Health and Nutrition Survey
2011 [13]), the average weight of 6-year-old children was 20.2 kg for girls and 20.9 kg for
boys. This study will therefore enroll children weighing at least 20 kg.
7. In consideration of possible effects on the evaluation of TAK-536 and the subject safety, the
subject who has undergone kidney transplantation will be eligible only if his/her clinical
course has been stable.
8. RAS inhibitors are contraindicated in pregnant women based on the disorders and deaths in
fetuses and new-born children reported for women using them during pregnancy.
9. These were set in consideration of subject safety.
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received any investigational compound within 30 days prior to screening or is
participating in another clinical study or a post-marketing clinical study.
Note: This does not apply to subjects participating in observational studies without
interventional or invasive therapy.
2. The subject previously received therapy with azilsartan.
Note: This does not apply to subjects participating in single dose pharmacokinetic studies of
TAK-536.


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3. The subject has poorly controlled hypertension indicated by an office sitting systolic blood
pressure higher by at least 15 mmHg and/or an office sitting diastolic blood pressure higher by
at least 10 mmHg than the 99 percentiles of the reference blood pressure values of children by
gender and age (Table 5.a).
4. The subject has a diagnosis of malignant or accelerated hypertension.
5. The subject was noncompliant (< 70% or > 130%)* with the study drug during the Run-in
Period.
*: The proportion of the number of the received the study drug to the number of the study drug which the subjects
should receive.
6. The subject has severe renal dysfunction (eGFR < 30 mL/min/1.73 m2), is receiving dialysis,
has a renovascular disease affecting one or both kidneys, severe nephrotic syndrome not in
remission, or a serum albumin level < 2.5 g/dL.
7. The subject has a history of, or the signs/symptoms of serious cardiovascular, hepatobiliary,
gastrointestinal, endocrine (eg, hyperthyroidism, Cushing’s syndrome), hematological,
immunological, urinogenital, psychiatric disease, cancer, or any other disease that adversely
affects subject’s health, or, in the opinion of the investigator or subinvestigator, potentially
confounds the study results.
8. The subject has hemodynamically significant left ventricular outflow obstruction due to aortic
stenosis or aortic valvular disease, or is scheduled to undergo a medical procedure affecting
blood pressure during the study (eg, correction of arterial anomaly).
9. The subject has a history of or concurrent clinically significant abnormality of 12-lead ECG
that, in the opinion of the investigator or subinvestigator, disqualifies the subject for
participation in the study.
10. The subject has poorly controlled diabetes mellitus indicated by HbA1c > 9.0% at screening.
11. The subject has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level
≥ 2.5 × the upper limit of normal (ULN), or a total bilirubin level ≥ 1.5 × ULN at screening,
severely impaired hepatic function, any active liver disease (regardless of the cause), or
jaundice.
12. The subject has hyperkalemia exceeding ULN at screening.
13. The subject has a history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
infection at screening.
14. The subject has a known hypersensitivity or allergy to any ARBs.
15. The subject needs treatment with any of the excluded medication.
16. If female, the subject is pregnant or lactating or intending to become pregnant before, during,
or within 1 month after the completion of this study.
[Justification of Exclusion Criteria] 
1, 15. These were set as the standard exclusion criteria used for clinical studies. 


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2. This was set because of the potential for bias in evaluation of the safety and the efficacy.
3,4, 6-11, 13,14. These were set in consideration of the subject safety.
5. This was set to assure the appropriateness of the evaluation in this study.
12. This was set in consideration of the subject safety; hyperkalemia may develop after the
administration of RAS inhibitors.
16. This was set as a standard requirement used for clinical studies. It was also due to a
contraindication for pregnant females, because RAS inhibitors have caused fetal and neonatal
disorders and death when used during pregnancy, and were transferred in the milk and affected
nursing neonates when administered to lactating animals in nonclinical studies.
7.3 
Excluded Medications and Treatments 
7.3.1 
Excluded Medications 
The following medications including over-the-counter (OTC) drugs will be prohibited at the 
specified period during the study (Run-in Period and Treatment Period). 
Subjects and subjects’ parent or the subjects’ legal guardian must be instructed not to take any 
medications including OTC products, without first consulting with the investigator or 
subinvestigator. 
Other medications that are listed in the precautions for co-administration section of the package 
inserts of TAK-536 must be administered with caution. 
<Run-in Period and Treatment Period I> 
The following medications will be prohibited during the Run-in Period and Treatment Period I. A 
subject can continue the conventional therapy for the concurrent medical conditions without 
changing daily dosage except the excluded medications. 
(1) RAS inhibitors (ACE inhibitors, ARB, and DRI)
(2) Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) excluding acetaminophen (4
days or more per week)
(3) Lithium
(4) Monoamine oxidase inhibitors
(5) Tricyclic antidepressants
(6) Amphetamine or it-derived materials (exception for the materials shown in the section of
Medications Permitted with Conditions)
(7) Dopamine agonist
(8) Atypical antipsychotics
(9) Anticonvulsants
(10) Trazodone 


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(11) Nitrates 
(12) Estrogen preparations 
<Treatment Period II>
The following medications will be prohibited during the Treatment Period II.
(1) RAS inhibitors (ACE inhibitors, ARB, and DRI)
(2) Chronic use of NSAIDs excluding acetaminophen (4 days or more per week)
(3) Lithium
(4) Monoamine oxidase inhibitors
(5) Nitrates
(6) Estrogen preparations
[Justification for Excluded Medications]
<Run-in Period and Treatment Period I>
(1)
These similar drugs are excluded because they could influence the evaluation of
TAK-536 efficacy.
(2), (4)-(12) 
These drugs are excluded because they could increase or decrease blood pressure 
and influence the evaluation of TAK-536 efficacy. 
(3)
This drug is prohibited because their concomitant use with ARBs could cause
poisoning.
<Treatment Period II> 
(1)
These similar drugs are excluded because they could influence the evaluation of
TAK-536 efficacy.
(2), (4)-(6) 
These drugs will be supposed to be used chronically and are excluded because they 
could increase or decrease blood pressure and influence the evaluation of TAK-536 
efficacy when these are used chronically. 
(3)
This drug is prohibited because their concomitant use with ARBs could cause
poisoning.
7.3.2 
Medications Permitted with Conditions 
Following medications will be permitted with conditions in consideration of subject safety during 
the Run-in Period and Treatment Period I. 
(1) Antihypertensive drugs other than RAS inhibitors: Subjects who treated with antihypertensive
drugs other than RAS inhibitors until the start of the Run-in Period can continue to receive a
single antihypertensive drug in addition to the study drug if the subjects are considered to need
the additional treatment for hypertension in the Treatment Period I by the investigator or
subinvestigator; the antihypertensive drug should be administered under the same dosage at


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the time of the start of the Run-in Period. If subjects have difficulty in discontinuing 
antihypertensive drugs completely at the start of the Run-in Period, the antihypertensive drugs 
can be down-titrated concurrently with administration of placebo. In the case of the 
down-titration, antihypertensive drugs should be discontinued at least 1 week (7 days) before 
the start of the Treatment Period I. Especially, beta-blockers (BBs) should be tapered off 
gradually since sudden discontinuation of BBs may cause withdrawal syndrome. 
(2) Steroids: Systemic steroid is permitted as an alternative therapy on a stable low dose/
maintenance dose in subjects with adrenal insufficiency. The highest dose per day is
12 mg/m2 for hydrocortisone or equivalent dose to hydrocortisone for other steroids.
Prednisolone or other steroids can be administered up to 15 mg/m2 per day or equivalent dose
to prednisolone for other steroids as an immunosuppressive therapy in subjects after renal
transplantation or with glomerular disease. The steroids are permitted on a stable dose from 30
days or more prior to the screening to the end of the Treatment Period I (alternate-day
administration is also permitted). Topical or inhaled steroid is permitted but the dose cannot
be changed unless there are no medical needs.
(3) Central nervous system stimulants, non-central nervous system stimulants: Use for treatment
of attention deficit/hyperactivity disorder is permitted on a stable dose from 30 days prior or
more to the screening to the end of the Treatment Period I.
7.4 
Diet, Fluid, and Activity Control 
The investigator, the subinvestigator, and the study collaborator should instruct the subject, the 
subject’s parent or the subject’s legal guardian to adhere the following study requirements. 
1. Subjects will be instructed to ask the investigator, the subinvestigator, or the study collaborator
by telephone for their instructions or visit the study site, as soon as they experience vomiting or
diarrhea frequently throughout the study.
2. Subjects will be fully explained about the possibility of excessive reduction in the blood
pressure associated with TAK-536 treatment. Subjects will be instructed to rest in a supine
position, as soon as they experience any symptoms suggesting decreased blood pressure (eg,
dizziness, lightheadedness, etc.) outside the study site on days other than the scheduled visit.
Subjects were instructed to ask the investigator, subinvestigator, or the study collaborator by
telephone for further instructions, or to visit the study site, if the symptoms did not subside.
3. Subjects will be instructed to ask the investigator, subinvestigator, or the study collaborator by
telephone for their instructions, or to visit the study site, as soon as they experience any
symptoms associated with increased blood pressure (eg, headache, palpitations, hot flushes,
perspiration, etc.) outside the study site on days other than the scheduled visit.
4. Subjects will be instructed to take the study drugs as directed (1 tablet or 1 sachet once daily)
without fail and continue receiving the study drug at the same timing (before or after breakfast)
throughout the study. Subjects will be instructed to take the study drug at the same time every
day except for scheduled visit day. Subjects will be instructed to take the study drug by AM
9:00 at the latest, setting ±3-hours for acceptable range. Subjects will be instructed that they
will be allowed to take the study drug when they realize it in case of failing to take the study


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drug, but will not be allowed to take the study drugs for 2 days at once. On the day before 
scheduled visit, subjects must take the study drug 24 hours (acceptable range, 21 to 27 hours) 
before office blood pressure measurement on the following day. TAK-536 2.5 mg granules 
should be administered immediately after the sachet (aluminum strip) is torn off. TAK-536 
2.5 mg granules sachet should not be administered if the sachet is torn off at least 1 hour before 
the administration. 
5. Subjects will be fully explained about how to adequately measure home blood pressure.
Subjects will be instructed to measure the home blood pressure, preferably consecutive 2 times
daily immediately before the study drug administration for 1 week each before and after the
visit at the start of the Treatment Period I, for 1 week after the following day of a visit of each
time point between Week 2 and Week 8 of the Treatment Period I, and for 1 week from the day
before the visit at Week 12 of the Treatment Period I. Subjects will be instructed to inform the
study site if a home sitting systolic blood pressure which is higher by at least 15 mmHg and/or
a home sitting diastolic blood pressure which is higher by at least 10 mmHg than the 99
percentiles of the reference blood pressure values of children by gender and age in Table 5.a
(See Section 9.1.6).
6. Subjects will be instructed not to eat or bathe within 1 hour before office blood pressure
measurement, not to intake any caffeine containing product within 30 minutes before the
measurement.
7. Subjects will be instructed to comply with and not to change a fixed diet (eg, caloric and salt
intake) and/or exercise therapies, if performed, throughout the study.
8. Subjects will be instructed to avoid food with a high salt and to take adequate hydration and to
maintain a routine sleep, behavior and caffeine intake. In addition, subjects will be instructed
to avoid excessive drinking/eating, significant change of diet (eg, excessively high-fat diet),
excessive exercise, and staying up late. Especially, subjects will be instructed to maintain a
regular lifestyle on the day before visit days.
9. Subjects will be instructed to inform the investigator, subinvestigator before receiving
treatment from another doctor, or to provide details of treatment the subject received in case of
reporting afterwards. Subjects receiving treatment by another doctor will be instructed to
inform another doctor of their participation in this study before the participation, as far as
possible.
10. Subjects will be instructed to consult the investigator or subinvestigator before using or
changing the dosage of any drug not prescribed by the investigator or subinvestigator
(including vitamins supplements, OTC drugs, and herbal preparations). Subjects will be
instructed to promptly provide the details when they use any such drug.
11. Subjects will be instructed to visit the study site at the scheduled times to undergo
examinations and tests by the investigator or subinvestigator. Subjects will be instructed to
promptly inform the investigator or subinvestigator when they are unable to visit the study site
as scheduled.


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12. Female subjects of childbearing potential (eg, a female subject of childbearing potential is
defined by the investigator’s or subinvestigator’s positive opinion about the subject’s
reproductive potential) will be instructed to use appropriate contraception from signing of
informed consent to 1 month after completing the study (see Section 9.1.10).
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the case report form (eCRF) using the following categories. For subject 
failure, refer to Section 9.1.14. 
1. Death. The subject died on study.
Note: If the subject dies on study, the event will be considered as SAE. See Section 10.2.2 for
the reporting procedures.
2. AE. The subject has experienced an 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 AE.
• Acute deterioration of renal function
Acute deterioration of renal function or increase in potassium value should be monitored
carefully. If 50% reduction in estimated glomerular filtration rate [eGFR] or less than
30 mL/min/1.73 m2, or serum potassium value over 5.5 mEq/L is seen at consecutive 2 time
points, discontinuation should be considered. Appropriate follow-up should be performed
for all subjects who discontinue the study until the subjects have been recovered or
stabilized (see Section 9.1.9).
• Liver Function Test (LFT) Abnormalities
Study drug should be discontinued immediately with appropriate clinical follow-up
(including repeat laboratory tests, until a subject’s laboratory profile has returned to
normal/baseline status, see Section 9.1.9), if the following circumstances occur at any time
during study drug treatment:
–
ALT or AST > 8 ×ULN, or
–
ALT or AST > 5 × ULN and persists for more than 2 weeks, or
–
ALT or AST > 3 × ULN in conjunction with elevated total bilirubin > 2 × ULN or
international normalized ratio (INR) > 1.5, or
–
ALT or AST > 3 × ULN with appearance of fatigue, nausea, vomiting, right upper quadrant
pain or tenderness, fever, rash and/or eosinophilia (> 5%).
3. Protocol deviation. The discovery after the start of the Treatment Period 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.
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject,
the subject’s parent or the subject’s legal guardian were unsuccessful. Attempts to contact the


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subject, the subject’s parent or the subject’s legal guardian must be documented in the 
subject’s source documents. 
5. Withdrawal by subject. The subject wishes to withdraw from the study. The reason for
withdrawal, if provided, should be recorded in the eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and,
where possible, the primary underlying reason should be recorded (i.e., withdrawal due to an
AE).
6. Withdrawal by parent or guardian. The subject’s parent or the subject’s legal guardian wishes
to withdraw the subject from the study. The reason for withdrawal, if provided, should be
recorded in the eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and,
where possible, the primary underlying reason should be recorded (i.e., withdrawal due to an
AE).
7. Study terminated by sponsor. The sponsor terminates the study.
8. 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 9.1.11.
9. Lack of efficacy. The investigator or subinvestigator has determined that the subject is not
benefiting from study treatment; and, continued participation would pose an unacceptable risk
to the subject. For example, discontinuation should be considered in the following case; on
consecutive visits, an office sitting systolic blood pressure is persistently higher by at least
15 mmHg and/or an office sitting diastolic blood pressure is persistently higher by at least
10 mmHg than the 99 percentiles of the reference blood pressure values of children by gender
and age in Table 5.a, or, subjective symptoms or findings deemed associated with poorly
controlled blood pressure do not improve with titration of TAK-536 during the Treatment
Period I or with the addition of any other antihypertensive drugs other than RAS inhibitors
during the Treatment Period II.
10. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator or subinvestigator may discontinue 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 by the investigator or subinvestigator. In addition, efforts should be 
made to perform all procedures scheduled for the Early Termination Visit. 


