Clinical trial NCT04668157
Conditions: Hypertension
Sponsor: Takeda
Start date: 2021-05-17; Completion date: 2023-12-28
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main aim of this study is to check the safety of TAK-536. This study will take place in Japan. At the first visit, the study doctor will check if each child can take part. For those who can take part, each participant will have a check-up by the study doctor. After this, each participant will take placebo. This might take 2 weeks.

After this, parents or the caregivers of each participant will be given sachets that contain granules of TAK-536 to give to that participant. The participants will take the TAK-536 granules once a day for 52 weeks.

After treatment has finished, participants will visit the study clinic for a final check-up.

Detailed description:
The drug being tested in this study is called TAK-536. TAK-536 is being tested in pediatric participants with hypertension aged 2 to less than 6 years. This study will look at the safety, efficacy, and pharmacokinetics of long-term administration of TAK-536.

The study will enroll 10 participants. Participants will receive the study drug (TAK-536) orally once daily before or after breakfast.

The initial dose of TAK-536 will be 0.1 mg/kg (not exceeding 2.5 mg/day). After the initial dose, TAK-536 will be titrated to 0.2 mg/kg (not exceeding 5 mg/day), 0.4 mg/kg (not exceeding 10 mg/day), and 0.8 mg/kg (not exceeding 20 mg/day) if the participants do not achieve the target blood pressure and no concerns are found in safety and tolerability.

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 56 weeks. Participants will make multiple visits to the clinic.

Arms: arm 1: TAK-536 granule formulation, orally once daily before or after breakfast. The initial dose of TAK-536 will be 0.1 mg/kg (not exceeding 2.5 mg/day). After the initial dose, TAK-536 will be titrated to 0.2 mg/kg (not exceeding 5 mg/day), 0.4 mg/kg (not exceeding 10 mg/day), and 0.8 mg/kg (not exceeding 20 mg/day) if the subjects do not achieve the target blood pressure and no concerns are found in safety and tolerability.
Interventions: intervention 1: TAK-536
Intervention descriptions: intervention 1: TAK-536 granule formulation

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
NCT Number: NCT04668157 
Title: A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, 
Efficacy and Pharmacokinetics of TAK-536 in Pediatric Subjects from 2 to Less Than 6 
Years of Age with Hypertension 
Study Number: Azilsartan-3004 
Document Version and Date: Amendment 1 / 21-Feb-2023 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 