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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 Drug and Materials 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study drug refers to all or any of the drugs defined below. 
8.1.1.1 
Study Drug 
(1) Dosage form and manufacturing
Code name: TAK-536
Chemical name: 2-Ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)
biphenyl-4-yl]methyl}-1H-benzo[d]imidazole-7-carboxylic acid
Generic name: Azilsartan (JAN)
Formulation and Strength:
Study drug
Formulation
Strength
TAK-536 2.5 mg granules 
(placebo for the Run-in 
Period) 
White to nearly white granules
Contains no TAK-536 in 250 mg
TAK-536 2.5 mg granules 
(active drug for the 
Treatment Period) 
White to nearly white granules
Contains 2.5 mg of TAK-536 in 250 mg
TAK-536 5 mg tablet 
(placebo for the Run-in 
Period) 
Pale pink film-coated tablet
Contains no TAK-536 in 1 tablet
TAK-536 5 mg tablet 
(active drug for the 
Treatment Period) 
Pale pink film-coated tablet
Contains 5 mg of TAK-536 in 1 tablet
TAK-536 10 mg tablet 
Pale yellow to red film-coated 
tablet 
Contains 10 mg of TAK-536 in 1 tablet
TAK-536 20 mg tablet 
Pale-red film-coated tablet
Contains 20 mg of TAK-536 in 1 tablet
TAK-536 40 mg tablet 
Yellow film-coated tablet
Contains 40 mg of TAK-536 in 1 tablet
Manufacturing: TPC 
(2) Package and labeling
1) Package
–
TAK-536 2.5 mg granules (placebo for the Run-in Period, active drug for the Treatment
Period): For placebo for the Run-in Period, each aluminum strip sachet contains 250 mg of


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TAK-536 granules containing no TAK-536. Forty two sachets are packaged in a box. For 
active drug for the Treatment Period, each aluminum strip sachet contains 250 mg of 
TAK-536 granules containing 2.5 mg of TAK-536. Seventy sachets are packaged in a box. 
–
TAK-536 5 mg tablet (placebo for the Run-in Period, active drug for the Treatment
Period): For placebo for the Run-in Period, each press through package (PTP) sheet
contains 14 tablets of TAK-536. Three sheets are packaged in a box. For active drug for the
Treatment Period, each PTP sheet contains 14 tablets of TAK-536. Ten sheets are
packaged in a box.
–
TAK-536 10 mg, 20 mg, and 40 mg tablets: Each PTP sheet contains 14 tablets of
TAK-536. Ten sheets are packaged in a box.
2) Labeling
Each outer box indicates the following information: the drug is for the study use only, study drug 
name, amount, the sponsor’s name and address, batch number, and storage condition. 
8.1.2 
Storage 
The study drugs are to be stored at room temperature (1 to 30°C). 
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. Study drug 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 
During the Run-in Period, subjects will orally receive TAK-536 2.5 mg granules (placebo for the 
Run-in Period) if subjects weighing < 50 kg, or TAK-536 5 mg tablet (placebo for the Run-in 
Period) if subjects weighing ≥ 50 kg, once daily, before or after breakfast. During the Treatment 
Period, the same dose of the selected placebo during the Run-in Period will be the initial dose. 
After the initial dose, subjects will orally receive any of TAK-536 2.5 mg granules, TAK-536 
5 mg, 10 mg, 20 mg tablet, once daily, before or after breakfast, if subjects weighing < 50 kg, or 
any of TAK-536 5 mg, 10 mg, 20 mg, 40 mg tablet, if subjects weighing ≥ 50 kg. For dose titration 
method, see Section 6.1 Study Design. 
Because weight is likely to change during the study, the highest dose for the subjects is allowed to 
be changed if dose adjustment by changing of weight is required during the Treatment Period II.  
The investigator or subinvestigator may select the timing of the study drug administration (i.e., 
before or after breakfast) in consideration of subject lifestyle but should not change this timing 
throughout the study. The investigator or its designee will record the guidance provided about the 
timing of the study drug administration (before or after breakfast) at the start of the Run-in Period 
(Week -2) in the eCRF. 
At the start of the Run-in Period (Week -2), the study drug for the Run-in Period will be 
administered on the same day after completing all tests, observations, and evaluations. In case that 


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subjects take RAS inhibitors in the morning of the visit day, the administration of the study drug  
for the Run-in Period will be started from the next day. 
Except for Week 16, subjects will visit the study site on each visit day without taking the study 
drugs, and receive them only after completing all tests, observations, and evaluations. 
On the visit of Week 16, subjects, the subjects’ parent or the subjects’ legal guardian will be 
instructed to visit the study site after taking the study drug and the tests, observations, and 
evaluations 2 hour (acceptable time window, 1 to 3 hours) after taking the study drug will be 
performed. 
Regular doses on days except for the visits will be administered no later than 9:00 AM, regardless 
of the specified dosing timing (i.e., before or after breakfast). The study drug should be 
administered at the almost same time every day throughout the study (acceptable range is ± 3 
hours) except the visit day. The investigator or subinvestigator will confirm whether the subject 
has taken the study drug or not in the morning of each visit. 
8.1.4 
Overdose 
An overdose is defined as a known deliberate or accidental administration of study 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 AEs) about TAK-536 active drug for the 
Treatment Period, will be documented on an Overdose page of the eCRF, in order to capture this 
important safety information consistently in the database. Cases of overdose without manifested 
signs or symptoms are not considered AEs. AEs associated with an overdose will be documented 
on AE CRFs according to Section 10.0. 
SAEs associated with overdose should be reported according to the procedure outlined in Section 
10.2.2. 
In the event of drug overdose, the subject should be treated symptomatically. 
8.2 
Study Drug Dispensing Procedures 
The investigator or subinvestigator will dispense the study drug to subjects according to the study 
procedure. 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs 
The site designee will receive the procedures for handling, storage and management of study drugs 
created by the sponsor, according to which the site designee will appropriately manage the 
sponsor-supplied drug. The investigator will also receive those procedures from the sponsor. The 
procedures include those for ensuring appropriate receipt, handling, storage, management, 
dispensation of the sponsor-supplied drug, and collection of unused medications from the subject 
as well as return of them to the sponsor or destruction of them. 
The site designee will immediately return unused medications to the sponsor after the study is 
closed at the site. 


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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 and assent are described in Section 15.2. 
Informed assent of the subject, if deemed possible by the investigator or subinvestigator, and 
informed consent of the subject’s parent or the subject’s legal guardian must be obtained prior to 
the subject entering into the study, and before any protocol-directed procedures are performed. 
Assent and consent to participate in the study will be obtained from any subject before 
discontinuing the prior treatment (antihypertensive drugs). 
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is explained; 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, diagnosis timing and 
type of hypertension, and underlying diseases in case of secondary hypertension at screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the diseases under study that stopped within 1 year prior to 
informed consent. Any history of kidney transplantation should be documented regardless of the 
time elapsed. Ongoing conditions are considered concurrent medical conditions (see Section 
9.1.8). 
Medication history information to be obtained includes any medication stopped at or within 4 
weeks prior to VISIT 2. 
9.1.3 
Physical Examination Procedure 
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes;
(11) other. All subsequent physical examinations should assess clinically significant changes from
the assessment performed before the study drug administration.
9.1.4 
Weight, Height, and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below: The Takeda 
standard for collecting height is centimeters without decimal places and for weight it is kilograms 
(kg) with 1 decimal place. BMI should be derived as: 


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Metric: BMI = weight (kg)/height (m)2
Height in centimeters (cm) will be rounded to integers and weight in kilograms (kg) will be 
rounded to 1 decimal place. BMI will be rounded to 1 decimal place. 
9.1.5 
Vital Sign Procedure 
Vital signs will include office sitting blood pressure (systolic and diastolic), office standing blood 
pressure (systolic and diastolic), office sitting pulse rate, and office standing pulse rate (pulse rate 
per 1 minute). All office blood pressure will be measured with a blood pressure meter specified by 
the sponsor. 
Office blood pressure should be measured at the time of trough (approximately 21 to 27 hours after 
the latest dose, i.e., in the morning of that day) with the subject without taking the study drug in the 
morning of the scheduled visit except for Week 16. The subject, the subject’s parent, or legal 
guardian will be instructed strongly not to take the study drug at home on the scheduled visit day 
except for Week 16. The subject, the subject’s parent, or the subject’s legal guardian will be 
instructed again if the subject receives the study drug before the measurements of vital signs on the 
scheduled visit day by mistake. 
When vital signs are scheduled at the same time as blood draws, vital signs will be obtained before 
the scheduled blood draw. 
Office sitting blood pressure after taking the study drug will be also measured only at Week 16 of 
the Treatment Period; the time point which the pharmacokinetics after receiving the study drug is 
evaluated.  
Subjects will be instructed not to eat or bathe within 1 hour before office blood pressure 
measurement, not to intake any caffeine containing product 30 minutes before the measurement. 
<Determining difference in blood pressure between right and left arm> 
At screening, sitting blood pressure in the right and left arms will be measured once after sitting at 
rest for ≥ 5 minutes to determine the difference in blood pressure between the arms. The arm with 
a higher systolic blood pressure will be used to measure office blood pressure during the study. 
The right arm will be used if systolic blood pressure is the same on both sides. Change of the arm 
for measurement will not be allowed during the study. 
<Measuring sitting blood pressure and sitting pulse rate> 
Sitting blood pressure will be repeatedly measured 3 times at 1 to 2 minute intervals after the 
subject has been sitting at rest for at least 5 minutes and recorded in the subject source documents 
and eCRF. However, if 2 of the 3 systolic blood pressure measurements differ by more than 
8 mmHg or diastolic blood pressure measurements differ by more than 5 mmHg, a second set of 3 
sitting blood pressure measurements should be obtained and only the second set of readings should 
be recorded in the eCRF (even if these still differ by > 8 mmHg for systolic blood pressure or 
5 mmHg for diastolic blood pressure). Original and repeat readings must all be recorded in the 
source documents with an explanation. 


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The arithmetic mean (rounded to integers) of 3 measurements of a session will be used for 
determination of the subject eligibility. 
The pulse rate measured at the last measurement of the sitting blood pressure will be used as the 
sitting pulse rate value. 
Sitting blood pressure must be measured after resting in a sitting position for at least 5 minutes. An 
appropriately sized cuff (40% of the arm’s perimeter) should be used, and applied to an upper arm 
held at the heart level. All measurements must be made on the same arm using the same-sized cuff. 
Every effort should be made to standardize the condition of office blood pressure measurements as 
possible, such as measurement time, the same blood pressure device should be used, whenever 
possible, by the same investigator, subinvestigator, or the study collaborator. 
<Measuring standing blood pressure and standing pulse rate> 
Standing blood pressure will be measured to evaluate the orthostatic vital signs at the scheduled 
visit of Week 0, 12, 24 and 52. After measuring the sitting blood pressure, standing blood pressure 
will be measured once after the subject has been standing for 2 minutes. Standing systolic and 
diastolic blood pressure will be also measured with the same device which measures sitting blood 
pressure on the same arm. For standing blood pressure measurements, the arm should be supported 
and extended such that the cuff is at heart level. Standing pulse rate will be measured once during 
the subject maintains a standing position. 
9.1.6 
Measuring Home Blood Pressure 
Each subject, the subject’s parent, or the subject’s legal guardian will be provided a home blood 
pressure meter and adequately informed of the measurement procedures at the start of the Run-in 
Period (Week -2) by the sponsor through the study site. 
The subject, the subject’s parent, or the subject’s legal guardian will be instructed to measure home 
blood pressure (systolic and diastolic), preferably consecutive 2 times daily immediately before 
the study drug administration for 1 week each before and after the visit at the start of the Treatment 
Period I, and for 1 week after the following day of a visit of each time point between Week 2 and 
Week 8 of the Treatment Period I (including visit at Week 6, when performed), and for 1 week 
from the day before the visit at Week 12 of the Treatment Period I. 
The subject should measure blood pressure 2 times in a row after having been sitting for at least 5 
minutes with the blood pressure cuff applied to the same arm as used to measure blood pressure at 
the visits. The blood pressure measurements should be recorded in patient diary and reviewed by 
the investigator or subinvestigator at each visit. The blood pressure measured twice immediately 
before the study drug administration should be recorded in CRFs. The subject, the subject’s parent, 
or the subject’s legal guardian will be instructed to inform the study site if a home sitting systolic 
blood pressure which is higher by at least 15 mmHg and/or a home sitting diastolic blood pressure 
which is higher by at least 10 mmHg than the 99 percentiles of the reference blood pressure values 
of children by gender and age in Table 5.a. The subject, the subject’s parent, or the subject’s legal 
guardian will be instructed by the investigators to visit the study site to measure blood pressure 
again if needed. If the elevated blood pressure is confirmed by repeat measurements at the study 
site, the subject is to be considered to discontinue the study. 


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9.1.7 
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. 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 drug (used from the start of the Run-in Period [Week 2] through the end of the 
study), and all medication including vitamin supplements, OTC medications, and oral herbal 
preparations, must be recorded in the eCRF. 
If the concomitant medications are antihypertensive drugs, the daily dosage and unit of 
concomitant medications must be recorded in the eCRF as well. 
9.1.8 
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, ECG, or physical 
examination abnormalities noted at the first test after signing of informed consent. The condition 
(i.e., diagnosis) should be described. 
9.1.9 
Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 8 mL. 


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Table 9.a 
Clinical Laboratory Tests 
Hematology
Chemistry
Urinalysis 
Red blood cell count 
White blood cell count with 
differential (neutrophils, 
basophils, eosinophils, 
lymphocytes, monocytes) 
Hemoglobin 
Hematocrit 
Platelets 
Hemoglobin A1C/Hemoglobin (a)
ALT 
Albumin 
Alkaline phosphatase (ALP) 
AST 
Bilirubin (Total bilirubin) 
Blood urea nitrogen (BUN) (b) 
Calcium 
Chloride (b) 
Creatinine (b) 
Creatine kinase 
Cystatin C 
Glomerular Filtration Rate (b) 
Gamma-glutamyl transferase (GGT) 
Glucose 
Cholesterol (Total cholesterol) 
Triglyceride 
Phosphate 
Potassium (b) 
Sodium (b) 
Protein (Total protein) 
Lactate dehydrogenase (LDH) 
Qualitative tests for 
glucose, pH, protein, 
occult blood, Ketones 
Quantitative tests for 
protein, creatinine, 
Albumin 
Protein/creatinine ratio, 
albumin/creatinine ratio, 
specific gravity 
Other 
Urine qualitative human chorionic gonadotropin (hCG) pregnancy test (only female subjects of childbearing potential)
(a) Only patients with diabetes mellitus
(b) Only the laboratory tests associated with renal function. The local laboratory will perform the laboratory tests
associated with renal function in addition to measuring at the central laboratory to confirm the tolerability when
TAK-536 is titrating (including unscheduled visit), if needed at the investigator’s discretion.
The central laboratory will perform laboratory tests for hematology, chemistries, and urinalysis 
(acceptable under the fed condition). 
The local laboratory will perform the laboratory tests associated with renal function (BUN, 
chloride, creatinine, eGFR, potassium, and sodium) in addition to measuring at the central 
laboratory to confirm the tolerability when TAK-536 is titrating (including unscheduled visit), if 
needed at the investigator’s discretion. The results of the local measurements will not be required 
recording in the eCRF. 
The following formula proposed by the Committee for Pediatric Chronic Kidney Disease will be 
used to deduce eGFR in Japanese children. 


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eGFR in children (mL/min/1.73 m2) 
=110.2 × standard serum Cr (mg/dL)/serum Cr (mg/dL) + 2.93, 
where, the standard serum Cr (mg/dL) is calculated from the height (Ht, in meter; Ht measured 
most recently will be used) as follows: 
For a boy, -1.259 Ht5 + 7.815 Ht4 - 18.57 Ht3 + 21.39 Ht2 - 11.71 Ht + 2.628 
For a girl, -4.536 Ht5 + 27.16 Ht4 - 63.47 Ht3 + 72.43 Ht2 - 40.06 Ht + 8.778 
Uemura O, et al. Clin Exp Nephrol. 2014 [14] 
Follow-up laboratory tests should be performed to determine whether the subject continue the 
study or not, in case of acute deterioration of renal function (eg, ≥50% reduction in eGFR or less 
than 30 mL/min/1.73 m2 or serum potassium value over 5.5 mEq/L) (See Section 7.5). 
If subjects experience ALT or AST > 3 ×ULN after the start of the Run-in Period (Week -2), 
follow-up laboratory tests (at a minimum, ALP [serum], ALT, AST, bilirubin [total bilirubin], 
GGT, and INR) should be performed within a maximum of 7 days and preferably within 48-72 
hours after the abnormality was noted (Please refer to Section 7.5 for discontinuation criteria, and 
Section 10.2.3 for the appropriate guidance on Reporting of Abnormal Liver Function Tests in 
relation to ALT or AST >3 ×ULN in conjunction with total bilirubin >2 ×ULN.). 
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study drug, discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.3 
Reporting of Abnormal Liver Function Tests for reporting requirements). 
Only female subjects of childbearing potential, defined by the investigator’s or subinvestigator’s 
positive opinion about the subject’s reproductive potential, will undergo a qualitative hCG 
pregnancy test. The local laboratory will perform the test. 
The investigator or subinvestigator is reviewing and filing the laboratory results. The investigator 
will maintain a copy of the normal reference ranges including the archival records for the 
laboratory used. 
9.1.10 
Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, throughout the duration of the study, and for 1 month after the 
end of the study, 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 preserve or 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), who are postmenopausal (defined as at
least 5 years since last regular menses, confirmed before any study drug is implemented), or who
have no possibility of childbearing in the opinion of investigator or subinvestigator.
**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, female subjects of childbearing potential must use copper intrauterine devices 
(IUDs) combined with male condom or female condom. Medications and devices containing 
hormones are excluded. 
The subject and the subject’s parent, or the subject’s legal guardian will be provided with 
information on acceptable methods of contraception as part of the subject informed consent/assent 
process and will be asked to sign a consent/assent form stating that they understand the 
requirements for avoidance of pregnancy, preservation or donation of ova from providing the 
consent/assent until 1 month has passed from the end of the study. 
During the course of the study, regular urine hCG pregnancy tests will be performed only for 
female subjects of childbearing potential and subjects will receive continued guidance with respect 
to the avoidance of pregnancy as part of the study procedures (Appendix A). 
This protocol does not condone or endorse under-age sexual activity. 
9.1.11 
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 drug, or within 1 month of the last 
dose of active study drug, the pregnancy should be reported immediately, using a pregnancy 
notification form, to the contact listed in attachment 1. 
If the female subject and her parent, or the subject’s legal guardian agree to the primary care 
physician being informed, the investigator or subinvestigator 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 (blinded or unblinded, as applicable). 
All pregnancies in subjects on active study drug 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. 
9.1.12 
ECG Procedure 
A resting 12-lead ECG will be recorded. The investigator (or a qualified observer at the study site) 
will interpret the ECG using 1 of the following categories: normal or abnormal. The investigator 
(or a qualified observer at the study site) will judge if it is clinically significant. The following 
parameters will be recorded on the eCRF from the subject’s ECG trace: heart rate, RR interval, PR 
interval, QT interval, and QRS interval. 
QTc will be calculated by the sponsor using the Fredericia’s formula (QT/RR0.33). 
9.1.13 
Pharmacokinetic Sample Collection 
According to the study schedule (Appendix A), all pharmacokinetic samples should be collected 
on each visit except for Week 16, at the same time of blood sample collection for laboratory tests 


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to evaluate the trough values (approximately 21 to 27 hours after the latest dose) without taking the 
study drugs. 
In addition to collection of the pharmacokinetic samples at trough, pharmacokinetic samples will 
be also collected once (total twice before and after the administration of the study drug) 2 hour 
(acceptable time window, 1 to 3 hours) after taking the study drug from the available subjects to 
evaluate the pharmacokinetics after taking the study drug at each visit by Week 12 of the 
Treatment Period. 
On the visit of Week 16, subjects should visit the study site after taking the study drug to collect 
pharmacokinetic samples 2 hour (acceptable time window, 1 to 3 hours) after taking the study drug 
at the same time as the blood sample collection for laboratory tests. 
9.1.13.1 
Collection of Plasma for Pharmacokinetic Sampling 
Blood samples (one 2-mL sample per scheduled time) for pharmacokinetic analysis of TAK-536 
and its metabolites (M-I and M-II) will be collected into vacutainers containing 
ethylenediaminetetraacetic acid dipotassium salt dihydrate (EDTA-2K). After mixing the 
vacutainers 5 to 6 times by inversion immediately, vacutainers will be centrifuged at 4°C and 
3000 rpm for 10 minutes. The plasma will be dispensed from the vacutainers to polypropylene 
tube and be stored frozen below -20°C in a freezer until being shipped to the analytical institute. 
For each sample, the date and time of the latest study drug administration and the actual time of 
blood sample collection will be recorded in the eCRF. 
9.1.13.2 
Bioanalytical Method 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) will be measured by 
HPLC/MS/MS (high-performance liquid chromatography with tandem mass spectrometry) at 
 
9.1.14 
Documentation of Subjects Failure 
An eCRF must be created for all subjects giving informed consent who withdrawn before the start 
of the Treatment Period. 
The primary reason for subject failure is recorded in the eCRF using the following categories: 
•
Death
•
Adverse Event
•
Screen Failure (failed inclusion criteria or did meet exclusion criteria)
•
Protocol deviation.
•
Lost to follow-up.
•
Withdrawal by subject <specify reason>.
•
Withdrawal by parent or guardian <specify reason>.
PPD


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•
Study terminated by sponsor.
•
Pregnancy
•
Other <specify reason>.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.15 
Documentation of Study Entrance 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the Treatment Period. 
If the subject is found to be not eligible for the Treatment Period, the investigator or 
subinvestigator should record the primary reason for failure on the applicable eCRF. 
9.2 
 Monitoring Subject Treatment Compliance 
Compliance with study drug (amount of dispense and return) between the visits, timing of the 
study dose (before or after breakfast) and the latest dosing date and time before collecting sample 
for pharmacokinetic evaluation will be confirmed and recorded in the eCRF. 
Subjects, the subjects’ parent, or the subjects’ legal guardian will be instructed to be compliant 
with the study drug throughout the study. If a subject is noncompliant (< 70% or > 130%) with the 
study medication (TAK-536 placebo) during the Run-in Period, the subject will be excluded 
before the start of the Treatment Period, as indicated in the exclusion criteria No. 5. If a subject is 
noncompliant with the study medication (TAK-536) (eg, failure to take < 50% of the scheduled 
dosed after the last visit) after the start of the Treatment Period, 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. 
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 points. 
9.3.1 
Screening 
Subjects will be screened within 14 days prior to the start of the Run-in Period. Subjects will be 
screened in accordance with predefined inclusion and exclusion criteria as described in 
Section 7.0. 
9.3.2 
Start of the Run-in Period (Week -2) 
The study drug (TAK-536 placebo) for the Run-in Period will be administered on the same day 
after the tests, observations and evaluations specified for each visit are performed. In case that 
subjects take RAS inhibitors in the morning of the visit day, the administration of the study drug 
(TAK-536 placebo) for the Run-in Period will be started from the next day. 


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Two weeks will be set as the Run-in Period. The subjects whose blood pressures meet the 
inclusion criteria 1 week (at earliest) after receiving placebo during the Run-in Period can enter the 
Treatment Period. For the subjects only who treated with any antihypertensive drugs as a prior 
treatment, the Run-in Period could be extended up to 4 weeks if blood pressures do not meet the 
inclusion criteria. 
9.3.3 
End of the Run-in Period (Week 0) 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will be entered after 
performing the tests and observations specified for each visit and will be initiated to receive the 
study drug for the Treatment Period on the same day. 
The first and the last date of the study drugs administration for the Run-in Period will be recorded 
in the eCRF for those receiving the study drugs for the Run-in Period and subsequently received 
the study drug for the Treatment Period. 
See Section 9.1.14 for procedures for documenting subjects withdrawn before the start of the 
Treatment Period. 
9.3.4 
Treatment Period (Weeks 2, 4, 8, 12, 16, 20, 24, 32, and 40) 
The tests and observations specified for each visit will be performed. 
Between the visits of Week 4 and 8 during the Treatment Period I, an additional unscheduled visit 
of Week 6 may be requested at the investigator’s discretion in order to titrate the dose of the study 
drug in the subjects when the further decrease in blood pressure is needed. 
On the visit of Week 16, subjects should visit the study site after taking the study drug and the tests 
and observations specified will be performed. 
9.3.5 
Final Visit or Early Termination 
The Final Visit will be performed on Week 52 or at the Early Termination Visit. 
The tests and observations specified for each visit will be performed. 
For subjects early terminate the study after the start of the Treatment Period, if possible, the same 
tests, observations, and evaluations as those scheduled at Week 52 should be performed. 
Whenever possible, office sitting blood pressure should be determined within 3 days after early 
termination and the other tests, observations, and evaluations should be performed within 14 days 
after early termination (the next day of the final dose should be calculated as the first day). 
For all subjects who entered the Treatment Period, the investigator or subinvestigator must 
complete the Subject Status on eCRF page with the first day when the subjects received the study 
drug for the Treatment Period and study completion or early termination status until Week 24 and 
study completion status at Week 52 for subjects who continuingly received the study drug beyond 
Week 24. 


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9.3.6 
Follow-up Period: Week 54 
Follow-up Period will begin the first day after the final administration of TAK-536 for the 
Treatment Period and will continue until 2 weeks. The tests and observations specified for each 
visit will be performed. If subjects terminate the study drug in the Run-in Period or at an early 
stage of the Treatment Period, no tests, observations, and evaluations will be required but care 
should be taken for subject safety. 
9.3.7 
Post Study Care 
The study drug 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 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with this treatment or study participation. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the study participation 
whether or not it is considered related to the drug or study procedures. 
10.1.2 
Additional Points to Consider for AEs 
An untoward finding generally may: 
•
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent
events for pre-existing conditions or underlying disease should not be considered AEs.)
•
Necessitate therapeutic intervention.
•
Require an invasive diagnostic procedure.
•
Require discontinuation or a change in dose of study drug or a concomitant medication.
•
Be considered unfavorable by the investigator or subinvestigator for any reason.
•
AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as an AE.
Diagnoses vs signs and symptoms:
•
Each event should be recorded to represent a single diagnosis. Accompanying signs (including
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded
appropriately as an AE(s).
Laboratory values and ECG findings: 
•
Changes in laboratory values or ECG parameters are only considered to be AEs if they are
judged to be clinically significant (i.e., if some action or intervention is required or if the
investigator or subinvestigator 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.
•
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 an AE.


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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 AEs. Baseline evaluations (eg,
laboratory tests, ECG, X-rays etc.) should NOT be recorded as AEs unless related to study
procedures. However, if the subject experiences a worsening or complication of such a
concurrent medical condition after informed consent is signed, the worsening or complication
should be recorded appropriately as an AE. The investigator or subnvestigator 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 an AE if the episodes become more frequent, serious or
severe in nature, that is, the investigator or subinvestigator 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 medical condition (eg, cataracts, rheumatoid
arthritis), worsening of the condition should only be captured as an AE if occurring to a greater
extent to that which would be expected. Again, the investigator or subinvestigator should
ensure that the AE term recorded captures the change in the condition (eg, “worsening of …”).
Worsening of AEs: 
•
If the subject experiences a worsening or complication of an AE after starting administration of
the study drug, or if a sign or a symptom appears secondarily due to an AE, the worsening or
complication should be recorded appropriately as a new AE. The investigator or
subinvestigator 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 the study
drug, or if a sign or a symptom appears secondarily due to an AE, the worsening or
complication should be recorded as a new AE. The investigator or subinvestigator should
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs: 
•
If the subject experiences changes in severity of an AE that are not related to starting the study
drug or changing in the dose or regimen, 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 AEs. However, if a preplanned procedure is performed
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of
the condition should be captured appropriately as an AE. Complications resulting from any
planned surgery should be reported as AEs.


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Elective surgeries or procedures: 
•
Elective procedures performed where there is no change in the subject’s medical condition
should not be recorded as AEs, but should be documented in the subject’s source documents.
Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy): 
•
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as
an AE. The investigator or subinvestigator 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
AEs, but instead will be documented on an Overdose page of the eCRF. Any manifested side
effects will be considered AEs and will be recorded on the AE page of the eCRF.
10.1.3 
SAEs 
An SAE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study: 
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.
Leads to 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 seizure
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
10.1.4 
AEs of Special Interest 
An AEs of Special Interest (treatment-emergent only, serious or non-serious) is one of scientific 
and medical concern specific to the compound or program, for which ongoing monitoring and 
rapid communication by the investigator or subinvestigator to Takeda may be appropriate. Such 
events may require further investigation in order to characterize and understand them and would 
be described in protocols and instructions provided for the investigator or subinvestigator as to 
how and when they should be reported to Takeda. 
10.1.5 
Severity of AEs 
The different categories of 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 to Study Drugs 
The causality of each AE to study drugs will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including the course 
after withdrawal of the drug), or for which a causal relationship is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be responsible. 
Not 
related: 
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. 


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10.1.7 
Causality of AEs to Study Procedures 
The causality of each AE to study procedures will be assessed. 
The causality should be assessed as Related if the investigator or subinvestigator considers that 
there is reasonable possibility that an event is due to a study procedure. Otherwise, the causality 
should be assessed as Not Related. 
10.1.8 
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
the investigator or subinvestigator. 
10.1.9 
End Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
10.1.10 Pattern of Adverse Event 
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous. 
10.1.11 Action Taken with Study Treatment 
•
Drug withdrawn – a study drug is stopped due to the particular AE.
•
Dose not changed – the particular AE did not require stopping a study drug.
•
Unknown – only to be used if it has not been possible to determine what action has been taken.
•
Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the
study has been terminated, the subject died, dosing with study drug was already stopped before
the onset of the AE, the AE that occurred before the study drug administration.
•
Drug 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.
•
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 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 state remaining “Not recovered/not
resolved”.


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•
Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left with
permanent/significant impairment (eg, recovered from a cardiovascular accident but with
some persisting paresis.
•
Fatal – the AEs which are considered as the cause of death.
•
Unknown – the course of the AE 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 AE Collection Period 
Collection of AEs will commence from the time the subject signs the informed consent. Routine 
collection of AEs will continue until the end of the Follow-up Period (or the tests performed at 
early termination). 
10.2.1.2 AE Reporting 
At each study visit, the investigator or subinvestigator 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 AE that occurs prior to the first exposure to study drug 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 AEs that occur prior to 
the first exposure to study drug, related or unrelated to the study procedure, need not to be 
followed-up for the purposes of the protocol. 
All subjects experiencing AEs after the first exposure to study drug, whether considered associated 
with the use of the study drug 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 AEs will be documented in the AE page of 
the eCRF, whether or not the investigator or subinvestigator concludes that the event is related to 
the drug treatment. The following information will be documented for each event: 
1. Event term.
2. Start and end date.
3. Pattern.
4. Severity.
5. Investigator’s opinion of the causality between the event and administration of study drug(s).
6. Investigator’s opinion of the causality to study procedure(s), including the details of the
suspected procedure.


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7. Action taken with study treatment (not applicable for the AE that occurred before the study
drug administration).
8. Outcome of event.
9. Seriousness.
10. After administration of study drug.
11. Treatment emergent.
10.2.1.3 AEs of Special Interest Reporting 
Pediatric subjects, the subject population of this study, are vulnerable, and as such need special 
attention with regard to the risk of the over decrease in blood pressure accompanying the use of 
antihypertensive drugs. Furthermore, kidney function is often impaired in pediatric subjects with 
secondary hypertension. Administration of RAS inhibitors to such patients may reduce GFR, 
deteriorating the kidney function. Hence, the following adverse events related to hypotension or 
renal impairment will be investigated as special interest AEs in this study. 
[Hypotension-related AE] 
Hypotension, blood pressure decreased, orthostatic hypotension, blood pressure orthostatic 
decreased, dizziness, dizziness postural, vertigo, circulatory collapse, shock, loss of consciousness, 
syncope, and presyncope. 
[Renal dysfunction-related AE] 
Renal failure, acute renal failure, renal impairment, prerenal failure, acute prerenal failure, anuria, 
oliguria, nephropathy toxic, acute phosphate nephropathy, and azotaemia. 
If this AE of special interest occurs during the Run-in Period, the Treatment Period or the 
Follow-up Period, it should be reported to the sponsor (described in the separate contact 
information list) immediately or within 1 business day of first onset or subject’s notification of the 
event. Hypotension-related AE or renal dysfunction-related AE Form or an SAE Form should be 
completed, signed and/or sealed by the principal investigator, and reported to appropriate 
personnel in the separate contact information list within 10 business days. 
The AE of special interest have to be recorded as AEs in the eCRF. An evaluation form along with 
all other required documentation must be submitted to the sponsor. 
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: 
An SAE should be reported to the sponsor (described in the separate contact information list) 
within 1 business day of first onset or subject’s, the subject’s parent’s, or the subject’s legal 
guardian’s notification of the event. The principal investigator should submit the completed SAE 
form within 10 calendar days. The information should be completed as fully as possible but 
contain, at a minimum: 


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•
A short description of the event and the reason why the event is categorized as serious.
•
Subject identification number.
•
Investigator’s or subinvestigator’s name.
•
Name of the study drugs
•
Causality assessment.
Any SAE spontaneously reported to the investigator or subinvestigator following the AE 
collection period should be reported to the sponsor if considered related to study participation. 
10.2.3 
Reporting of Abnormal Liver Function Tests 
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 or subinvestigator must contact the sponsor for discussion 
of the relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or 
B or other acute liver disease or medical history/concurrent medical conditions. Follow-up 
laboratory tests as described in Section 9.1.9 must also be performed. 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator or subinvestigator should complete a follow-up SAE form or provide other written 
documentation and fax it immediately. Copies of any relevant data from the hospital notes (eg, 
ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the addressee, if 
requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 
Safety Reporting to Investigators, IRBs, 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, and 
the head of the study site, as applicable. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee , SUSARs will be submitted to the regulatory 
authorities as expedited report 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 a study drug/sponsor supplied drug or that would be sufficient to 
consider changes in the study drug/sponsor supplied drug administration or in the overall conduct 
of the trial. The study site also will forward a copy of all expedited reports to his or her IRB. 