TAKEDA PHARMACEUTICALS 
PROTOCOL 
A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, Efficacy and 
Pharmacokinetics of TAK-536 in Pediatric Subjects from 2 to Less Than 6 Years of Age 
with Hypertension 
A Phase 3 Long-term Study of TAK-536 in Pediatric Subjects from 2 to Less Than 6 Years 
of Age with Hypertension 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka, Japan
Study Number: 
Azilsartan-3004
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
TAK-536 (Azilsartan) 
Date: 
21 February 2023 
Version/Amendment 
Number: 
Version 2.0/ 
Amendment 1 
Amendment History: 
Date 
Amendment Number 
Region 
15 September 2020 
Initial version 
All sites 
21 February 2023 
Amendment 1 (Version 2.0) 
All sites 
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1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
See the annexes. 
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 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 1 Summary of Changes 
Protocol Amendment 1 Summary and Rationale 
This section describes the changes in reference to the protocol incorporating Amendment 1. The 
primary reasons for this amendment are to: 
•
Update the description of cuff size for blood pressure measurements.
•
Add the supply method of study drug to subjects and the acceptable time window for
scheduled visits in case subjects cannot visit the site due to the COVID-19 associated
event/issue.
•
Correct inconsistencies.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only. 
Protocol Amendment 1 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected 
by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1 
Section 7.3.2 
Medications 
Permitted with 
Conditions 
Deleted the terms “during this 
study” from the texts in the 
explanations of the highest dose of 
steroids. 
Correction of inconsistencies with the 
study design. 
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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 1 Summary of Changes...............................................................2 
2.0 
STUDY SUMMARY...........................................................................................................9 
3.0 
LIST OF ABBREVIATIONS ............................................................................................14 
4.0 
INTRODUCTION .............................................................................................................16 
4.1 
Background ..................................................................................................................16 
4.2 
Rationale for the Proposed Study ................................................................................17 
4.3 
Benefit/Risk Profile .....................................................................................................18 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................19 
5.1 
Objectives ....................................................................................................................19 
5.1.1 
Primary Objective ..................................................................................................19 
5.1.2 
Secondary Objectives.............................................................................................19 
5.2 
Endpoints .....................................................................................................................19 
5.2.1 
Primary Endpoints .................................................................................................19 
5.2.2 
Secondary Endpoints .............................................................................................19 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................21 
6.1 
Study Design ................................................................................................................21 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................23 
6.3 
Premature Termination or Suspension of Study or Study Site ....................................26 
6.3.1 
Criteria for Premature Termination or Suspension of the Study ...........................26 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites ........................26 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites ....................................................................................26 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............27 
7.1 
Inclusion Criteria .........................................................................................................27 
7.1.1 
Rationale of Inclusion Criteria ...............................................................................28 
7.2 
Exclusion Criteria ........................................................................................................29 
7.2.1 
Rationale of Exclusion Criteria ..............................................................................30 
7.3 
Excluded Medications and Treatments ........................................................................30 
7.3.1 
Excluded Medications ............................................................................................30 
7.3.2 
Medications Permitted with Conditions.................................................................32 
7.4 
Diet, Fluid, Activity Control ........................................................................................33 
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7.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................................34 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject .......................................35 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT .......................................................36 
8.1 
Study Drug and Materials ............................................................................................36 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ......................................36 
8.1.1.1 
Study drug ...................................................................................................36 
8.1.2 
Storage ...................................................................................................................36 
8.1.3 
Dose and Regimen .................................................................................................37 
8.1.4 
Overdose ................................................................................................................38 
8.2 
Study Drug Assignment and Dispensing Procedures ..................................................38 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs.......................................38 
9.0 
STUDY PLAN ...................................................................................................................40 
9.1 
Study Procedures .........................................................................................................40 
9.1.1 
Informed Consent Procedure .................................................................................40 
9.1.2 
Demographics, Medical History, and Medication History Procedure ...................40 
9.1.3 
Physical Examination Procedure ...........................................................................40 
9.1.4 
Weight, Height and BMI........................................................................................40 
9.1.5 
Vital Sign Procedure ..............................................................................................41 
9.1.6 
Measuring Home Blood Pressure ..........................................................................42 
9.1.7 
Documentation of Concomitant Medications ........................................................42 
9.1.8 
Documentation of Concurrent Medical Conditions ...............................................43 
9.1.9 
Procedures for Clinical Laboratory Samples .........................................................43 
9.1.10 ECG Procedure ......................................................................................................44 
9.1.11 Pharmacokinetic Sample Collection ......................................................................45 
9.1.11.1 Collection of Plasma for Pharmacokinetic Sampling .................................45 
9.1.11.2 Bioanalytical Method ..................................................................................45 
9.1.12 Documentation of Screen Failure ..........................................................................45 
9.1.13 Documentation of Study Entrance .........................................................................46 
9.2 
Monitoring Subject Treatment Compliance.................................................................46 
9.3 
Schedule of Observations and Procedures ...................................................................46 
9.3.1 
Screening................................................................................................................46 
9.3.2 
Start of the Run-in Period (Week -2) .....................................................................47 
9.3.3 
End of the Run-in Period (Week 0) .......................................................................47 
9.3.4 
Treatment Period (Weeks 2, 4, 8, 12, 16, 20, 24, 32, and 40) ...............................47 
9.3.5 
Final Visit or Early Termination ............................................................................48 
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9.3.6 
Follow-up Period: Week 54 ...................................................................................48 
9.3.7 
Post Study Care ......................................................................................................48 
10.0 
ADVERSE EVENTS .........................................................................................................49 
10.1 
Definitions....................................................................................................................49 
10.1.1 AEs .........................................................................................................................49 
10.1.2 Additional Points to Consider for AEs ..................................................................49 
10.1.3 SAEs ......................................................................................................................51 
10.1.4 AEs of Special Interest (AESI) ..............................................................................52 
10.1.5 Intensity of AEs .....................................................................................................52 
10.1.6 Causality of AEs ....................................................................................................53 
10.1.7 Causality to Study Procedures ...............................................................................53 
10.1.8 Start Date ...............................................................................................................53 
10.1.9 Stop Date ................................................................................................................53 
10.1.10 
Frequency .........................................................................................................53 
10.1.11 
Action Concerning Study Drug .......................................................................53 
10.1.12 
Outcome ...........................................................................................................54 
10.2 
Procedures ....................................................................................................................54 
10.2.1 Collection and Reporting of AEs ...........................................................................54 
10.2.1.1 AE Collection Period ..................................................................................54 
10.2.1.2 AE Reporting ..............................................................................................54 
10.2.1.3 AEs of Special Interest Reporting ...............................................................55 
10.2.2 Collection and Reporting of SAEs .........................................................................56 
10.2.3 Reporting of Abnormal Liver Function Tests ........................................................56 
10.3 
Follow-up of SAEs ......................................................................................................57 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities ...................57 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................58 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................59 
12.1 
CRFs (Electronic) ........................................................................................................59 
12.2 
Record Retention .........................................................................................................59 
13.0 
STATISTICAL METHODS ..............................................................................................61 
13.1 
Statistical and Analytical Plans ....................................................................................61 
13.1.1 Analysis Sets ..........................................................................................................61 
13.1.1.1 Safety Analysis Set .....................................................................................61 
13.1.1.2 Full Analysis Set .........................................................................................61 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................61 
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13.1.3 Efficacy Analysis ...................................................................................................61 
13.1.4 Pharmacokinetic Analysis ......................................................................................62 
13.1.5 Safety Analysis ......................................................................................................62 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................63 
13.3 
Determination of Sample Size .....................................................................................63 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................64 
14.1 
Study-Site Monitoring Visits .......................................................................................64 
14.2 
Protocol Deviations ......................................................................................................64 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................64 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................66 
15.1 
IRB Approval ...............................................................................................................66 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................66 
15.3 
Subject Confidentiality ................................................................................................67 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................68 
15.4.1 Publication and Disclosure ....................................................................................68 
15.4.2 Clinical Trial Registration......................................................................................68 
15.4.3 Clinical Trial Results Disclosure ...........................................................................68 
15.5 
Insurance and Compensation for Injury .......................................................................68 
16.0 
REFERENCES ..................................................................................................................70 
 
LIST OF IN-TEXT TABLES 
Table 5.a 
Reference Blood Pressure Values of Children by Gender and Age ......................20 
Table 9.a 
Clinical Laboratory Tests .......................................................................................43 
Table 10.a 
Takeda Medically Significant AE List ..................................................................52 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................23 
 
LIST OF APPENDICES 
 
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2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: 
TAK-536 (Azilsartan) 
Title of Protocol: A Phase 3, Open-label, Multicenter, 
Long-term Study to Evaluate the Safety, Efficacy and 
Pharmacokinetics of TAK-536 in Pediatric Subjects from 2 
to Less Than 6 Years of Age with Hypertension 
IND No.: 
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Number:Azilsartan-3004 
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 subjects with hypertension aged 2 to less than 6 
years. The study consists of a 2-week Run-in Period, a 52-week Treatment Period, and a 2-week Follow-up Period 
(56 weeks in total). 
Screening and Run-in Period 
Subjects eligible at screening will begin 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. However, at the earliest, the subjects should enter the Treatment 
Period 1 week after starting to receive placebo if his/her blood pressures meet the inclusion criteria. In addition, for 
the subjects who are treated with any antihypertensive drugs before the Run-in Period, the Run-in Period can be 
extended up to 4 weeks if blood pressures do not meet the inclusion criteria. 
Subjects who were treated with renin-angiotensin-system (RAS) inhibitors (angiotensin-converting enzyme [ACE] 
inhibitors, angiotensin II receptor blockers[ARB] and direct renin inhibitors[DRI]) must discontinue these 
medications at the start of the Run-in Period. 
Subjects who were 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 by the investigator or subinvestigator; the 
dose of the antihypertensive drug used before the Run-in period should be the same once the Run-in period starts. 
If termination of antihypertensive drugs other than RAS inhibitors requires a gradual down-titration, this can be 
accomplished while subjects are in the Run-in Period. In the case of the down-titration, the antihypertensive drugs 
should be discontinued at least 1 week (7 days) before the start of the Treatment Period. Antihypertensives, in 
particular beta-blockers (BBs), should be tapered off gradually as it may cause withdrawal syndrome, in which 
symptoms such as palpitations, restlessness, hypertension, headache would be observed upon abrupt discontinuation. 
Treatment Period 
Study drugs will be dosed according to the subject’s body weight. In the Treatment Period, the initial dose of TAK-
536 will be 0.1 mg/kg (not exceeding 2.5 mg/day). After the initial dose, TAK-536 will be titrated to 0.2 mg/kg (not 
exceeding 5 mg/day) , 0.4 mg/kg (not exceeding 10 mg/day), and 0.8 mg/kg (not exceeding 20 mg/day) if the 
subjects do not achieve the target blood pressure (Table 5.a) and no concerns are found in safety and tolerability. 
TAK-536 will be titrated at the visit in Weeks 2, 4, or 8. 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. Even if the dose is 
not titrated to the maximum dose (0.8 mg/kg) by Week 8, TAK-536 may be titrated to 0.2 mg/kg, 0.4 mg/kg, and 
0.8 mg/kg in a stepwise order after Week 8 if the subjects do not achieve the target blood pressure and there are no 
concerns regarding safety and tolerability. 
During the Treatment Period before Week 12, change in the dosage of any concomitant antihypertensive drug is not 
allowed in the subjects who are treated with a single antihypertensive drug other than RAS inhibitors. TAK-536 
dose can be reduced to 0.4 mg/kg, 0.2 mg/kg, or 0.1 mg/kg at the investigator’s or subinvestigator’s discretion if 
there are any concerns in safety and tolerability with upward titration of TAK-536 (ie, in case of occurring any 
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adverse events [AEs] associated with titration of TAK-536). 
During the Treatment Period after Week 12, when the subjects do not achieve the target blood pressure with the 
maximum dose (0.8 mg/kg) 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. TAK-536 dose can be reduced to 0.4 mg/kg, 0.2 mg/kg, or 0.1 mg/kg at the 
investigator’s or subinvestigator’s discretion if there are any concerns in safety and tolerability with upward titration 
of TAK-536. When the antihypertensive drugs require dose reduction or interruption because of concerns in safety 
and tolerability with titration, dosing of the antihypertensive drugs other than TAK-536 should be reduced or 
interrupted first. Thereafter, dose reduction or interruption of TAK-536 should be considered. 
Follow-up Period 
Follow-up Period will last 2 weeks from the day following the final dose of TAK-536, that is at Week 54 after the 
start of the Treatment Period. Safety will be evaluated up to that time. 
Primary Objectives: 
To evaluate the safety of TAK-536 in pediatric subjects with hypertension aged 2 to less than 6 years  
Secondary Objectives: 
To evaluate the efficacy and pharmacokinetics of TAK-536 in pediatric subjects with hypertension aged 2 to less 
than 6 years 
Subject Population: 
Pediatric subjects with essential or secondary hypertension aged 2 to less than 6 years 
Number of Subjects: 
Total of 10 subjects (who enter the Treatment Period). 
Number of Sites: 
Approximately 20 sites (Japan) 
Dose Level(s): 
<Regimen> 
Subjects will receive the study drug orally once daily 
before or after breakfast. 
<Dose *> 
Placebo during the Run-in Period. 
Subjects will receive TAK-536 0.1 mg/kg (not exceeding 
2.5 mg/day), or 0.2 mg/kg (not exceeding 5 mg/day), or 
0.4 mg/kg (not exceeding 10 mg/day), or 0.8 mg/kg (not 
exceeded 20 mg/day) 
* Dose of the study drug for each subject will be decided 
based on each subject’s body weight. 
Route of Administration: 
Oral 
Duration of Treatment: 
52 weeks 
Period of Evaluation: 
2 weeks of the Run-in Period (acceptable range, 1 to 
4 weeks) 
52 weeks of the Treatment Period 
2 weeks of the Follow-up Period 
Main Criteria for Inclusion: 
• 
A 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 ≥95th percentile for essential hypertension without concomitant hypertensive organ 
damage, and ≥90th percentile for secondary hypertension with concomitant chronic kidney disease (CKD), 
diabetes mellitus, heart failure or hypertensive organ damage. 
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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 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 meets the 
above criteria for hypertension on 3 separate time points including screening and the end of the Run-in 
Period (Week 0). In addition, for a subject with essential hypertension without hypertensive organ 
damage, the subject does not respond to non-pharmacologic therapy such as diet modification or exercises 
for at least 3 months within 1 year prior to the start of screening. 
• 
The subject is male or female and aged 2 to less than 6 years at the time of informed consent. 
• 
At screening, the subject has not less than minus 2 standard deviations from mean weight for age of reference 
population shown in the table of pediatric body weight by the Japanese Society for Pediatric Endocrinology. 
• 
A subject who has undergone kidney transplantation is eligible if he/she underwent the transplantation, 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 [computed tomography] scan or MRI [magnetic 
resonance imaging]) excluding transplanted 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 22 mmHg and/or an office sitting diastolic blood pressure higher by at least 17 mmHg than the 95th 
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 (compliance: <70% or >130%) with the study drug during the Run-in Period. 
• 
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. 
• 
The subject has a history of, or the signs/symptoms of serious cardiovascular, hepatobiliary, gastrointestinal, 
endocrine (eg, hyperthyroidism, Cushing’s syndrome), hematological, immunological, urogenital, 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 
uncorrected 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 (regardless of the cause), or jaundice. 
• 
The subject has hyperkalemia exceeding ULN at screening. 
Main Criteria for Evaluation and Analyses: 
(1) Primary Endpoints 
Safety: 
• 
AEs 
• 
Resting 12-lead ECG parameters 
• 
Anthropometric measurements (weight, height, and body mass index [BMI]) 
• 
Laboratory test values 
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• 
Vital sign measurements (office sitting pulse rate* and home sitting blood pressure*) 
*These should be measured in a sitting position. For subjects who are unable to assume a sitting position, blood 
pressure measurements can be obtained while in other positions such as a supine position. In this case, all 
measurements should be conducted in the same position during the study. 
(2) Secondary Endpoints 
Efficacy: 
• 
Change from baseline in office trough sitting diastolic and systolic blood pressure at Week 12 and 52 (last 
observation carried forward [LOCF]) 
• 
Proportion of subjects who achieve the target blood pressure at Week 12 and 52 (LOCF) 
Note: The target blood pressure is <95th percentile for essential hypertension and <90th percentile for subjects with 
secondary hypertension. 
Pharmacokinetics: 
Plasma concentrations of TAK-536 
Statistical Considerations: 
<Primary endpoints and analytical methods> 
[Primary endpoints] 
AEs, resting 12-lead ECG parameters, anthropometric measurements (weight, height, and BMI), laboratory test 
values, and vital sign measurements (office sitting 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, and 
until the end of follow-up period (or the tests performed at early termination). 
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) Resting 12-lead ECG parameters, anthropometric measurements (weight, height and BMI), laboratory test 
values, and vital sign measurements (office sitting 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. The number and 
percentage of Markedly Abnormal Values (MAV) for serum chemistry will be provided. 
Sample Size Rationale: 
Total of 10 subjects to enter the Treatment Period was set in consideration of feasibility. 
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Interim Analysis 
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 after being locked. This analysis is not intended to inform the trial for any decisions such as 
to continue or discontinue this study. 
 