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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 and medical history including 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 eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs. 
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 eCRFs 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. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs. 
The following data will not be recorded into the eCRFs: 
•
Results of clinical laboratory tests conducted at the central laboratory
•
Results of pharmacokinetics conducted at the analytical institute
After the lock of the clinical study database, any change of, modification of or addition to the data 
on the eCRFs should be made by the investigator or subinvestigator with use of change and 
modification records of the eCRFs (Data Clarification Form) provided by the sponsor. The 
principal investigator must review the data change for completeness and accuracy, and must sign, 
or sign and seal, and date. 
eCRFs 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 eCRFs. The completed eCRFs 
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 and the head of the study site agree to keep the records stipulated in Section 12.1 
and those documents that include (but are not limited to) the study-specific documents, the 


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identification log of all participating subjects, medical records, source worksheets, all original 
signed and dated informed consent forms, electronic copy of eCRFs, including the audit trail, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities, the 
sponsor or its designees. Any source documentation printed on degradable thermal sensitive paper 
should be photocopied by the site and filed with the original in the subject’s chart to ensure long 
term legibility. Furthermore, the investigator and the head of the site are required to retain essential 
relevant documents until the day specified as 1) or 2) below, whichever comes later. However, if 
the sponsor requests a longer time period for retention, the head of the site should discuss how long 
and how to retain those documents with the sponsor. 
1. The day on which marketing approval of the study drug is obtained (or the day 3 years after the
date of notification in the case that the investigation is discontinued.)
2. The day 3 years after the date of early termination or completion of the clinical study.
In addition, the investigator and the head of the site should retain the essential relevant documents 
until the receipt of a sponsor-issued notification to state the retention is no longer required. 


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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 database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. 
A data review will be conducted prior to database lock. This review will assess the accuracy and 
completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods. 
At the time when the data of approximately 25 subjects are collected, the data until Week 12 in the 
Treatment Period will be analyzed. In addition, at the time when all subjects complete Week 24 or 
52 in the Treatment Period, the data until Week 24 or 52 in the Treatment Period will be analyzed 
separately after being locked. 
13.1.1 
Analysis Sets 
In this study, 2 kinds of analysis sets are defined: a full analysis set (FAS) and a safety analysis set. 
The safety analysis set used for safety analysis will be defined as “all subjects who received at least 
1 dose of the study drug for the Treatment Period.” The definition of each analysis set will be 
described in the Handling Rule for Analysis. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. The Handling Rule for Analysis must be 
finalized prior to database lock. 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Demographics will be summarized using the safety analysis set. 
13.1.3 
Efficacy Analysis 
(1) Secondary endpoints and analytical methods
[Secondary endpoints]
Office trough sitting systolic and diastolic blood pressure, proportion of subjects who achieve the 
target blood pressure 
[Analytical methods] 
The analyses discussed below will be conducted with the FAS. 
Summary statistics (number of subjects, mean, standard deviation, maximum, minimum, and 
quartiles; hereinafter the same) and 2-sided 95% confidence intervals for mean values will be 
calculated for the office trough sitting systolic and diastolic blood pressure at each time point 
(including the end of the Treatment Period I and the end of the Treatment Period II; hereinafter the 
same). 


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Summary statistics and 2-sided 95% confidence intervals for mean values will be calculated 
referring to a 1-sample t-test for the change of office trough sitting systolic and diastolic blood 
pressure from the end of the Run-in Period (Week 0) to each time point during the Treatment 
Period. 
The proportion of subjects who achieve the target blood pressure at each time point during the 
Treatment Period will be summarized. 
(2) Data conversion methods and handling of missing data
Details of data conversion methods and handling of missing data will be defined in the Handling 
Rule for Analysis and SAP. 
(3) Significant level and confidence coefficient
Significant level: 5% (2-sided test)
Confidence coefficient: 95% (2-sided estimates)
13.1.4 
Pharmacokinetic Analysis 
Pharmacokinetic endpoints and analytical methods 
[Secondary endpoints] 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) 
[Analytical methods] 
The following analyses will be conducted with the subjects who have adequately measured plasma 
concentration of TAK-536 in the FAS. 
Concentration of TAK-536 and its metabolites (M-I and M-II) in plasma will be summarized at 
each time point. 
A population pharmacokinetic analysis will be conducted with the subjects who have adequately 
measured plasma concentration of TAK-536 in the FAS. Population pharmacokinetic parameters 
in pediatric patients with hypertension will be estimated and the effect of weight on the 
pharmacokinetics of TAK-536 will be assessed quantitatively. In addition, other factors which 
affect the pharmacokinetics of TAK-536 will be explored. When the above analyses are conducted, 
an integrated analysis will be also performed with the data of the prior pharmacological study in 
pediatric patients with hypertension (TAK-536/CPH-103) as needed, and a SAP and an analysis 
results will be provided separately from those of this study. 
13.1.5 
Safety Analysis 
[Primary endpoints] 
AEs, anthropometric (weight, height and BMI) measurements, laboratory tests, resting 12-lead 
ECG, and vital signs (office standing blood pressure, office sitting pulse rate, office standing pulse 
rate, and home sitting blood pressure) 
[Analytical methods] 


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The following analyses will be conducted with the safety analysis set. 
1)
AEs (Treatment-emergent AEs)
A treatment-emergent AE (TEAE) is defined as any AE occurring after the start of TAK-536 
administration of the Treatment Period. 
The incidence of TEAEs listed below will be analyzed. TEAEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). The frequency distribution will be provided 
using the system organ class (SOC) and preferred term (PT) using MedDRA as follows: 
•
TEAEs
•
Drug-related TEAEs
•
Severity of TEAEs
•
Severity of drug-related TEAEs
•
TEAEs leading to study drug discontinuation
•
Serious TEAEs
•
TEAEs over time
2)
Anthropometric (weight, height and BMI) measurements, laboratory tests, resting 12-lead
ECG, and vital signs (office standing blood pressure, office sitting pulse rate, office standing
pulse rate, and home sitting blood pressure)
For continuous variables, the observed values and the changes from the end of the Run-in Period 
(Week 0) will be summarized for each time point. In addition, individual figures of the observed 
values will be provided. 
For categorical values, shift tables of the data before and after administration will be provided. 
13.2 
Interim Analysis and Criteria for Early Termination 
At the time when the data of approximately 25 subjects are collected, the data until Week 12 in the 
Treatment Period will be analyzed. In addition, at the time when all subjects complete Week 24 in 
the Treatment Period, the data until Week 24 in the Treatment Period will be analyzed separately 
after being locked. These analyses will not intend to continue or discontinue this study. 
13.3 
Determination of Sample Size 
Total of 50 subjects (who enter the Treatment Period). 
[Justification for Determination of Sample Size] 
Total of 50 subjects to enter the Treatment Period was set in consideration of feasibility. 
Assuming the mean change of trough sitting diastolic blood pressure from the end of the Run-in 
Period (Week 0) to the end of the Treatment Period I of -6.5 mmHg and an SD of 10.5 mmHg, and 
the mean change of trough sitting systolic blood pressure from the end of the Run-in Period 
(Week 0) to the end of the Treatment Period I of -9.5 mmHg and an SD of 15.5 mmHg, planned 50 


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subjects will provide at least 90% power by a 1-sample t-test at the 0.05 significance level 
(2-sided). 


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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 eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and site guarantee access to source documents by the sponsor or its designee 
(CRO) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the Investigator’s Binder, study drug, subject medical records, 
informed consent documentation, and review of eCRFs and associated source documents. It is 
important that the investigator, subinvestigator 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 or subinvestigator can deviate and change from the protocol for any medically 
unavoidable reason, for example, to eliminate an immediate hazard to study subjects, without a 
prior written agreement with the sponsor or a prior approval from IRB. In the event of a deviation 
or change, the principal investigator should notify the sponsor and the head of the site of the 
deviation or change as well as its reason in a written form, and then retain a copy of the written 
form. When necessary, the principal investigator may consult and agree with the sponsor on a 
protocol amendment. If the protocol amendment is appropriate, the amendment proposal should be 
submitted to the head of the site as soon as possible and an approval from IRB should be obtained. 
The investigator or subinvestigator should document all protocol deviations. Significant protocol 
deviations will be entered into the eCRF, which is reviewed by the study sponsor or designee. 
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
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 Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency [MHRA], PMDA). If the study site is 
contacted for an inspection by a regulatory body, the sponsor should be notified immediately. The 
investigator and site 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 (i.e., 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 Approval 
IRBs 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. If any member of the IRB 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 for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent/assent 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 for approval. The IRB’s written approval of the protocol and 
subject informed consent/assent must be obtained and submitted to the sponsor or designee before 
commencement of the study (i.e., before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB approval must refer to the study by exact protocol title, number, and 
version date; identify versions of other documents (eg, informed consent/assent form) reviewed; 
and state the approval date. The sponsor will notify site once the sponsor has confirmed the 
adequacy of site regulatory documentation. Until the site receives notification no protocol 
activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent/assent 
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, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee. 
Subject/parent/legal guardian incentives should not exert undue influence for participation. 
Payments to subjects, the subjects’ parent, or the subjects’ legal guardian must be approved by the 
IRB and sponsor. 
15.2 
Subject Information, Informed Consent/Assent, 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. An assent document describes the study, using a language 
appropriate to the subject’s age and development, to potential subjects with enough mental 
capacity to understand what it means to participate in a clinical study, and is used to obtain the 


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subject’s assent (a pediatric subject’s consent, which is not a regulatory requirement) separately 
from the subject’s parent’s, or the subject’s legal guardian’s consent. The informed consent form 
describes 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 
further explains 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 approval of the informed 
consent and assent forms. The informed consent and assent forms must be approved by both of the 
IRB and sponsor prior to use. 
The subject assent form must be written in a language appropriate to the subject’s age and 
development to the prospective subject. The informed consent form must be written in a language 
fully comprehensible to a subject’s parent or the subjects’ legal guardian. It is the responsibility of 
the investigator or subinvestigator to explain the subject assent form to the subject using a 
language and terms comprehensible and to explain the detailed elements of the informed consent 
form to a subject. Information should be given in both oral and written form whenever possible 
and in the manner deemed appropriate by the IRB. 
The subject and the subject’s parent, or the subject’s legal guardian 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’s parent or the subject’s legal guardian determines the subject will 
participate in the study, then the informed consent form must be signed and dated by the subject’s 
parent or the subject’s legal guardian at the time of consent and prior to the subject entering into 
the study. 
Whenever possible, the subject’s own assent should be obtained in addition to the subject’s 
parent’s or the subject’s legal guardian’s consent. The subject’s assent will be preferably obtained 
in writing, if he/she is a junior high school student or of a higher age. Whenever a written assent is 
not provided, though preferable also for subjects aged below junior high school students, the 
subject’s oral assent must be documented in the informed consent form signed by the subject’s 
parent or the subject’s legal guardian. The subject’s parent or the subject’s legal guardian should 
be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. 
Once signed, the original informed consent form, and the subject assent form (if applicable, the 
same hereinafter) will be stored in the investigator’s site file. The investigator or subinvestigator 
must document and the dates the subject’s parent or the subject’s legal guardian signs the informed 
consent form and the date the subject signs the informed assent form in the subject’s medical 
record. Copies of the signed informed consent form and the signed subject assent form shall be 
given to the subject, the subject’s parent, or the subject’s legal guardian. 
All revised informed consent/assent forms must be reviewed and signed by relevant subjects, the 
relevant subject’s parent or the subject’s legal guardian in the same manner as the original 
informed consent/assent. The date the revised consent/assent was obtained should be recorded in 


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the subject’s medical record, and the subject, the subject’s parent, or legal guardian should receive 
a copy of the revised informed consent/assent 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 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, MHRA, PMDA), the sponsor’s designated auditors, and the 
appropriate IRBs 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 and the subject’s parent, or the subject’s legal guardian as part of the informed 
consent/assent (if deemed appropriate by the investigator or subinvestigator) process (see Section 
15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
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 and after 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 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. 
The investigator and subinvestigator need to obtain a prior written approval from the sponsor to 
publish any information from the study externally such as to a professional association. 
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 laws, regulations and guidance, Takeda will, at a minimum register 


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interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, 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 and subinvestigator have questions 
regarding this policy, he or she should contact the sponsor or sponsor’s designee. 


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16.0 
REFERENCES 
1. Uchiyama M, Sakai K. Studies of blood pressures in school children in northern Japan. Public
Health. 1985;99:18-22.
2. Tochikubo O, Sasaki O, Umemura S, Kaneko Y. Management of hypertension in high school
students by using new salt titrator tape. J Hypertension. 1986;8:1164-71.
3. Stabouli S, Kotsis V, Zakopoulos N. Ambulatory blood pressure monitoring and target organ
damage in pediatrics. J Hypertens. 2007;25(10):1979-86.
4. Lurbe E, Cifkova R, Cruickshank JK, Dillon MJ, Ferreira I, Invitti C, et al. Management of
high blood pressure in children and adolescents: recommendations of the European Society of
Hypertension. J Hypertens. 2009;27:1719-42.
5. Bao W, Threefoot SA, Srinivasan SR, Berenson GS. Essential hypertension predicted by
tracking of elevated blood pressure from childhood to adulthood: the Bogalusa Heart Study.
Am J Hypertens. 1995;8:657-65.
6. The Japanese Society of Hypertension Committee for Guidelines for the Management of
Hypertension. The Japanese Society of Hypertension Guidelines for the Management of
Hypertension (JSH 2014). Tokyo: The Japanese Society of Hypertension; 2014.
7. The Japanese Circulation Society. The Guidelines for Drug Therapy in Pediatric Patients with
Cardiovascular Diseases: V. Antihypertensive Drugs. In: The Guidelines for Diagnosis and
Therapy of Cardiovascular Diseases (JCS 2012: The 2010-2011 Report of the Joint Working
Group). 2013. [cited 2014 Sep]. 184 pages. Available from:
http://www.j-circ.or.jp/guideline/index.htm. Accessed September 2014.
8. The final report on the Guidelines for Clinical Evaluation of Antihypertensive Drugs in
Children, a part of MHLW-commissioned research enterprise on the Guidelines for Clinical
Evaluation of New Drugs for Pediatric Disease.
9. Japanese Society of Nephrology. Evidence-based Clinical Practice Guideline for CKD 2013.
Tokyo Igakusha; 2013.
10. Principles for Clinical Evaluation of New Antihypertensive Drugs. (Notification No. 0128001
of the Evaluation and Licensing Division, PFSB dated January 28, 2002)
11. “The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for
Long-Term Treatment of Non-Life-Threatening Conditions” (PAB/ELD Notification No. 592,
Evaluation and Licensing Division, Pharmaceutical Affairs Bureau, Ministry of Health,
Labour and Welfare; May 24, 1995).
12. Partial Revision of the Guideline on Bioequivalence Studies of Generic Drugs: Pharmaceutical
and Food Safety Bureau Notification No.0229-10, February 29, 2012.
13. MHLW. The physical status survey: Part 2 of the National Health and Nutrition Survey 2011.
2013. [cited 2014 Sep]. 46 pages. Available from:
http://www.mhlw.go.jp/bunya/kenkou/eiyou/h23-houkoku.html. Accessed September 2014.


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14. Uemura O, Nagai T, Ishikura K, Ito S, Hataya H, Gotoh Y, et al. Creatinine-based equation to
estimate the glomerular filtration rate in Japanese children and adolescents with chronic
kidney disease. Clin Exp Nephrol. 2014;18:626-33.


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Appendix C Detailed Description of Amendments to Text 
The primary sections of the protocol affected by the changes in amendment 01 are described. The 
corresponding text has been revised throughout the protocol. 
The primary change: Section 7.3.1 Excluded Medications 
Existing Text: RAS inhibitors 
Revised Text: RAS inhibitors (ACE inhibitors, ARB, and DRI) 
Rationale for Amendment: Clarify definition of RAS inhibitors. 
The primary change: Section 8.1.3 Dose and Regimen 
Added Text: 
At the start of the Run-in Period (Week -2), the study drug for the Run-in Period will be 
administered on the same day after completing all tests, observations, and evaluations. In 
case that subjects take RAS inhibitors in the morning of the visit day, the administration of 
the study drug for the Run-in Period will be started from the next day. 
Rationale for Amendment: Clarify dosage of the Run-in Period (Week -2). 
The primary change: Section 9.1.10 Contraception and Pregnancy Avoidance Procedure 
Existing Text: 
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 excluded, the only 
acceptable methods of contraception are: 
Barrier methods (each time the subject has intercourse): 
Intrauterine devices (IUDs): 
•
Male condom PLUS spermicide.
•
Copper T PLUS condom.
The subject and the subject’s parent, or the subject’s legal guardian will be provided with 
information on acceptable methods of contraception as part of the subject informed consent/assent 
process and will be asked to sign a consent/assent form stating that they understand the 
requirements for avoidance of pregnancy, donation of ova from providing the consent/assent until 
1 month has passed from the end of the study. 
Revised Text: 
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, female subjects of childbearing potential must use copper intrauterine devices 
(IUDs) combined with male condom or female condom. Medications and devices containing 
hormones are excluded. 
The subject and the subject’s parent, or the subject’s legal guardian will be provided with 
information on acceptable methods of contraception as part of the subject informed consent/assent 


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process and will be asked to sign a consent/assent form stating that they understand the 
requirements for avoidance of pregnancy, preservation or donation of ova from providing the 
consent/assent until 1 month has passed from the end of the study. 
Rationale for Amendment: Clarify examples of contraceptive methods and add the description 
as to avoiding preservation of ova. 