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3.0 
LIST OF ABBREVIATIONS 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ARB 
angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC∞ 
area under the concentration-time curve from time 0 to infinity 
BBs 
beta-blockers 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CKD 
chronic kidney disease 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
CT 
computed tomography 
DB 
double-blind 
DTP 
Direct to Patient 
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 
HbA1c 
hemoglobin A1c 
HIV 
human immunodeficiency virus 
HPLC/MS/MS 
high-performance liquid chromatography with tandem mass spectrometry 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
IRT 
interactive response technology system 
JCS 2018 
Guideline on the Clinical Examination for Decision Making of Diagnosis and Drug 
therapy in Pediatric Patients with Congenital Heart Disease and Cardiovascular Disorder 
JSH2019 
Guidelines for the Management of Hypertension 2019 
LDH 
lactate dehydrogenase 
LFT 
liver function tests 
LOCF 
last observation carried forward 
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MAV 
markedly abnormal values 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
NSAIDs 
non-steroidal anti-inflammatory drugs 
OL 
open-label 
OTC 
over-the-counter 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PT 
preferred term 
QOL 
quality of life 
RAS 
renin-angiotensin-system 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SUSARs 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WD 
withdrawal 
WHO 
World Health Organization 
 
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4.0 
INTRODUCTION 
4.1 
Background 
TAK-536 (azilsartan) is a novel angiotensin-receptor blocker (ARB) produced by Takeda 
Pharmaceutical Company Limited 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. As hypertension affects not only adults but children and adolescents as 
well, Takeda is further developing TAK-536 for pediatric use. 
While there are few epidemiological reports about the number of Japanese pediatric patients with 
hypertension less than 6 years of age, it is reported that hypertension was detected in 0.1% to 
4.4% of students in elementary-school and junior-high-school at general health checkups[1], and 
it is anticipated that the number of patients less than 6 years of age with hypertension is similar. 
For pediatric hypertension, it is known that the prevalence of secondary hypertension is higher in 
younger children, especially in patients under 12 years of age [2]. The most common etiology for 
hypertension in children less than 6 years of age is renal parenchymal diseases, aortic stenosis 
and renal artery stenosis [3]. Although the prognosis of secondary hypertension depends on the 
underlying disease and its treatment [4], both essential hypertension and secondary hypertension 
set target blood pressures as part of their treatment goals, in order to prevent organ damage due 
to hypertension [5]. Hypertension persisting from childhood is likely to cause cardiovascular 
diseases and organ damage including renal dysfunction. This can markedly affect 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 at an early stage. 
According to the Japanese Society of Hypertension Guidelines for the Management of 
Hypertension 2019 (JSH 2019) [6], drug therapy is indicated for children with hypertension 
meeting the following criteria: persistent hypertension despite non-drug therapy involving 
lifestyle modifications, symptomatic hypertension, secondary hypertension requiring drug 
therapy, the concomitant development of target organ damage, the presence of chronic kidney 
disease (CKD), and the presence of diabetes mellitus. 
While a number of antihypertensive drugs for adults are available in Japan, only 5 drugs are 
indicated for hypertension in children, ie, valsartan and candesartan as ARBs, enalapril and 
lisinopril as angiotensin-converting enzyme (ACE) inhibitors, and amlodipine as calcium 
channel blocker. Of these, only candesartan and enalapril have an indication for patients less than 
6 years of age. Furthermore, currently marketed antihypertensive drugs have no formulation 
developed for pediatric patients even though this is strongly desired in medical settings. 
Therefore, the existing treatment options for pediatric patients with hypertension are not 
sufficient.  
Thus, to resolve the unmet needs in the present treatment of pediatric hypertension, TAK-536 
clincal studies are being conducted and a pediatric-specific granule formulation for this drug has 
been developed and will be the formulation used for this study. 
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Findings from Clinical Studies of TAK-536 
For adult subjects with hypertension, 4 phase 3 studies to evaluate the efficacy and safety of 
TAK-536 were conducted. In the Phase 3 studies, doses of TAK-536 from 10 to 40 mg showed 
clinically significant and stable antihypertensive effects and were well-tolerated. 
For pediatric subjects with hypertension, a phase 3 study for TAK-536 (TAK-536/OCT-101) and 
another phase 3 study (AR14.001) using TAK-491, a prodrug of TAK-536, were conducted. 
TAK-536/OCT-101 study is a Phase 3, open-label, long-term study to evaluate the safety, 
efficacy and pharmacokinetics of administration of TAK-536 once daily for 52 weeks in 
Japanese pediatric patients aged 6 to less than 16 years with hypertension. The initial dose of 
TAK-536 was 2.5 mg for the subjects weighing <50 kg or 5 mg for the subjects weighing 
≥50 kg. After the initial dose, TAK-536 was 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 if the subjects 
did not achieve the target blood pressure. A total of 27 subjects participated. A decrease of office 
trough sitting diastolic and systolic blood pressures started at Week 2 and significant reduction 
was shown at the End of the Treatment Period I (Week 12) and the End of the Treatment (Week 
52). TAK-536 once daily for 52 weeks was well-tolerated. 