SAP_001.pdf: 
 
 
Title: A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, 
Efficacy and Pharmacokinetics of TAK-536 in Pediatric Patients 6 to Less Than 16 Years 
of Age with Hypertension 
 
NCT Number: NCT02791438 
Statistical analysis plan Approve Date: 05-OCT-2018 
 
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. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
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. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 


1.0 
TITLE PAGE 
 
STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: TAK-536/OCT-101 
A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, Efficacy and 
Pharmacokinetics of TAK-536 in Pediatric Patients 6 to Less Than 16 Years of Age with 
Hypertension 
 
PHASE 3 
Version: 1.0 
Date: 05 October 2018 
 
 
 
 
Prepared by: 
 
 
 
 
 
Based on: 
Protocol Version: Amendment 02 
Protocol Date: 12 Apr 2017 
 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
PPD
PPD


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This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda. 


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Approval Signatures 
Electronic signatures can be found on the last page of this document. 


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2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .................................................................................................................. 1 
 
Approval Signatures .................................................................................................. 3 
2.0 
TABLE OF CONTENTS ................................................................................................ 4 
List of In-Text Tables ........................................................................................................... 5 
List of In-Text Figures .......................................................................................................... 6 
3.0 
LIST OF ABBREVIATIONS .......................................................................................... 7 
4.0 
OBJECTIVES ................................................................................................................. 9 
 
Primary Objectives .................................................................................................... 9 
 
Secondary Objectives ................................................................................................ 9 
 
Study Design ............................................................................................................. 9 
5.0 
ANALYSIS ENDPOINTS ............................................................................................ 12 
6.0 
DETERMINATION OF SAMPLE SIZE ....................................................................... 13 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .................................................. 14 
 
General Principles ................................................................................................... 14 
 Study Definitions ............................................................................................... 14 
 Definition of Study Days ................................................................................... 15 
 Definition of Study Visit Windows .................................................................... 15 
 Significance Level and Confidence Coefficient .................................................. 18 
 Conventions for Missing Adverse Event Dates .................................................. 18 
 Conventions for Missing Concomitant Medication Dates ................................... 19 
 
Analysis Sets ........................................................................................................... 19 
 
Disposition of Subjects ............................................................................................ 19 
 Study Information .............................................................................................. 19 
 Screen Failures .................................................................................................. 19 
 Subject Eligibility .............................................................................................. 20 
 Number of Subjects Who Entered the Treatment Period by Site ......................... 20 
 Disposition of Subjects ...................................................................................... 20 
 Study Drug Completion Status ........................................................................... 21 
 Protocol Deviations and Analysis Sets ............................................................... 22 
 
Demographic and Other Baseline Characteristics ..................................................... 23 
 
Medical History and Concurrent Medical Conditions............................................... 24 
 
Medication History and Concomitant Medications .................................................. 25 
 
Study Drug Exposure and Compliance .................................................................... 26 
 Study Drug Exposure and Compliance ............................................................... 26 


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 Dose Escalation ................................................................................................. 26 
 
Efficacy Analysis .................................................................................................... 27 
 Primary Efficacy Endpoint(s)............................................................................. 27 
 Secondary Efficacy Endpoint(s) ......................................................................... 27 
 Additional Efficacy Endpoint(s) ........................................................................ 28 
 Statistical/Analytical Issues ............................................................................... 28 
 
Pharmacokinetic/Pharmacodynamic Analysis .......................................................... 29 
 Pharmacokinetic Analysis .................................................................................. 29 
 Pharmacodynamic Analysis ............................................................................... 30 
 
Other Outcomes ...................................................................................................... 30 
 
Safety Analysis........................................................................................................ 30 
 Adverse Events .................................................................................................. 30 
 Clinical Laboratory Evaluations ......................................................................... 34 
 Vital Signs and Weight ...................................................................................... 36 
 12-Lead ECGs ................................................................................................... 37 
 Other Observations Related to Safety................................................................. 38 
 
Interim Analysis ...................................................................................................... 38 
 
Changes in the Statistical Analysis Plan................................................................... 38 
8.0 
REFERENCES ............................................................................................................. 39 
9.0 
APPENDIX................................................................................................................... 40 
 
AEs of Special Interest ............................................................................................ 40 
 
Criteria for Markedly Abnormal Values .................................................................. 41 
 
Criteria for Home Blood Pressure ............................................................................ 42 
 
LIST OF IN-TEXT TABLES 
Table 5.a  Reference Blood Pressure Values of Children by Gender and Age .......................... 12 
Table 7.a  Visit Window of Office Sitting Blood Pressure and Pulse Rate ............................... 16 
Table 7.b  Visit Window of Clinical Laboratory Test Items ..................................................... 16 
Table 7.c  Visit Window of Office Standing Blood Pressure and Pulse Rate............................ 17 
Table 7.d  Visit Window of Height and Weight ....................................................................... 17 
Table 7.e  Visit Window of Resting 12-lead ECG ................................................................... 17 
Table 7.f  Visit Window of Plasma Drug Concentration (day of blood sample collection) ....... 17 
Table 7.g  Visit Window of Plasma Drug Concentration (time of blood sample collection) ..... 18 
Table 7.h  Visit Window of Home Blood Pressure .................................................................. 18 
Table 9.a  Hypotention-related AE .......................................................................................... 40 


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Table 9.b  Renal Dysfunction-related AE ................................................................................ 41 
Table 9.c  MAV Criteria for Serum Chemistry ........................................................................ 42 
Table 9.d  Criteria for Home Blood Pressure ........................................................................... 43 
 
LIST OF IN-TEXT FIGURES 
Figure 4.a  Schematic of Study Design .................................................................................... 11 
 


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3.0 
LIST OF ABBREVIATIONS 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ARB 
angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
BBs 
beta-blockers 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CKD 
chronic kidney disease 
CRO 
contract research organization 
CT 
computed tomography 
CCB 
calcium channel blocker 
CV 
coefficient of variation 
DRI 
direct renin inhibitor 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
hCG 
human chorionic gonadotropin 
HIV 
human immunodeficiency virus 
HPLC/MS/MS 
high-performance liquid chromatography with tandem mass spectrometry 
Ht 
height 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
JCS 2012 
Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular Diseases by the 
Japanese Circulation Society 
JSH 2014 
Guidelines for the Management of Hypertension 2014 
LDH 
lactate dehydrogenase 
LFT 
Liver Function Test 
LLN 
lower limit of normal 
MAV 
markedly abnormal value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
NSAIDs 
non-steroidal anti-inflammatory drugs 


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OTC 
over-the-counter 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PT 
preferred term 
PTE 
pretreatment event 
PTP 
press through package 
QOL 
quality of life 
RAS 
renin-angiotensin-system 
RBC 
red blood cell 
SAE 
serious AE 
SAP 
statistical analysis plan 
SDTM 
study data tabulation model 
SOC 
system organ class 
SUSARs 
suspected unexpected serious adverse reactions 
SV 
subject visits 
TEAE 
treatment emergent AE 
TPC 
Takeda Pharmaceutical Company Limited 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO 
World Health Organization 
WHO Drug 
World Health Organization Drug Dictionary 
 


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4.0 
OBJECTIVES 
 
Primary Objectives 
To evaluate the safety of administration of TAK-536 in pediatric patients aged 6 to less than 16 
years with hypertension 
 
Secondary Objectives 
To evaluate the efficacy and pharmacokinetics of administration of TAK-536 in pediatric 
patients aged 6 to less than 16 years with hypertension 
 
Study Design 
This is a phase 3, open-label, multicenter study to evaluate the safety, efficacy, and 
pharmacokinetics of long-term administration of TAK-536 once daily for 52 weeks in pediatric 
patients aged 6 to less than 16 years with hypertension. 
The study consists of a 2-week Run-in Period, a 52-week Treatment Period (Treatment Period I, 
12 weeks; Treatment Period II, 40 weeks), and a 2-week Follow-up Period (56 weeks in total). 
(1) Screening and Run-in Period 
Subjects eligible at screening will initiate to receive the placebo in a single-blinded fashion at the 
start of the Run-in Period. 
The duration of the Run-in Period will be 2 weeks. The subjects whose blood pressures meet the 
inclusion criteria 1 week (at earliest) after receiving placebo in the Run-in Period can enter the 
Treatment Period. For subjects who have been treated with any antihypertensive drugs as a prior 
treatment, the Run-in Period can be extended up to 4 weeks if their blood pressures do not meet 
the inclusion criteria. 
Subjects who have been treated with renin-angiotensin-system (RAS) inhibitors (ACE inhibitors, 
ARB, and DRI) until the start of the Run-in Period should discontinue them at the start of the 
Run-in Period. Subjects who have been treated with antihypertensive drugs other than RAS 
inhibitors until the start of the Run-in Period can continue to receive a single antihypertensive 
drug in addition to the study drug if the investigator or subinvestigator considers that the subjects 
need additional treatment for hypertension in Treatment Period I; the antihypertensive drug 
should be administered under the same dosage at the time of the start of the Run-in Period. If 
subjects have difficulty in discontinuing antihypertensive drugs completely at the start of the 
Run-in Period, the antihypertensive drugs can be down-titrated concurrently with the 
administration of placebo. In the case of down-titration, antihypertensive drugs should be 
discontinued at least 1 week (7 days) before the start of Treatment Period I. Specifically, 
beta-blockers (BBs) should be tapered off gradually since sudden discontinuation of BBs may 
cause withdrawal syndrome. 


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(2) Treatment Period I 
In Treatment Period I (Week 0 to 12), the initial dose of TAK-536 will be 2.5 mg for subjects 
weighing < 50 kg or 5 mg for subjects weighing ≥ 50 kg. After the initial dose, TAK-536 will be 
titrated to 5 mg, 10 mg, and 20 mg for subjects weighing < 50 kg or to 10 mg, 20 mg, and 40 mg 
for subjects weighing ≥ 50 kg at the investigator’s or subinvestigator’s discretion when the 
subjects do not achieve the target blood pressure* and no concerns are found in tolerability. 
TAK-536 will be titrated at any scheduled visit for Week 2, 4, or 8 in Treatment Period I, as a 
general rule. Between the visits for Week 4 and 8 during Treatment Period I, an additional 
unscheduled visit during Week 6 may be requested at the investigator’s or subinvestigator’s 
discretion in order to titrate the dose of the study drug in the subjects when a further decrease in 
blood pressure is needed. TAK-536 can be reduced at the investigator’s or subinvestigator’s 
discretion if there are any concerns about tolerability with titration of TAK-536 (i.e., in case of 
the occurrence of any adverse events [AEs] caused by titration of TAK-536). During Treatment 
Period I, change in the dosage of the antihypertensive drug is prohibited in subjects who are 
being treated with a single antihypertensive drug other than RAS inhibitors at the start of 
Treatment Period I. 
*target blood pressure: 
< 95th percentile shown in Table 5.a  Reference Blood Pressure Values of Children by Gender 
and Age for essential hypertension, < 90th percentile shown in Table 5.a  Reference Blood 
Pressure Values of Children by Gender and Age for secondary hypertension 
(3) Treatment Period II 
During Treatment Period II (Week 12 to 52), the treatments at the End of Treatment Period I will 
be continued. TAK-536 can be titrated to the highest dose (20 mg for subjects weighing < 50 kg 
or 40 mg for subjects weighing ≥ 50 kg, the same hereinafter) at the investigator’s or 
subinvestigator’s discretion when the subjects do not achieve the target blood pressure and no 
concerns are found in tolerability. When the subjects do not achieve the target blood pressure 
with the highest dose of TAK-536, the subjects can receive additional antihypertensive drugs 
(other than RAS inhibitors) or can change in dose of the antihypertensive drug in addition to 
TAK-536 at the investigator’s or subinvestigator’s discretion. 
When the antihypertensive drugs require dose reduction or interruption because of concerns in 
tolerability with titration in Treatment Period II (i.e., excessive reduction in blood pressure, other 
AEs, etc.), the antihypertensive drugs other than TAK-536 (in case of concomitant use) should 
be reduced or interrupted first. Thereafter, dose reduction or interruption of TAK-536 should be 
considered. 
(4) Follow-up Period 
The Follow-up Period will be 2 weeks from the day after the final dose of TAK-536. Safety will 
be evaluated at Week 54 after the start of the Treatment Period. 
At the time when the data from approximately 25 subjects are collected, the data until Week 12 
in the Treatment Period will be analyzed. In addition, at the time when all subjects complete 


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Statistical Analysis Plan Version 1.0 
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CONFIDENTIAL 
Week 24 in the Treatment Period, the data until Week 24 in the Treatment Period will be 
analyzed separately after being locked. These analyses will not intend to continue or discontinue 
this study. 
A schematic of the study design is included as Figure 4.a. 
 
 
 
 
Run-in 
Period 1),2) 
Treatment Period I* 
Treatment Period II 
Follow-up 
Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 mg (< 50 kg) or 40 mg (≥ 50 kg) 3),4) 
 
 
 
 
 
 
 
 
 
 
 
10 mg (< 50 kg) or 20 mg (≥ 50 kg) 3),4) 
 
 
 
 
 
 
 
 
 
5 mg (< 50 kg) or 10 mg (≥ 50 kg) 3),4) 
 
 
 
 
 
Placebo 
2.5 mg (< 50 kg) or 5 mg (≥ 50 kg) 3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-2W 
0W 
2W 
4W 
8W 
 
12W 
 
52W 
54W 
Concomitant use 
of 
antihypertensive 
drugs 
RAS inhibitors are prohibited. 
 
 
 
Subjects who have been treated with antihypertensive drugs other than RAS 
inhibitors until the start of the Run-in Period can continue to receive a single 
antihypertensive drug in addition to the study drug (Change in the dosage of the 
antihypertensive drug is prohibited).2),5) 
Subjects can receive 
antihypertensive drugs (other than 
RAS inhibitors) or can change the 
dosage of the antihypertensive 
drug in addition to TAK-536.6) 
 
 
 
1) The subjects whose blood pressures meet the inclusion criteria 1 week (at the earliest) after receiving placebo in the Run-in Period can enter 
the Treatment Period. For subjects who have been treated with any antihypertensive drugs as a prior treatment, the Run-in Period can be 
extended up to 4 weeks if their blood pressures do not meet the inclusion criteria. 
2) If subjects have difficulty in discontinuing antihypertensive drugs completely at the start of the Run-in Period, the antihypertensive drugs can 
be down-titrated concurrently with the administration of placebo. In the case of down-titration, antihypertensive drugs should be discontinued 
at least 1 week (7 days) before the start of Treatment Period I. Specifically, beta-blockers (BBs) should be tapered off gradually since sudden 
discontinuation of BBs may cause withdrawal syndrome. 
3) In Treatment Period I, TAK-536 can be titrated biweekly when the subjects do not achieve the target blood pressure while evaluating safety 
and tolerability. TAK-536 can be reduced at the investigator’s or subinvestigator’s discretion if there are any concerns about tolerability with 
titration of TAK-536 (i.e., in case of the occurrence of any adverse events [AEs] caused by titration of TAK-536). 
4) When the antihypertensive drugs require dose reduction or interruption because of concerns in tolerability with titration in Treatment Period II 
(i.e., excessive reduction in blood pressure, other AEs, etc.), the antihypertensive drugs other than TAK-536 (in case of concomitant use) 
should be reduced or interrupted first. Thereafter, dose reduction or interruption of TAK-536 should be considered. 
5) Subjects who have been treated with antihypertensive drugs other than RAS inhibitors until the start of the Run-in Period can continue to 
receive a single antihypertensive drug in addition to the study drug if the investigator or subinvestigator considers that the subjects need 
additional treatments for hypertension in Treatment Period I. Change in the dosage of the antihypertensive drug at the start of the Run-in 
Period I is prohibited until the End of Treatment Period I. 
6) In Treatment Period II, when the subjects do not achieve the target blood pressure with the highest dose of TAK-536, the subjects can receive 
antihypertensive drugs (other than RAS inhibitors) or can change in dosage of the antihypertensive drug in addition to TAK-536 at the 
investigator’s or subinvestigator’s discretion. 
* Between the visits for Week 4 and 8, an additional unscheduled visit during Week 6 may be requested at the investigator’s or subinvestigator’s 
discretion in order to titrate the dose of the study drug in the subjects when a further decrease in blood pressure is needed. 
Figure 4.a  Schematic of Study Design 
Screening 


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CONFIDENTIAL 
5.0 
ANALYSIS ENDPOINTS 
Primary Efficacy Endpoint 
<Safety> 
AEs, anthropometric (weight, height, and body mass index [BMI]) measurements, laboratory 
tests, resting 12-lead electrocardiogram (ECG), and vital signs (office standing blood pressure, 
office sitting pulse rate, office standing pulse rate, and home sitting blood pressure) 
Secondary Efficacy Endpoints 
<Efficacy> 
Office trough* sitting diastolic and systolic blood pressures 
* Trough: The time point immediately before the next dosing, when the blood drug 
concentration is assumed to be lowest 
Proportion of subjects who achieve the target blood pressure** 
** Target blood pressure: < 95th percentile shown in Table 5.a  Reference Blood Pressure 
Values of Children by Gender and Age for essential hypertension, < 90th percentile shown 
in Table 5.a  Reference Blood Pressure Values of Children by Gender and Age for 
secondary hypertension 
Table 5.a  Reference Blood Pressure Values of Children by Gender and Age 
 
Boy 
Girl 
 
90th 
95th 
99th 
90th 
95th 
99th 
6 years old 
110/70 
114/74 
121/82 
108/70 
111/74 
119/81 
7 years old 
111/72 
115/76 
122/84 
109/71 
113/75 
120/82 
8 years old 
112/73 
116/78 
123/86 
111/72 
115/76 
122/83 
9 years old 
114/75 
118/79 
125/87 
113/73 
117/77 
124/84 
10 years old 
115/75 
119/80 
127/88 
115/74 
119/78 
126/86 
11 years old 
117/76 
121/80 
129/88 
117/75 
121/79 
128/87 
12 years old 
120/76 
123/81 
131/89 
119/76 
123/80 
130/88 
13 years old 
122/77 
126/81 
133/89 
121/77 
124/81 
132/89 
14 years old 
125/78 
128/82 
136/90 
122/78 
126/82 
133/90 
15 years old 
127/79 
131/83 
138/91 
123/79 
127/83 
134/91 
16 years old 
130/80 
134/84 
141/92 
124/80 
128/84 
135/91 
Systolic/diastolic blood pressures (mmHg, JCS2012) 
The 90th, 95th, and 99th indicate 90th, 95th, and 99th percentiles, respectively. 
<Pharmacokinetics> 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) 


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CONFIDENTIAL 
6.0 
DETERMINATION OF SAMPLE SIZE 
Total of 50 subjects (who enter the Treatment Period). 
 