AR14.001 study is a global, Phase 3, efficacy and safety study of TAK-491 in pediatric subjects 
aged 6 to less than 18 years with hypertension. This study included a 6 week, double-blind, 
randomized, treatment double-blind (DB) Phase, followed by a 2-week, double-blind, 
randomized placebo-controlled withdrawal (WD) Phase. In the DB Phase, 215 subjects were 
randomized (1:1:1:1) to the following groups: TAK-491-L, TAK-491-M, and TAK-491-H, or 
losartan. In the WD Phase, 203 subjects were randomized (1:1) to continue taking their 
previously assigned active treatment or were switched to placebo. This study also included a 44-
week, open-label (OL) Phase in which all 197 subjects received TAK-491 and other 
antihypertensive medications (if needed) according to a titrate-to-target blood pressure 
algorithm. TAK-491 demonstrated statistically significant and clinically relevant improvements 
of efficacy endpoints. Treatment with TAK-491 in low, medium, and high doses was safe and 
well-tolerated during the DB Phase, WD Phase and OL Phase of the study. 
In TAK-536/OCT-101 study and AR14.001 study, no safety signals were identified in subjects 
aged 6 years and older and it was assessed that the risks of TAK-536 administration in pediatric 
subjects were similar to that of adults. 
4.2 
Rationale for the Proposed Study 
After completion of the clinical studies for TAK-536 in subjects 6 to less than 16 years of age in 
which blood pressure reduction effects of TAK-536 and no significant safety issues were 
observed, this current study is planned to evaluate the safety, efficacy, and pharmacokinetics of 
52-week administration of TAK-536 in pediatric patients with hypertension aged 2 to less than 6 
years. 
Before conducting this study, the sponsor had the consultation with the Pharmaceuticals and 
Medical Devices Agency of Japan (PMDA) in June 2020. 
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4.3 
Benefit/Risk Profile 
TAK-536 has been approved for adult patients with hypertension since 2014. It has also 
demonstrated long-term consistent antihypertensive effects in 2 Phase 3 studies for pediatric 
subjects with either primary or secondary hypertension aged 6 years and older (TAK-536/OCT-
101 study and AR14.001 study of TAK-491, a prodrug of TAK-536). Therefore, TAK-536 is 
expected to show similar antihypertensive effects and to contribute to the appropriate 
management of hypertension in subjects 2 to less than 6 years of age in this study. 
With respect to safety, hypotension, impairment in renal function and hyperkalemia are 
important risks identified in the adult population as class effect of ARBs. In TAK-536/OCT-101 
study and AR14.001 study, no new safety signals were identified in subjects aged 6 years and 
older and it was assessed that the risks of TAK-536 administration in pediatric subjects were 
similar to that of adults. 
This is the first study for TAK-536 in pediatric subjects less than 6 years of age, and appropriate 
considerations are included in this study to manage the risks for this drug. This study has an 
open-label, optional titration design in which TAK-536 is initially administrated at a low dose, 
and can be titrated while monitoring subject condition. Additionally, as the subjects of this study 
may have other comorbidities, certain medications are allowed to be used concomitantly. 
Subjects with high risk of renal function impairment and of hyperkalemia will be excluded in 
this study. In addition, during the study, the investigator or subinvestigator will carefully monitor 
subjects’ condition, especially hypotension, renal dysfunction and hyperkalemia. 
Based on the benefits that can be conferred to pediatric subjects with hypertension, as well as the 
risks and the appropriate measures to mitigate them, it is assessed that the benefit-risk profile 
would be acceptable for this population. 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
To evaluate the safety of TAK-536 in pediatric subjects with hypertension aged 2 to less than 6 
years 
5.1.2 
Secondary Objectives 
To evaluate the efficacy and pharmacokinetics of TAK-536 in pediatric subjects with 
hypertension aged 2 to less than 6 years 
5.2 
Endpoints 
5.2.1 
Primary Endpoints  
Safety: 
• Adverse events (AEs) 
• Resting 12-lead electrocardiogram (ECG) parameters 
• Anthropometric measurements (weight, height, and body mass index [BMI]) 
• Laboratory test values 
• Vital sign measurements (office sitting pulse rate* and home sitting blood pressure*) 
*These should be measured in a sitting position. For subjects who are unable to assume a 
sitting position, blood pressure measurements can be obtained while in other positions such 
as a supine position. In this case, all measurements should be conducted in the same position 
during the study. 
5.2.2 
Secondary Endpoints 
Efficacy: 
• Change from baseline in office trough sitting diastolic and systolic blood pressure at Week 
12 and 52 (last observation carried forward [LOCF]) 
• Proportion of subjects who achieve the target blood pressure at Week 12 and 52 (LOCF) 
Note: The target blood pressure is <95th percentile for essential hypertension and <90th 
percentile for subjects with secondary hypertension [3]. The values are shown in Table 5.a. 
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Table 5.a 
Reference Blood Pressure Values of Children by Gender and Age 
Age (years) 
Male 
Female 
90th 
95th 
95th 
+ 12 mmHg 
90th 
95th 
95th 
+ 12 mmHg 
2 
102/56 
106/59 
118/71 
103/60 
106/64 
118/76 
3 
103/59 
107/62 
119/74 
104/62 
108/66 
120/78 
4 
105/62 
108/66 
120/78 
106/65 
109/69 
121/81 
5 
106/65 
109/69 
121/81 
107/67 
110/71 
122/83 
6 
107/68 
111/71 
123/83 
108/69 
111/72 
123/84 
Systolic/diastolic blood pressures (mmHg), Guidelines on the Clinical Examination for Decision Making of 
Diagnosis and Drug Therapy in Pediatric Patients with Cardiovascular Diseases and Cardiovascular Disorder by the 
Japanese Circulation Society (JCS2018) [3] 
The 90th and 95th indicate 90th and 95th percentile, respectively. 
 
Pharmacokinetics: 
Plasma concentrations of TAK-536 
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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 with hypertension aged 2 to less than 6 years. 
The study consists of a 2-week Run-in Period, a 52-week Treatment Period, and a 2-week 
Follow-up Period (56 weeks in total). 
Screening and Run-in Period: 
Subjects eligible at screening will begin 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. However, at the earliest, the subjects should 
enter the Treatment Period 1 week after starting to receive placebo if his/he blood pressures meet 
the inclusion criteria. In addition, for the subjects who are treated with any antihypertensive 
drugs before the Run-in Period, the Run-in Period can be extended up to 4 weeks if blood 
pressures do not meet the inclusion criteria. 
Subjects who were treated with renin-angiotensin-system (RAS) inhibitors (ACE inhibitors, 
ARB and direct renin inhibitors [DRI]) must discontinue these medications at the start of the 
Run-in Period. 
Subjects who were 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 by the investigator or subinvestigator. The dose of the antihypertensive drug 
used before the Run-in period should be the same once the Run-in period starts.  
If termination of antihypertensive drugs other than RAS inhibitors requires a gradual down-
titration, this can be accomplished while subjects are in the Run-in Period. In the case of the 
down-titration, the antihypertensive drugs should be discontinued at least 1 week (7 days) before 
the start of the Treatment Period. Antihypertensives, in particular beta-blockers (BBs), should be 
tapered off gradually, as it may cause withdrawal syndrome, in which symptoms such as 
palpitations, restlessness, hypertension, headache would be observed upon abrupt 
discontinuation. 
Treatment Period: 
Study drugs will be dosed according to the subject’s body weight. In the Treatment Period, the 
initial dose of TAK-536 will be 0.1 mg/kg (not exceeding 2.5 mg/day). After the initial dose, 
TAK-536 will be titrated to 0.2 mg/kg (not exceeding 5 mg/day), 0.4 mg/kg (not exceeding 
10 mg/day), and 0.8 mg/kg (not exceeding 20 mg/day) if the subjects do not achieve the target 
blood pressure and no concerns are found in safety and tolerability. The target blood pressure is 
<95th percentile for essential hypertension and <90th percentile for subjects with secondary 
hypertension (Table 5.a)  
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TAK-536 will be titrated at the visits of Weeks 2, 4, or 8. 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. Even if the dose is not titrated to the maximum dose 
(0.8 mg/kg) by Week 8, TAK-536 may be titrated to 0.2 mg/kg, 0.4 mg/kg, or 0.8 mg/kg in a 
stepwise order after Week 8 if the subjects do not achieve the target blood pressure and there are 
no concerns regarding safety and tolerability.  
During the Treatment Period before Week 12, change in the dosage of any concomitant 
antihypertensive drug is not allowed in the subjects who are treated with a single 
antihypertensive drug other than RAS inhibitors. TAK-536 dose can be reduced to 0.4 mg/kg, 
0.2 mg/kg, or 0.1 mg/kg at the investigator’s or subinvestigator’s discretion if there are any 
concerns in safety and tolerability with upward titration of TAK-536 (ie, in case of occurring any 
AEs associated with titration of TAK-536). 
During the Treatment Period after Week 12, when the subjects do not achieve the target blood 
pressure with the maximum dose (0.8 mg/kg) 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. TAK-536 dose 
can be reduced to 0.4 mg/kg, 0.2 mg/kg, or 0.1 mg/kg at the investigator’s or subinvestigator’s 
discretion if there are any concerns in safety and tolerability with upward titration of TAK-536 
(ie, in case of occurring any AEs associated with titration of TAK-536). When the 
antihypertensive drugs require dose reduction or interruption because of concerns in safety and 
tolerability with titration, dosing of the antihypertensive drugs other than TAK-536 should be 
reduced or interrupted first. Thereafter, dose reduction or interruption of TAK-536 should be 
considered. 
Follow-up Period: 
Follow-up Period will last 2 weeks from the day following the final dose of TAK-536, that is at 
Week 54 after the start of the Treatment Period. Safety will be evaluated up to that time. 
Sites will employ all efforts to see subjects in the clinic for assessments. In unavoidable 
circumstances (eg, a widespread disease outbreak such as the coronavirus disease 2019 [COVID-
19] pandemic or natural disaster), exceptions may be consulted for alternative visits or 
assessments for conducting subject visits with approval by the Medical Monitor and/or sponsor. 
Such instances will be documented in the study records as related to COVID-19. 
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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inhibitors in the same dosage until TAK-536 is titrated to the maximum dose (0.8 mg/kg) 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. If TAK-536 is already titrated to the 
maximum dose (0.8 mg/kg) and the subjects blood pressure is still not reduced to the target 
blood pressure, the subject 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 in 
the treatment period and the influence of antihypertensive drugs as a prior treatment in subjects 
who were taking them. In addition, the Run-in Period allows the opportunity to assess subject 
compliance with the study procedures 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] 
A population pharmacokinetic model was developed based on data from 85 subjects (33 for 
pediatric patients aged ≥6 to <16 years [TAK-536/OCT-101 and TAK-536/CPH-103] and 52 for 
healthy adults [TAK-536/CPH-101]). Then, a virtual population of subjects was generated and 
were uniformly distributed by age from ≥2 to <6 years and by sex based on pediatric body 
weight data in Japanese children [8] and equally allocated to TAK-536 doses range from 0.1 to 
1.0 mg/kg. This virtual population was composed of a total of 28800 subjects, 3600 subjects for 
each age (ie, 2, 3, 4, 5 years of age) and sex. 
The population pharmacokinetic model was then used to simulate the exposures (Cmax and AUC) 
of TAK-536 following a single oral dose of each dose for each age and sex category for the 
virtual pediatric population. Results simulated with the virtual population were compared with 
actual parameters of Cmax and AUC (TAK-536/CPH-001) following a single oral dose of TAK-
536 10-80 mg in Japanese healthy subjects. Based on the simulation, estimated exposures in 
pediatric patients aged from ≥2 to <6 years after receiving TAK-536 0.1, 0.2, 0.4 or 0.8 mg/kg 
are similar to or lower than those in healthy adults receiving TAK-536 5, 10, 20 or 40 mg, 
respectively. In TAK-536/OCT-101 study for subjects with hypertension aged ≥6 to <16 years, 
safety and tolerability were evaluated at TAK-536 2.5, 5, 10 and 20 mg in subjects weighing <50 
kg. Similarly, these dose levels were selected as the exposures at each dose level would be 
similar to or lower than that in adults at doses of TAK-536 5, 10, 20, 40 mg. 
In this study, using 0.1, 0.2, 0.4 or 0.8 mg/kg in subjects who are over 25 kg will result in doses 
that exceed TAK-536/OCT-101 doses (2.5, 5, 10, and 20 mg). Therefore, to avoid this, a dosing 
cap is set to reflect the doses used in TAK-536/OCT-101 pediatric subjects <50 kg. 
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[Justification for the Regimen] 
Based on the results of the food effect study for TAK-536 (Azilsartan-1005), food did not affect 
the pharmacokinetics of TAK-536 in adults. In this study the subjects may receive the study drug 
before or after breakfast. 
[Justification of Endpoints] 
Based on the ICH-E11 guideline, efficacy data from a reference population may be extrapolated 
to pediatric subjects (target population) provided there is sufficient similarity in the course of the 
disease and the expected response to the therapy. For this study, the efficacy data from the 