[Sample Size Justification] 
A total of 50 subjects to enter the Treatment Period was set in consideration of feasibility. 
Assuming a mean change of trough sitting diastolic blood pressure from the end of the Run-in 
Period (Week 0) to the end of Treatment Period I of −6.5 mmHg and an SD of 10.5 mmHg, and 
a mean change of trough sitting systolic blood pressure from the end of the Run-in Period (Week 
0) to the end of Treatment Period I of −9.5 mmHg and an SD of 15.5 mmHg, the planned 50 
subjects will provide at least 90% power by a 1-sample t-test at a 0.05 significance level 
(2-sided). 


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Statistical Analysis Plan Version 1.0 
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CONFIDENTIAL 
7.0 
METHODS OF ANALYSIS AND PRESENTATION 
 
General Principles 
 Study Definitions 
• Day of last observation/test or contact, whichever comes later: Last date of SDTM.SV 
• Treatment-emergent adverse event (TEAE): Any AE occurring after the first study drug 
administration for the Treatment Period 
• Pretreatment event (PTE): Any AE occurring after obtaining informed consent but before the 
first study drug administration for the Run-in Period 
• Adverse event during the Run-in Period: For subjects who enter the Treatment Period, any 
AE occurring after the first study drug administration for the Run-in Period until the first 
study drug administration for the Treatment Period. For subjects who do not enter the 
Treatment Period, any AE occurring after the first study drug administration for the Run-in 
Period 
• Summary statistics: Number of subjects, mean, standard deviation, maximum, minimum, and 
quartiles 
• Duration of exposure to study drug for the Treatment Period: Date of the last study drug 
administration for the Treatment Period − Date of the first study drug administration for the 
Treatment Period + 1 
• Study period after the study drug administration for the Treatment Period: Date of last 
observation/test or contact − Date of the first study drug administration for the Treatment 
Period + 1 
• Compliance rate with the study drug for the Treatment Period: Total number of doses of 
study drug for the Treatment Period (Amount of study drug dispensed for the Treatment 
Period − Amount of study drug returned for the Treatment Period) / Duration of exposure to 
study drug for the Treatment Period × 100 (rounded to 1 decimal place) 
• Office trough sitting diastolic and systolic blood pressures on each measuring day: The mean 
of 3 values on a given measuring day (rounded to integers) is used as the representative value 
of that measuring day. 
• Achievement of target blood pressure on each measuring day: Subjects are determined to 
have achieved their target blood pressures if their blood pressures are the < 95th percentile 
(both diastolic and systolic) shown in Table 5.a  Reference Blood Pressure Values of 
Children by Gender and Age for essential hypertension or < 90th percentile (both diastolic 
and systolic) shown in Table 5.a  Reference Blood Pressure Values of Children by Gender 
and Age for secondary hypertension. If either systolic or diastolic blood pressure is missing, 
it will be handled as missing data. The age at the time of informed consent will be used. 


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CONFIDENTIAL 
• Disease duration (years): (Date of informed consent [year and month] − Time of onset [or 
diagnosis] of underlying disease [year and month]) / 12 (rounded to 1 decimal place) 
For the date of informed consent, only the year and month will be used. If the year of onset 
(or diagnosis) of underlying disease is unknown, it will be classified as “Unknown.” If only 
the month of onset (or diagnosis) of underlying disease is unknown, the disease duration will 
be calculated with the month of onset (or diagnosis) of underlying disease as January. 
• QTcF interval: Fridericia's formula (QT interval / [RR interval0.33]) 
• CV (%): Standard deviation / mean × 100 
 Definition of Study Days 
• Study Day: The day before the first study drug administration for the Treatment Period will 
be defined as Day −1 and the day of the first study drug administration for the Treatment 
Period will be defined as Day 1. 
• Follow-up Day: The day after the last study drug administration for the Treatment Period will 
be defined as Follow-up Day 1. 
 Definition of Study Visit Windows 
For each test, observation, and endpoint except for home blood pressure, all evaluable data (i.e., 
non-missing data) will be handled according to the following rules. 
For each visit other than the End of Treatment Period I and the End of Treatment Period, the 
evaluable data within the acceptable time window will be used. If more than one evaluable 
datum lies within the same acceptable time window, the data whose test/observation/evaluation 
time point is closest to the scheduled time point will be used. If there are two data equidistant to 
the scheduled time point, the data obtained later will be used. The temporal distance from the 
scheduled time point will be determined based on the Study Day and the time interval between 
the latest study drug administration and the blood sample collection. 
For the End of Treatment Period I and the End of the Treatment Period, the evaluable data within 
the acceptable time window with the largest Study Day will be used. 


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CONFIDENTIAL 
Table 7.a  Visit Window of Office Sitting Blood Pressure and Pulse Rate 
Visit 
Scheduled Study Day 
Acceptable Time Window 
Study Day 
Follow-up Day 
At the End of Run-in Period 
(Week 0) 
Study Day: 1 
−28 to 1 
 
Week 2 
Study Day: 15 
2 to 22 
< 4 
Week 4 
Study Day: 29 
23 to 43 
< 4 
Week 8 
Study Day: 57 
44 to 71 
< 4 
Week 12 
Study Day: 85 
72 to 99 
< 4 
Week 16 (postdose) 
Study Day: 113 
100 to 127 
< 4 
Week 20 
Study Day: 141 
128 to 155 
< 4 
Week 24 
Study Day: 169 
156 to 183 
< 4 
Week 32 
Study Day: 225 
184 to 253 
< 4 
Week 40 
Study Day: 281 
254 to 323 
< 4 
Week 52 
Study Day: 365 
324 to 372 
< 4 
Week 54 (Follow-up Period) 
Study Day: 379 
373 to 386 
> 0 
At the End of Treatment 
Period I*1 
  
2 to 99 
< 4 
At the End of Treatment 
Period*2 
  
2 ≤ 
< 4 
*1 Data obtained after the earliest day of addition or dose change of antihypertensive drugs other than RAS 
inhibitors during the Treatment Period will not be used for summaries. Not applicable for office sitting pulse rate. 
*2 The condition of *1 will not apply to this handling. Not applicable for office sitting pulse rate. 
Table 7.b  Visit Window of Clinical Laboratory Test Items 
Visit 
Scheduled Study Day 
Acceptable Time Window 
Study Day 
Follow-up Day 
At the End of Run-in Period 
(Week 0) 
Study Day: 1 
−28 to 1 
 
Week 2 
Study Day: 15 
2 to 22 
< 15 
Week 4 
Study Day: 29 
23 to 43 
< 15 
Week 8 
Study Day: 57 
44 to 71 
< 15 
Week 12 
Study Day: 85 
72 to 99 
< 15 
Week 16 (postdose) 
Study Day: 113 
100 to 141 
< 15 
Week 24 
Study Day: 169 
142 to 225 
< 15 
Week 40 
Study Day: 281 
226 to 323 
< 15 
Week 52 
Study Day: 365 
324 to 379 
< 15 
 


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CONFIDENTIAL 
Table 7.c  Visit Window of Office Standing Blood Pressure and Pulse Rate 
Visit 
Scheduled Study Day 
Acceptable Time Window 
Study Day 
Follow-up Day 
At the End of Run-in Period 
(Week 0) 
Study Day: 1 
−28 to 1 
 
Week 12 
Study Day: 85 
2 to 127 
< 4 
Week 24 
Study Day: 169 
128 to 267 
< 4 
Week 52 
Study Day: 365 
268 to 379 
< 4 
 
Table 7.d  Visit Window of Height and Weight 
Visit 
Scheduled Study Day 
Acceptable Time Window 
Study Day 
Follow-up Day 
At the End of Run-in Period 
(Week 0) 
Study Day: 1 
−28 to 1 
 
Week 12 
Study Day: 85 
2 to 127 
< 15 
Week 24 
Study Day: 169 
128 to 225 
< 15 
Week 40 
Study Day: 281 
226 to 323 
< 15 
Week 52 
Study Day: 365 
324 to 379 
< 15 
 
Table 7.e  Visit Window of Resting 12-lead ECG 
Visit 
Scheduled Study Day 
Acceptable Time Window 
Study Day 
Follow-up Day 
At the End of Run-in Period 
(Week 0) 
Study Day: 1 
−42 to 1 
 
Week 12 
Study Day: 85 
2 to 127 
< 15 
Week 24 
Study Day: 169 
128 to 267 
< 15 
Week 52 
Study Day: 365 
268 to 379 
< 15 
 
Table 7.f  Visit Window of Plasma Drug Concentration (day of blood sample collection) 
Visit 
Scheduled Study Day 
Acceptable Time Window 
Study Day 
Week 2 (predose, postdose) 
Study Day: 15 
2 to 22 
Week 4 (predose, postdose) 
Study Day: 29 
23 to 43 
Week 8 (predose, postdose) 
Study Day: 57 
44 to 71 
Week 12 (predose, postdose) 
Study Day: 85 
72 to 99 
Week 16 (postdose) 
Study Day: 113 
100 to 127 
 


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Statistical Analysis Plan Version 1.0 
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CONFIDENTIAL 
Table 7.g  Visit Window of Plasma Drug Concentration (time of blood sample collection) 
Time Point 
Time Interval between the Latest Study Drug Administration and the Blood Sample 
Collection 
Scheduled Time 
Acceptable Time Window 
Predose 
24 hours 
21 to 27 hours 
Postdose 
2 hours 
1 to 3 hours 
 
For home blood pressure, the mean of 2 values on a given measuring day will be used as the 
representative value of that measuring day (do not round off). If only one measurement is 
performed on a given measuring day, that value will be used as the representative value. Next, 
based on Table 7.h, the mean of the representative values on each measuring day within each 
acceptable time window (rounded to integers) will be used as the values for each visit. However, 
if the representative values on the measuring day within the time window include values for 3 
days or less, this visit will be handled as missing. At the End of Treatment Period I, among the 
values from Week 0 (postdose) to Week 12 included based on Table 7.h, the value at the last 
visit excluding missing data will be used. If the acceptable time window overlaps at different 
visits, the value will be included in the earlier visit and excluded from the later visit. 
Table 7.h  Visit Window of Home Blood Pressure 
Visit 
Reference Day 
Acceptable Time Window 
Number of Days from 
Reference Day* 
Follow-up Day 
Week 0 (predose) 
Visit day for Week 0  
−7 to −1 
 
Week 0 (postdose) 
Visit day for Week 0  
2 to 8 
< 4 
Week 2 
Visit day for Week 2  
2 to 8 
< 4 
Week 4 
Visit day for Week 4  
2 to 8 
< 4 
Week 8 
Visit day for Week 8  
2 to 8 
< 4 
Week 12 
Visit day for Week 12  
−7 to −1 
< 4 
*: The day before the Reference Day will be defined as Day −1 and the Reference Day as Day 1. 
 Significance Level and Confidence Coefficient 
• Significance level: 5% (2-sided test) 
• Confidence coefficient: 95% (2-sided estimates) 
No statistical testing and calculation of confidence interval will be performed if there are less 
than 2 subjects to be analyzed. 
 Conventions for Missing Adverse Event Dates 
Not applicable in this study. 


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Statistical Analysis Plan Version 1.0 
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CONFIDENTIAL 
 Conventions for Missing Concomitant Medication Dates 
Not applicable in this study. 
 
Analysis Sets 
• Full analysis set (FAS): All subjects who received at least 1 dose of the study drug for the 
Treatment Period 
• Safety analysis set: All subjects who received at least 1 dose of the study drug for the 
Treatment Period 
 
Disposition of Subjects 
 Study Information 
Analysis set: 
All subjects who signed the informed consent form 
Analysis variable(s): 
Date the first subject signed the informed consent form 
Date of last observation/test or contact, whichever comes later 
MedDRA version 
WHO Drug version 
SAS version used for creating the data sets 
Analytical method(s): 
The following analysis will be performed for the above analysis variables. 
(1) Display of analysis variables 
 Screen Failures 
Analysis set: 
All subjects who did not enter the Treatment Period 
Analysis variable(s): 
Categories in parenthesis [  ] (hereinafter, the same) 
Age (years) 
[6, 7, 8, 9, 10, 11, 12, 13, 14, 15] 
Gender 
[Male, Female] 
Analytical method(s): 
The following analysis will be performed for the above analysis variables. 


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(1) Frequency distributions for categorical variables and summary statistics for continuous 
variables 
 Subject Eligibility 
Analysis set: 
All subjects who signed the informed consent form 
Analysis variable(s): 
Entrance into the Treatment Period 
[Yes, No] 
Primary reason for subject not entering the Treatment Period 
[Death, 
Adverse 
event, 
Screening failure, Protocol deviation, Lost to follow-up, Withdrawal by subject, Withdrawal 
by parent/guardian, Study terminated by sponsor, Pregnancy, Other] 
Analytical method(s): 
The following analysis will be performed for the above analysis variables. 
When calculating the percentages for the primary reasons for subjects not entering the 
Treatment Period, the total number of subjects who did not enter the Treatment Period will 
be used as the denominator. 
(1) Frequency distributions 
 Number of Subjects Who Entered the Treatment Period by Site 
Analysis set: 
All subjects who entered the Treatment Period 
Analysis variable(s): 
Entrance into the Treatment Period 
[Yes] 
Stratum: 
Study Site 
[Study site number is used for site classification] 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by each stratum. 
(1) Frequency distributions 
 Disposition of Subjects 
Analysis set: 
All subjects who entered the Treatment Period 
Analysis variable(s): 
Completed study drug for the Treatment Period 
[Completed, Prematurely discontinued] 


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Reason for discontinuation 
[Death, Adverse event, Protocol deviation, Lost to follow-up, 
Withdrawal by subject, Withdrawal by parent/guardian, Study terminated by Sponsor, 
Pregnancy, Lack of efficacy, Other] 
Completed Follow-up Period [Completed, Prematurely discontinued] 
Reason for discontinuation 
[Death, Adverse event, Protocol deviation, Lost to follow-up, 
Withdrawal by subject, Withdrawal by parent/guardian, Study terminated by Sponsor, 
Pregnancy, Lack of efficacy, Other] 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by weight group (< 
50 kg, ≥ 50 kg) and in the combined weight groups. When calculating the percentages for the 
reasons for subjects not receiving the study drug, the total number of subjects who did not 
receive the study drug for the Treatment Period will be used as the denominator and when 
calculating the percentages for the reasons for discontinuation, the total number of subjects 
who prematurely discontinued will be used as the denominator. 
(1) Frequency distributions 
 Study Drug Completion Status 
Analysis set: 
All subjects who entered the Treatment Period 
Analysis variable(s): 
Completed study drug for the Treatment Period [Completed, Prematurely discontinued] 
Reason for discontinuation 
[Death, Adverse event, Protocol deviation, Lost to follow-up, 
Withdrawal by subject, Withdrawal by parent/guardian, Study terminated by Sponsor, 
Pregnancy, Lack of efficacy, Other] 
Categories: 
Duration of exposure to study drug for the Treatment Period (days) 
[0, 1≤ - ≤84, 85≤ - 
≤168, 169≤ - ≤252, 253≤ - ≤336, 337≤ - ≤420, 421≤ - ≤Max] 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by weight group (< 
50 kg, ≥ 50 kg) and in the combined weight groups. 
(1) Frequency distributions by duration of exposure to study drug for the Treatment Period 