reference population of older pediatric subjects aged 6 years and older (TAK-536/OCT-101 and 
AR14.001) can be extrapolated to the younger age subjects less than 6 years of age. In the same 
guideline, it is stated that safety data is required in the target population; therefore, safety was set 
as a primary endpoint for this study. 
Variables commonly used to evaluate the safety of antihypertensive medication were selected as 
the primary endpoints. In addition, anthropometric data is included to assess the safety of TAK-
536 on growth and development in this pediatric population. 
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 [9] and JSH2019 [6]. 
Plasma concentrations of TAK-536 will be measured in order to evaluate the pharmacokinetics 
of TAK-536 in pediatric patients with hypertension aged 2 to less than 6 years. 
[Justification for Study Duration] 
a) Run-in Period 
It is defined 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 in this study. This period would 
be equaled at least 5 half-lives of the relevant drug; the period is defined as 2 weeks in 
accordance with the half-life of antihypertensive drugs [10]. The subjects whose blood pressures 
meet the inclusion criteria 1 week (at the earliest) after receiving placebo during the Run-in 
Period should enter the Treatment Period in consideration of subject safety. 
b) Treatment Period 
JSH2019 [6] recommends that low-dose therapy with a single antihypertensive drug should be 
initiated first for the treatment of the hypertensive patients, and the effect must be evaluated at 2- 
to 4-week intervals. The dose should be increased slowly with the speed to achieve the target 
blood pressure. Additionally, in phase 3 studies (TAK-536/CCT-005 and TAK-536/OCT-101), a 
decrease of office trough sitting diastolic and systolic blood pressures started at Week 2. An 8-
week period was set as the optional titration period with 3 titration point and 2 or 4 weeks for 
each titration point for evaluating the safety and tolerability. In addition, TAK-536/CCT-005 
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 
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set as the duration of administration with the highest dose in case of the titration of TAK-536 to 
the highest dose (0.8 mg/kg). 
After Week 12, 40 weeks was set as the Treatment Period 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 
this study. 
c) 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 on temporary 
suspension or early termination are satisfied. 
• 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 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. 
3. A 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 (refer to Table 5.a); office sitting diastolic or systolic blood pressure ≥95th percentile 
for essential hypertension without concomitant hypertensive organ damage, and ≥90th 
percentile for secondary hypertension with concomitant CKD, diabetes mellitus, heart failure 
or hypertensive organ damage. 
In addition, subjects need to meet the following criteria:  
If currently treated with any antihypertensive drugs at the start of the Run-in Period: Subject 
has a documented 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). 
If currently untreated with any antihypertensive drugs at the start of the Run-in Period: 
Subject meets the above criteria for hypertension on 3 separate time points including 
screening and the end of the Run-in Period (Week 0). In addition, for a subject with essential 
hypertension without hypertensive organ damage, the subject does not respond to non-
pharmacological therapy such as diet modification or exercises for at least 3 months within 1 
year prior to the start of screening. 
*Japanese is defined as those who are in Japan, are born in Japan and have Japanese parents 
and Japanese maternal and paternal grandparents. 
4. The subject is male or female and aged 2 to less than 6 years at the time of informed consent. 
5. At screening, the subject has not less than minus 2 standard deviations from mean weight for 
age of reference population shown in the table of pediatric body weight by the Japanese 
Society for Pediatric Endocrinology[8]. 
6. The subject is able to swallow the study drug. 
7. A subject who has undergone kidney transplantation is eligible if he/she underwent the 
transplantation, 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 [computed tomography] scan or MRI [magnetic resonance imaging]) excluding 
transplanted kidney arterial stenosis. A subject on immunosuppressive therapy with a stable 
dose at least 30 days prior to screening is eligible. 
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8. The subject, judged by the investigator or subinvestigator, who can safely discontinue the 
therapy with RAS inhibitors for 2 weeks prior to the Treatment Period. This period may 
change to between 1 and 4 weeks depending on the subject’s duration of Run-in Period. 
7.1.1 
Rationale of Inclusion Criteria 
1. 2. 6. These were set as the standard requirements for clinical studies in pediatric subjects. 
3. This inclusion criterion was set according to the criteria for initiation of Pharmacotherapy 
indicated in the Japanese guidelines, ie, JCS2018 Guideline on the Clinical Examinations for 
Decision Making of Diagnosis and Drug therapy in Pediatric Patients with Congenital Heart 
Disease and Cardiovascular Disorder (JCS2018 Yasukochi) [3] and Evidence-based Clinical 
Practice Guideline for CKD 2018 [13]. In both guidelines, reference blood pressure value of 
hypertension in the US guideline for children in the 50th percentile for height (categorized by 
age and gender) was adopted as reference blood pressure value for Japanese children. Thus, it 
was reflected in Table 5.a. 
The criteria, “to meet the hypertension criteria on 3 separate time points” was set for subjects 
untreated with any antihypertensive drugs at the start of the Run-in Period, in accordance 
with the 2 guidelines mentioned above as well as JSH2019 [6]. 
In the guidelines of JCS2018 Yasukochi and JSH2019, non-pharmacotherapy is 
recommended for the treatment of essential hypertension without hypertensive organ damage 
before starting pharmacotherapy. Additionally, in JSH2019, it is recommended that blood 
pressure should be measured every 3 months during non-pharmacotherapy. According to 
these guidelines, the criterion “a subject with essential hypertension without hypertensive 
organ damage does not respond to non-pharmacological therapy for at least 3 months within 
1 year prior to the start of the screening” was set. 
4. The lower limit of age is set as 2 years old based on the nonclinical study results. In the series 
of juvenile toxicity studies using post-natal day (PND) 0, 7, 14, or 21 rats, more pronounced 
renal toxicities were observed, while the kidney findings in PND 21 rats were comparable to 
those in adult rats, indicating that younger juvenile rats whose kidney is immature were more 
sensitive to the pharmacologic effect of ARBs. For human, the kidney is expected to be 
morphologically and functionally matured at the age of 2 [14]. Thus, the lower limit of age is 
set as 2 years old in this study. 
5. The weight limit was set from a subject safety perspective reffering to the criterion of World 
Health Organization (WHO) for “underweight”, ie, weight for age <-2 standard deviations of 
the WHO Child Growth Standards median. 
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. The investigator’s judgment on ability to discontinue RAS therapy for 2 weeks is needed in 
consideration of subject safety. 
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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 surgical therapy. 
2. The subject previously received therapy with azilsartan. 
3. The subject has poorly controlled hypertension indicated by an office sitting systolic blood 
pressure higher by at least 22 mmHg and/or an office sitting diastolic blood pressure higher 
by at least 17 mmHg than the 95th percentiles of the reference blood pressure values of 