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Statistical Analysis Plan Version 1.0 
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CONFIDENTIAL 
 Protocol Deviations and Analysis Sets 
 Protocol Deviations 
Analysis set: 
All subjects who entered the Treatment Period 
Analysis variable(s): 
Protocol deviations 
[Deviations of protocol entry criteria, Deviations concerning excluded 
medication or therapy, Noncompliance with protocol, Deviations related to the treatment 
procedure or dose, Deviations of discontinuation criteria, Major GCP violations] 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by weight group (< 
50 kg, ≥ 50 kg) and in the combined weight groups. 
Frequency distribution of subjects with protocol deviations will be provided for above each 
deviation category. A subject who has several deviations that can be classified into the same 
category will be counted once in each appropriate category (overlapped counting). 
(1) Frequency distributions 
 Analysis Sets 
Analysis set: 
All subjects who entered the Treatment Period 
Analysis variable(s): 
Handling of subjects in analysis sets 
[Categories are based on the specifications in 
Subject Evaluability List] 
Inclusion/exclusion of analysis set 
Full analysis set 
[Included] 
Safety analysis set 
[Included] 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by weight group (< 
50 kg, ≥ 50 kg) and in the combined weight groups. 
For (1), a subject who falls into several categories will be counted once in each appropriate 
category (overlapped counting). 
(1) Frequency distributions concerning handling of subjects in each analysis set 
(2) Frequency distributions concerning number of subjects included in each analysis set 


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CONFIDENTIAL 
 
Demographic and Other Baseline Characteristics 
Analysis set: 
Safety analysis set 
Analysis variable(s): 
Age (years) 
[6, 7, 8, 9, 10, 11, 12, 13, 14, 15] 
Gender 
[Male, Female] 
Height (cm) at Week 0 
[Min≤ - ≤99, 100≤ - ≤109, 110≤ - ≤119, 120≤ - ≤129, 130≤ - 
≤139, 140≤ - ≤149, 150≤ - ≤159, 160≤ - ≤169, 170≤ - ≤179, 180≤ - ≤Max] 
Weight (kg) at Week 0 
[Min≤ - ≤19.9, 20.0≤ - ≤29.9, 30.0≤ - ≤39.9, 40.0≤ - ≤49.9, 
50.0≤ - ≤59.9, 60.0≤ - ≤69.9, 70.0≤ - ≤79.9, 80.0≤ - ≤Max] 
[Min≤ - ≤49.9, 50.0≤ - ≤Max] 
BMI (kg/m2) at Week 0 
[Min≤ - ≤14.9, 15.0≤ - ≤17.9, 18.0≤ - ≤20.9, 21.0≤ - ≤23.9, 
24.0≤ - ≤26.9, 27.0≤ - ≤Max] 
Disease duration (years) 
[Min≤ - ≤0.9, 1.0≤ - ≤1.9, 2.0≤ - ≤2.9, 3.0≤ - ≤3.9, 4.0≤ - ≤Max] 
Type of hypertension [Essential hypertension, Secondary hypertension] 
Drug induced hypertension 
[Yes, No] 
Disease induced hypertension 
[Yes, No] 
History of kidney transplantation 
[Yes, No] 
Antihypertensive drugs prior to Run-in Period 
[Yes, No] 
ACE inhibitors 
[Yes, No] 
ARB 
[Yes, No] 
DRI 
[Yes, No] 
CCB 
[Yes, No] 
Diuretics 
[Yes, No] 
Alpha-blockers 
[Yes, No] 
Beta-blockers 
[Yes, No] 
Other 
[Yes, No] 
RAS inhibitors (ACE inhibitors, ARB, and DRI) prior to Run-in Period 
[Yes, No] 
Antihypertensive drugs at the start of Treatment Period I 
[Yes, No] 
CCB 
[Yes, No] 
Diuretics 
[Yes, No] 


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CONFIDENTIAL 
Alpha-blockers 
[Yes, No] 
Beta-blockers 
[Yes, No] 
Other 
[Yes, No] 
Office sitting blood pressure (systolic) (mmHg) at Week 0 
[Min≤ - ≤109, 110≤ - ≤119, 
120≤ - ≤129, 130≤ - ≤139, 140≤ - ≤Max] 
Office sitting blood pressure (diastolic) (mmHg) at Week 0 
[Min≤ - ≤69, 70≤ - ≤79, 80≤ - 
≤89, 90≤ - ≤99, 100≤ - ≤Max] 
eGFR (mL/min/1.73 m2) 
[Min≤ - ≤29, 30≤ - ≤59, 60≤ - ≤89, 90≤ - ≤Max] 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by weight group (< 
50 kg, ≥ 50 kg) and in the combined weight groups. 
(1) Frequency distributions for categorical variables and summary statistics for continuous 
variables 
 
Medical History and Concurrent Medical Conditions 
Analysis set: 
Safety analysis set 
Analysis variable(s): 
Underlying diseases of secondary hypertension 
Medical history (other than the underlying disease of secondary hypertension) 
Concurrent medical conditions (other than the underlying disease of secondary hypertension) 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by weight group (< 
50 kg, ≥ 50 kg) and in the combined weight groups. 
Analysis variables will be coded using MedDRA and will be summarized based on SOCs and 
PTs. SOCs will be sorted alphabetically and PTs will be sorted in decreasing frequency. 
(1) Frequency distributions for underlying diseases of secondary hypertension by SOC and 
PT 
(2) Frequency distributions for medical history by SOC and PT 
(3) Frequency distributions for concurrent medical conditions by SOC and PT 
The frequency distributions will be provided according to the rules below: 
[Number of subjects] 


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Statistical Analysis Plan Version 1.0 
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CONFIDENTIAL 
A subject with multiple occurrences of medical history or concurrent medical condition 
within a SOC will be counted only once in that SOC. A subject with multiple occurrences of 
medical history or concurrent medical condition within a PT will be counted only once in 
that PT. 
 
Medication History and Concomitant Medications 
Analysis set: 
Safety analysis set 
Analysis variable(s): 
Medication history 
Concomitant medications (antihypertensive drugs) 
Concomitant medications (other than antihypertensive drugs) 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by weight group (< 
50 kg, ≥ 50 kg) and in the combined weight groups. 
Analysis variables will be coded using the WHO Drug and will be summarized based on 
Preferred Name, which will be sorted in decreasing frequency. A subject who has been 
administered several medications with the same Preferred Name will be counted only once 
for that Preferred Name. 
(1) Frequency distributions for medication history 
(2) Frequency distributions for concomitant medications (antihypertensive drugs) that 
stopped prior to the study drug administration for the Treatment Period 
(3) Frequency distributions for concomitant medications (antihypertensive drugs) that 
started prior to the study drug administration for the Treatment Period and were ongoing 
during the Treatment Period 
(4) Frequency distributions for concomitant medications (antihypertensive drugs) that 
started after the study drug administration for the Treatment Period 
(5) Frequency distributions for concomitant medications that started prior to the study drug 
administration for the Treatment Period and were ongoing during the Treatment Period 
and concomitant medications (other than antihypertensive drugs) that started after the 
study drug administration for the Treatment Period 


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Study Drug Exposure and Compliance 
 Study Drug Exposure and Compliance 
Analysis set: 
Safety analysis set 
Analysis variable(s): 
Duration of exposure to study drug for the Treatment Period (days) 
[1≤ - ≤84, 85≤ - ≤168, 
169≤ - ≤252, 253≤ - ≤336, 337≤ - ≤420, 421≤ - ≤Max] 
Study drug compliance rate for the Treatment Period (%) 
[Min≤ - ≤69.9, 70.0≤ - ≤79.9, 
80.0≤ - ≤89.9, 90.0≤ - ≤Max] 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by weight group (< 
50 kg, ≥ 50 kg) and in the combined weight groups. 
(1) Frequency distributions for categorical variables and summary statistics for continuous 
variables 
 Dose Escalation 
Analysis set: 
Safety analysis set 
Analysis variable(s): 
Dose dispensed at each visit 
[2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg] 
Visit: 
Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 32, 40, and at the End of Treatment Period 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by weight group (< 
50 kg, ≥ 50 kg) and in the combined weight groups. 
For the dose dispensed at each visit, the dose dispensed on the day of first study drug 
administration for the Treatment Period will be used for Week 0 and the dose dispensed on 
the day before the visit day will be used except for Week 0. If dose on the visit day is missing, 
the last dose dispensed by the scheduled study day (Days 1, 15, 29, 43, 57, 85, 113, 141, 169, 
225, and 281 for Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 32, and 40, respectively [the day of the 
first study drug administration for the Treatment Period to be defined as Day 1]) will be used 
until the day of study drug discontinuation. After the day of study drug discontinuation, the 
dose dispensed on that visit will be handled as missing and excluded from summaries. 


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The dose dispensed at the End of the Treatment Period will be the last dose dispensed for 
each subject. 
(1) Frequency distributions 
 
Efficacy Analysis 
 Primary Efficacy Endpoint(s) 
The safety endpoints are the primary endpoints in this study. 
 Secondary Efficacy Endpoint(s) 
Analysis set: 
Full analysis set 
Analysis variable(s): 
Office trough sitting diastolic blood pressure 
Office trough sitting systolic blood pressure 
Proportion of subjects who achieved the target blood pressure 
Visit: 
Weeks 0, 2, 4, 8, 12, 16 (postdose), 20, 24, 32, 40, 52, 54 (Follow-up Period), at the End of 
Treatment Period I, and at the End of Treatment Period 
Analytical method(s): 
The following analyses (1) and (2) will be performed for office trough sitting diastolic and 
systolic blood pressures by weight group (< 50 kg, ≥ 50 kg) and in the combined weight 
groups. 
The following analysis (3) will be performed for the proportion of subjects who achieved the 
target blood pressure by weight group (< 50 kg, ≥ 50 kg) and in the combined weight groups. 
The measurement at Week 16 (postdose) will be performed after the study drug 
administration, while the measurement at other visits than Week 16 (postdose) will be 
performed before the study drug administration. 
(1) Summary statistics and 2-sided 95% confidence intervals of means at each visit will be 
calculated. 
(2) Summary statistics and 2-sided 95% confidence intervals of means will be calculated for 
changes (each visit after Week 2 − Week 0) at each visit. For the population in the 
combined weight groups, a one-sample t-test will be applied for reference. 
(3) Frequency distributions will be provided at each visit and the 2-sided 95% confidence 
interval of the proportion will be calculated. 


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 Additional Efficacy Endpoint(s) 
Analysis set: 
Full analysis set 
Analysis variable(s): 
Home sitting diastolic blood pressure 
Home sitting systolic blood pressure 
Visit: 
Weeks 0 (predose), 0 (postdose), 2, 4, 8, 12, and at the End of Treatment Period I 
Analytical method(s): 
The following analyses will be performed for home sitting diastolic and systolic blood 
pressures by weight group (< 50 kg, ≥ 50 kg) and in the combined weight groups. 
(1) Summary statistics and 2-sided 95% confidence intervals of means at each visit will be 
calculated. 
(2) Summary statistics and 2-sided 95% confidence intervals of means will be calculated for 
changes (each visit after Week 0 (postdose) − Week 0 (predose) at each visit. For the 
population in the combined weight groups, a one-sample t-test will be applied for 
reference. 
 Statistical/Analytical Issues 
 Adjustments for Covariates 
Not applicable in this study. 
 Handling of Dropouts or Missing Data 
Missing test results will be excluded from statistical analyses and estimations for that item. 
Plasma concentrations and clinical laboratory data below the lower limit of quantification will be 
handled as 0. Clinical laboratory data above the upper limit of quantification will be handled as 
the upper limit of quantification. 
 Multicenter Studies 
This is a single arm study, and thus no arms-sites interaction will be analyzed. 
 Multiple Comparison/Multiplicity 
Not applicable in this study. 
 Use of an "Efficacy Subset" of Subjects 
Not applicable in this study. 


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 Active-Control Studies Intended to Show Equivalence or Non-Inferiority 
Not applicable in this study. 
 Examination of Subgroups 
Analysis set: 
Full analysis set 
Analysis variable(s): 
Office trough sitting diastolic blood pressure (change at the End of Treatment Period I) 
Office trough sitting systolic blood pressure (change at the End of Treatment Period I) 
Proportion of subjects who achieved the target blood pressure (at the End of Treatment 
Period I) 
Stratum: 
Gender 
[Male, Female] 
Type of hypertension 
[Essential hypertension, Secondary hypertension] 
RAS inhibitors (ACE inhibitors, ARB, and DRI) prior to Run-in Period 
[Yes, No] 
Antihypertensive drugs at the start of Treatment Period I 
[Yes, No] 
eGFR (mL/min/1.73 m2) 
[Min≤ - ≤59, 60≤ - ≤89, 90≤ - ≤Max] 
Analytical Method(s): 
The following analysis (1) will be performed for office trough sitting diastolic and systolic 
blood pressures by each stratum. The following analysis (2) will be performed for the 
proportion of subjects who achieved the target blood pressure by each stratum. 
(1) Summary statistics 
(2) Frequency distributions 
 
Pharmacokinetic/Pharmacodynamic Analysis 
 Pharmacokinetic Analysis 
Analysis set: 
Subjects who underwent proper determination of plasma concentrations of TAK-536 in the 
“full analysis set” 
Analysis variable(s): 
Plasma concentrations of TAK-536 and its metabolites (M-I and M-II) 


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Visit: 
Week 2 (predose), Week 2 (postdose), Week 4 (predose), Week 4 (postdose), Week 8 
(predose), Week 8 (postdose), Week 12 (predose), Week 12 (postdose), and Week 16 
(postdose) 
Analytical method(s): 
The following analysis (1) will be performed for the above analysis variables by weight 
group (< 50 kg, ≥ 50 kg) and in the combined weight groups. The dose immediately before 
the blood sample collection for plasma concentrations will be used. The following analysis 
(2) will be performed in the combined weight groups. 
(1) Summary statistics and CV (%) by dose at each visit 
(2) A scatter plot for TAK-536 plasma concentration at Week 2 (predose) and changes in 
office sitting blood pressure (diastolic and systolic) at the same visit will be presented. 
 Pharmacodynamic Analysis 
Not applicable in this study. 
 
Other Outcomes 
Not applicable in this study. 
 
Safety Analysis 
The safety endpoints are the primary endpoints in this study. 
 Adverse Events 
 Overview of Treatment-Emergent Adverse Events 
Analysis set: 
Safety analysis set 
Analysis variable(s): 
TEAE 
Categories: 
Relationship to study drug 
[Related, Not related] 
Intensity 
[Mild, Moderate, Severe] 
Analytical method(s): 
The following summaries will be provided for the above analysis variables by weight group 
(< 50 kg, ≥ 50 kg) and in the combined weight groups. 
(1) Overview of TEAE 


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1) All TEAEs (number of events, number and percentage of subjects) 
2) Relationship of all TEAEs to study drug (number of events, number and percentage 
of subjects) 
3) Intensity of all TEAEs (number of events, number and percentage of subjects) 
4) TEAEs leading to study drug discontinuation (number of events, number and 
percentage of subjects) 
5) Serious TEAEs (number of events, number and percentage of subjects) 
6) Relationship of serious TEAEs to study drug (number of events, number and 
percentage of subjects) 
7) Serious TEAEs leading to study drug discontinuation (number of events, number 
and percentage of subjects) 
8) TEAEs resulting in death (number of events, number and percentage of subjects) 
TEAEs will be counted according to the rules below: 
[Number of subjects] 
• In case of “summaries by relationship to study drug” 
A subject with occurrences of TEAE in both categories (i.e., Related and Not related) 
will be counted once in the Related category. 
• In case of “summaries by intensity” 
A subject with multiple occurrences of TEAE will be counted once for the TEAE with 
the maximum intensity. 
• In case of summaries other than the above 
A subject with multiple occurrences of TEAE will be counted only once. 
[Number of events] 
For each summary, the total number of events will be calculated. 
 Displays of Treatment-Emergent Adverse events 
Analysis set: 
Safety analysis set 
Analysis variable(s): 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 


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Time of onset (day) 
[1≤ - ≤14, 15≤ - ≤28, 29≤ - ≤42, 43≤ - ≤56, 57≤ - ≤70, 71≤ - ≤84, 
85≤ - ≤Max] [1≤ - ≤84, 85≤ - ≤168, 169≤ - ≤252, 253≤ - ≤336, 337≤ - ≤420, 421≤ - ≤Max] 
Analytical method(s): 
The following summaries will be provided for the above analysis variables using frequency 
distributions by weight group (< 50 kg, ≥ 50 kg) and in the combined weight groups. 
TEAEs will be coded using MedDRA and will be summarized based on SOCs and PTs. 
SOCs will be sorted alphabetically and PTs will be sorted in decreasing frequency for tables 
provided by SOC and PT. SOC and PT will be sorted in decreasing frequency for tables 
provided by SOC only or PT only. 
See "9.0 APPENDIX" for definitions of the TEAEs related to hypotension and renal 
dysfunction. 
(1) All TEAEs by SOC and PT 
(2) All TEAEs by SOC 
(3) All TEAEs by PT 
(4) Drug-related TEAEs by SOC and PT 
(5) Intensity of all TEAEs by SOC and PT 
(6) Intensity of drug-related TEAEs by SOC and PT 
(7) TEAEs leading to study drug discontinuation by SOC and PT 
(8) Serious TEAEs by SOC and PT 
(9) All TEAEs by SOC and PT over time 
(10) TEAEs related to hypotension by SOC and PT 
(11) TEAEs related to renal dysfunction by SOC and PT 
(12) Non-serious TEAEs whose incidence summarized by PT is ≥ 2% by SOC and PT 
The frequency distribution and incidence will be provided according to the rules below: 
[Number of subjects] 
• In case of “summaries by SOC and PT, by SOC only, or PT only” 
A subject with multiple occurrences of TEAE within a SOC will be counted only once 
in that SOC. A subject with multiple occurrences of TEAE within a PT will be counted 
only once in that PT. Also, when calculating the percentages for TEAEs, the number of 
subjects in the safety analysis set will be used as the denominator. 
• In case of “summaries of intensity by SOC and PT” 
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted 
only once for the TEAE with the maximum intensity. Also, when calculating the 


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percentages for TEAEs, the number of subjects in the safety analysis set will be used as 
the denominator. 
• In case of “summaries by SOC and PT over time” 
A subject with a TEAE that occurs in more than one interval is counted in all the 
intervals that the TEAE occurs. For each time interval, a subject with multiple 
occurrences of TEAE within a SOC or a PT will be counted only once in that SOC or 
PT. When calculating the percentages of TEAEs for each time interval, the number of 
subjects at risk (i.e., “subjects who either have an exposure to study drug or have an 
occurrence of TEAE, during or after the corresponding time interval”) will be used as 
the denominator. The number of subjects whose “onset of any one of the TEAEs is 
within the time interval” will be used as the numerator. 
 Displays of Pretreatment Events 
Analysis set: 
All subjects who signed the informed consent form 
Analysis variable(s): 
PTE 
Analytical method(s): 
The following analysis will be performed for the above analysis variables using frequency 
distributions. 
PTEs will be coded using MedDRA and will be summarized based on SOCs and PTs. SOCs 
will be sorted alphabetically and PTs will be sorted in decreasing frequency. 
(1) All PTEs by SOC and PT 
(2) Serious PTEs by SOC and PT 
The frequency distributions will be provided according to the rules below: 
[Number of subjects] 
A subject with multiple occurrences of PTE within a SOC will be counted only once in that 
SOC. A subject with multiple occurrences of PTE within a PT will be counted only once in 
that PT. 
 Displays of Run-in Adverse Events 
Analysis set: 
All subjects who received the study drug for the Run-in Period 
Analysis variable(s): 
AEs during the Run-in Period 


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Analytical method(s): 
The following analysis will be performed for the above analysis variables using frequency 
distributions. 
AEs during the Run-in Period will be coded using MedDRA and will be summarized based 
on SOCs and PTs. SOCs will be sorted alphabetically and PTs will be sorted in decreasing 
frequency. 
(1) All AEs during the Run-in Period by SOC and PT 
(2) Serious AEs during the Run-in Period by SOC and PT 
The frequency distributions will be provided according to the rules below: 
[Number of subjects] 
A subject with multiple occurrences of AE within a SOC will be counted only once in that 
SOC. A subject with multiple occurrences of AE within a PT will be counted only once in 
that PT. 
 Clinical Laboratory Evaluations 
 Hematology and Serum Chemistry 
Analysis Set: 
Safety analysis set 
Analysis variable(s): 
Hematology 
Red blood cell count, White blood cell count with differential (neutrophils, basophils, 
eosinophils, lymphocytes, monocytes), Hemoglobin, Hematocrit, Platelets 
Serum Chemistry 
ALT, Albumin, ALP, AST, Total bilirubin, BUN, Calcium, Chloride, Creatinine, 
Creatinine kinase, Cystatin C, eGFR, GGT, Glucose, Total cholesterol, Triglycerides, 
Phosphate, Potassium, Sodium, Total Protein, LDH 
Categories: 
Results of determination based on normal reference range 
[Below lower limit of normal 
range, Within normal range, Over upper limit of normal range] 
Visit: 
Weeks 0, 2, 4, 8, 12, 16 (postdose), 24, 40, and 52 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by weight group (< 
50 kg, ≥ 50 kg) and in the combined weight groups. 


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When performing analyses on MAV, if a laboratory parameter has both lower and upper 
MAV criteria, an analysis will be performed for each. See “9.0 APPENDIX” for test items to 
be analyzed and definitions of MAV criteria. 
The measurement at Week 16 will be performed after the study drug administration, while 
the measurement at other visits than Week 16 will be performed before the study drug 
administration. 
(1) Summary statistics for observed values and changes (each visit after administration 
[Week 2 to Week 52] − Week 0) will be provided for each visit. 
(2) Case Plots 
(3) Shift tables showing results of determination based on normal reference range at Week 0 
and each visit after administration 
(4) Overall frequency distributions of MAV during the Treatment Period 
 Urinalysis 
Analysis set: 
Safety analysis set 
Analysis variable(s): 
Quantitative variable(s) 
Specific gravity, Protein, Creatinine, Albumin, Protein/creatinine ratio, 
Albumin/creatinine ratio 
Qualitative variable(s) 
Glucose, pH, Protein, Occult blood, Ketones 
Categories: 
Results of determination based on normal reference range 
[Below lower limit of normal 
range, Within normal range, Over upper limit of normal range] 
Visit: 
Weeks 0, 2, 4, 8, 12, 16 (postdose), 24, 40, and 52 
Analytical method(s): 
The following analyses (1), (2), and (4) will be performed for the quantitative variables by 
weight group (< 50 kg, ≥ 50 kg) and in the combined weight groups. 
The following analyses (3) and (4) will be per formed for the qualitative variables, by weight 
group (< 50 kg, ≥ 50 kg) and in the combined weight groups. 


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The measurement at Week 16 will be performed after the study drug administration, while 
the measurement at other visits than Week 16 will be performed before the study drug 
administration. 
(1) Summary statistics for observed values and changes (each visit after administration 
[Week 2 to Week 52] − Week 0) will be provided for each visit. 
(2) Case Plots 
(3) Shift tables at Week 0 and each visit after administration 
(4) Shift tables showing results of determination based on normal reference range at Week 0 
and each visit after administration (variables with normal reference range) 
 Vital Signs and Weight 
Analysis set: 
Safety analysis set 
Analysis variable(s): 
Office sitting pulse rate 
Office standing systolic blood pressure, Office standing diastolic blood pressure, Office 
standing pulse rate 
Home sitting systolic and diastolic blood pressures 
Height, Weight 
Visit 
Office sitting pulse rate: Weeks 0, 2, 4, 8, 12, 16 (postdose), 20, 24, 32, 40, 52, 54 
(Follow-up Period) 
Office standing blood pressure and pulse rate: Weeks 0, 12, 24, and 52 
Home blood pressure: Week 0 (predose), Week 0 (postdose), Weeks 2, 4, 8, and 12 
Height and weight: Weeks 0, 12, 24, 40, and 52 
Analytical method(s): 
The following analysis will be performed for the above analysis variables by weight group (< 
50 kg, ≥ 50 kg) and in the combined weight groups. 
The measurement of office sitting pulse rate at Week 16 will be performed after the study 
drug administration, while the measurement at other visits than Week 16 will be performed 
before the study drug administration. 
(1) Summary statistics for observed values and changes (each visit after administration 
[each visit other than Week 0] − Week 0) will be provided for each visit. 


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Home blood pressure will be provided for changes (each visit after administration 
[each visit other than Week 0 (predose)] − Week 0 [predose]). 
(2) Case Plots 
(3) Overall frequency distributions of home blood pressure during the Treatment Period. See 
“9.0 APPENDIX" for the criteria.” 
 12-Lead ECGs 
Analysis set: 
Safety analysis set 
Analysis variable(s): 
Heart rate 
RR interval 
PR interval 
QT interval 
QTcF interval 
QRS interval 
Resting 12-lead ECG interpretation 
[Within normal limits, Abnormal but not clinically 
significant, Abnormal and clinically significant] 
Visit: 
Weeks 0, 12, 24, and 52 
Analytical method(s): 
The following analyses (1) and (2) will be performed for the above analysis variables 
excluding resting 12-lead ECG interpretation by weight group (< 50 kg, ≥ 50 kg) and in the 
combined weight groups. 
The following analysis (3) will be performed for resting 12-lead ECG interpretation by 
weight group (< 50 kg, ≥ 50 kg) and in the combined weight groups. 
(1) Summary statistics for observed values and changes (each visit after administration 
[Week 12 to Week 52] − Week 0) will be provided for each visit. 
(2) Case Plots 
(3) Shift tables at Week 0 and each visit after administration 


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 Other Observations Related to Safety 
 Displays of Treatment-Emergent Adverse Events (Japanese) 
Analysis set: 
Safety analysis set 
Analysis variable(s): 
TEAE 
Analytical method(s): 
The similar summaries as Section 7.11.1.2 will be provided for the above analysis variables. 
All summaries will be presented in Japanese. 
 
Interim Analysis 
At the time when the data from approximately 25 subjects are collected, the data until Week 12 
in the Treatment Period will be analyzed. In addition, at the time when all subjects complete 
Week 24 in the Treatment Period, the data until Week 24 in the Treatment Period will be 
analyzed separately after being locked. These analyses will not intend to continue or discontinue 
this study. 
The analyses at Week 12 will be performed only for items required to examine the study design 
for subjects aged less than 6 years in this statistical analysis plan. Specifically, they are 7.3.5, 
7.3.6, 7.4, 7.5, 7.7.1, 7.7.2, 7.8.2, 7.8.4.7, 7.9.1 (1), 7.11.1, 7.11.1.2, (1), (4) to (11) (and the 
corresponding Japanese analysis [7.11.5.1]), and 7.11.2.1. The results of these analyses will be 
included in the consultation materials with regulatory authorities and not included in the clinical 
study report. Additional analyses may be performed in response to changes in the policy for 
preparing consultation materials or requests from regulatory authorities. In such cases, the 
statistical analysis plan will not be revised or the additional analysis plan will not be prepared. 
 
Changes in the Statistical Analysis Plan 
Although home blood pressure is defined as a safety endpoint in the protocol, it will be also 
evaluated as an efficacy endpoint as described in 7.8.3 in this statistical analysis plan. 


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8.0 
REFERENCES 
Not applicable. 


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9.0 
APPENDIX 
 
AEs of Special Interest 
Table 9.a  Hypotention-related AE 
PT_NAME 
PT_CODE 
Bezold-Jarisch reflex 
10076999 
Blood pressure ambulatory decreased 
10005731 
Blood pressure decreased 
10005734 
Blood pressure diastolic decreased 
10005737 
Blood pressure immeasurable 
10005748 
Blood pressure orthostatic abnormal 
10053354 
Blood pressure orthostatic decreased 
10053356 
Blood pressure systolic decreased 
10005758 
Blood pressure systolic inspiratory decreased 
10005761 
Capillary leak syndrome 
10007196 
Cardiogenic shock 
10007625 
Cardiovascular insufficiency 
10065929 
Circulatory collapse 
10009192 
CT hypotension complex 
10078280 
Diastolic hypotension 
10066077 
Dizziness 
10013573 
Dizziness exertional 
10013576 
Dizziness postural 
10013578 
Hypoperfusion 
10058558 
Hypotension 
10021097 
Hypotensive transfusion reaction 
10072264 
Hypovolaemia 
10021137 
Hypovolaemic shock 
10021138 
Mean arterial pressure decreased 
10026983 
Mesenteric traction syndrome 
10069699 
Neonatal hypotension 
10049223 
Obstructive shock 
10073708 
Orthostatic hypotension 
10031127 
Orthostatic intolerance 
10063927 
Presyncope 
10036653 
Procedural hypotension 
10062300 
Shock 
10040560 
Shock haemorrhagic 
10049771 
Shock symptom 
10040581 
Syncope 
10042772 
Vascular resistance systemic decreased 
10047106 
Vasoplegia syndrome 
10067080 
Loss of consciousness 
10024855 
Vertigo 
10047340 
MedDRA Version 21.0 


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Table 9.b  Renal Dysfunction-related AE 
PT_CODE 
PT_NAME 
10069339 
Acute kidney injury 
10069688 
Acute phosphate nephropathy 
10002847 
Anuria 
10003885 
Azotaemia 
10066338 
Continuous haemodiafiltration 
10061105 
Dialysis 
10078987 
Foetal renal impairment 
10018875 
Haemodialysis 
10053090 
Haemofiltration 
10077515 
Hyponatriuria 
10049778 
Neonatal anuria 
10029155 
Nephropathy toxic 
10030302 
Oliguria 
10034660 
Peritoneal dialysis 
10072370 
Prerenal failure 
10038435 
Renal failure 
10038447 
Renal failure neonatal 
10062237 
Renal impairment 
10049776 
Renal impairment neonatal 
MedDRA Version 21.0 
 
Criteria for Markedly Abnormal Values 
For each test item, MAV will be determined according to the table below for evaluable data (i.e., 
non-missing data) obtained within 14 days after the last study drug administration for the 
Treatment Period (including Day 14 after the last study drug administration for the Treatment 
Period; the day after the last study drug administration for the Treatment Period to be defined as 
Day 1). The lower limit of the normal range and the upper limit of the normal range of each test 
item are abbreviated as LLN and ULN in the table below. 


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Table 9.c  MAV Criteria for Serum Chemistry 
Test Item 
Gender 
Age 
(years) 
MAV Criteria 
Lower 
Upper 
BUN (mg/dL) 
- 
- 
- 
> 30 
Chloride (mEq/L) 
- 
- 
< 75 
> 126 
Creatinine (mg/dL) 
- 
- 
- 
> 2.0 
Potassium (mEq/L) 
 
 
< 3.0 
> 6.0 
Sodium (mEq/L) 
 
 
< 130 
> 150 
eGFR (mL/min/1.73 m2) 
 
 
< 30 
 
ALT (IU/L) 
- 
- 
- 
> 3 × ULN 
AST (IU/L) 
- 
- 
- 
> 3 × ULN 
GGT (IU/L) 
- 
- 
- 
> 3 × ULN 
Total bilirubin (mg/dL) 
- 
- 
- 
> 2.0 
Creatinine kinase (U/L) 
 
 
 
> 5×ULN 
 
Classifying Subjects for the Overall Treatment Period 
For each test item and subject, MAV will be determined according to the conditions [1] to [3] 
provided below. If there are criteria for “Upper” and “Lower” in the MAV Criteria for the same 
test item, the determination will be made for each criterion. 
[1] A subject will be classified as those “with MAV” if he/she has at least one data that “meets 
the MAV Criteria” among the evaluable data obtained after the study drug administration for 
the Treatment Period. 
[2] A subject will be classified as those “without MAV” if he/she does not meet condition [1] 
and has at least one data that does “not meet the MAV Criteria” among the evaluable data 
obtained after the study drug administration for the Treatment Period. 
[3] A subject who does not meet conditions [1] or [2] will be excluded from the analysis of 
MAV for that item. 
 
Criteria for Home Blood Pressure 
For each test item, home blood pressure will be determined according to the table below for 
evaluable data (i.e., non-missing data) obtained within 3 days after the last study drug 
administration for the Treatment Period (including Day 3 after the last study drug administration 
for the Treatment Period; the day after the last study drug administration for the Treatment 
Period to be defined as Day 1). The value before calculating the representative value on each 
measuring day (value described in the case report form) will be used for this determination. 


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05 October 2018
 
CONFIDENTIAL 
Table 9.d  Criteria for Home Blood Pressure 
Test Item 
Gender 
Age 
(years) 
Criteria 
Lower 
Upper 
Home 
sitting 
systolic 
blood 
pressure 
(mmHg) 
- 
- 
- 
≥ 99th percentile of 
Table 5.a + 15 mmHg 
Home 
sitting 
diastolic 
blood 
pressure 
(mmHg) 
- 
- 
- 
≥ 99th percentile of 
Table 5.a + 10 mmHg 
 
Classifying Subjects for the Overall Treatment Period 
For each test item and subject, home blood pressure will be determined according to the 
conditions [1] to [3] provided below. 
[1] A subject will be classified as those “with markedly abnormal blood pressure” if he/she has 
at least one data that “meets the Criteria for Home Blood Pressure” among the evaluable 
data obtained after the study drug administration for the Treatment Period. 
[2] A subject will be classified as those “without markedly abnormal blood pressure” if he/she 
does not meet condition [1] and has at least one data that does “not meet the Criteria for 
Home Blood Pressure” among the evaluable data obtained after the study drug 
administration for the Treatment Period. 
[3] A subject who does not meet conditions [1] or [2] will be excluded from the analysis of 
home blood pressure for that item.