children by gender and age (refer to the Table 5.a). 
4. The subject has a diagnosis of malignant or accelerated hypertension. 
5. The subject was noncompliant (compliance*: <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, urogenital, 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 uncorrected aortic valvular disease, or is scheduled to undergo a medical 
procedure affecting blood pressure during the study (eg, correction of arterial anomaly). 
Note: This does not apply to subjects who received medical procedure(s) (eg, surgery for 
aortic coarctation) before the study and investigator or subinvestigator assess that subject’s 
condition is stable at screening. 
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, 
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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. 
7.2.1 
Rationale of Exclusion Criteria  
1. 15. These were set as the standard exclusion criteria used for clinical studies. 
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. 
7.3 
Excluded Medications and Treatments 
7.3.1 
Excluded Medications 
Subjects and subjects’ parent or the subjects’ legal guardian must be instructed not to take any 
medications including over-the-counter (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. 
A subject can continue the conventional therapy for the concurrent medical conditions without 
changing daily dosage except the excluded medications. 
<During Run-in Period and Treatment Period before Week 12> 
The following medications will not be allowed. 
(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 
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(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 
(11) Nitrates 
(12) Estrogen preparations 
<During Treatment Period after Week 12> 
The following medications will not be allowed. 
(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 
[Rationale for Excluded Medications] 
<During the Run-in Period and Treatment Period before Week 12> 
(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. 
<During Treatment Period after Week 12> 
(1) 
These similar drugs are excluded because they could influence the evaluation of 
TAK-536 efficacy. 
(2), (4)-(6) 
These drugs are excluded because they could be used chronically and 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. 
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7.3.2 
Medications Permitted with Conditions 
Certain medications will be permitted with conditions in consideration of subject safety between 
Week 0 and 12 in which TAK-536 is titrated. Details of the following permitted medications 
(start and end date of administration, generic name or commercial name, total daily doses, route 
of administration) should be recorded in the electronic case report form (eCRF). These 
medications and the conditions for their use are as follows: 
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 by the investigator or subinvestigator. The antihypertensive drug should be administered 
with 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. 
Antihypertensives, in particular BBs, should be tapered off gradually, as it may cause withdrawal 
syndrome, in which symptoms such as palpitations, restlessness, hypertension, headache would 
be observed upon abrupt discontinuation. 
2. Steroids: 
For subjects who are receiving steroid therapy (oral, topical or inhaled), the dosage and 
administration should not be changed after study drug administration is initiated unless there are 
medical indications. 
Hydrocortisone or equivalent dose to hydrocortisone for other steroids are permitted for subjects 
with adrenal insufficiency. The highest dose per day should be capped at 15 mg/m2 which is 
recommended for chronic adrenal insufficiency in childhood in the guideline [15]. 
Prednisolone or equivalent dose to prednisolone for other steroids are permitted in subjects after 
renal transplantation or with glomerular disease. The highest dose per day should be capped at 60 
mg/m2 which is recommended for steroid sensitive nephrotic syndrome in the guideline [16]. 
Especially for subjects who need higher dose of steroids (eg, 60 mg/m2 of prednisolone), the 
investigator or subinvestigator need to confirm these subjects’ safety and consider whether 
continuous administration of the study drug is acceptable. Additionally, pulse therapy with 
extremely high dose of steroid (eg, >60 mg/m2 of prednisolone) is prohibited. 
3. Central nervous system stimulants, non-central nervous system stimulants: 
Use for treatment of attention deficit/hyperactivity disorder is permitted but its dosage and 
administration should not be changed as much as possible after study drug administration is 
initiated. 
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7.4 
Diet, Fluid, Activity Control 
The investigator, subinvestigator, or study collaborator should instruct the subject, the subject’s 
parent or the subject’s legal guardian to adhere the following study requirements.  
1. The subject’s parent or the subject’s legal guardian should ask the investigator or 
subinvestigator by telephone for instructions or visit the study site, as soon as the subject 
experiences vomiting or diarrhea frequently throughout the study. 
2. The investigator or subinvestigator will explain the possibility of excessive reduction in the 
blood pressure associated with TAK-536 treatment to the subject’s parent or the subject’s 
legal guardian. The subject’s parent or the subject’s legal guardian should make the subject 
rest in a supine position, as soon as the subject experiences any symptoms suggesting 
decreased blood pressure (eg, dizziness, lightheadedness, etc.) outside the study site on days 
other than the scheduled visit, and ask the investigator or subinvestigator by telephone for 
further instructions, or visit the study site, if the symptoms did not subside. 
3. The subject’s parent or the subject’s legal guardian should ask the investigator or 
subinvestigator by telephone for instructions, or visit the study site, as soon as the subject 
experiences 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. The subject should not eat or bathe within 1 hour before office blood pressure measurement, 
no intake of any caffeine containing product within 30 minutes before the measurement. 
5. The subject should comply with and not to change a fixed diet (eg, caloric and salt intake) 
and/or exercise therapies, if performed, throughout the study. 
6. The subject should avoid food with high salt content, to take adequate hydration, and to 
maintain a routine sleep, behavior and caffeine intake. In addition, the subject should avoid 
excessive drinking/eating, significant change of diet (eg, excessively high-fat diet), excessive 
exercise, and staying up late. The subject will maintain a regular lifestyle on the day before 
visit days. 
7. The subject’s parent or the subject’s legal guardian should inform the investigator or 
subinvestigator before receiving treatment from another doctor, or to provide details of 
treatment the subject received in case of reporting afterwards. If subject receives treatment by 
another doctor, the subject’s parent or the subject’s legal guardian should inform another 
doctor of his/her participation in this study before the treatment, as far as possible. 
8. The subject’s parent or the subject’s legal guardian should consult the investigator or 
subinvestigator before the subject’s using or changing the dosage of any drug not prescribed 
by the investigator or subinvestigator (including vitamins supplements, OTC drugs, and 
herbal preparations). The subject’s parent or the subject’s legal guardian will promptly 
provide the details when the subject uses any such drug.  
9. The subject should visit the study site at the scheduled times to undergo examinations and 
tests by the investigator or subinvestigator. The subject’s parent or the subject’s legal 
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guardian will promptly inform the investigator or subinvestigator when the subject is unable 
to visit the study site as scheduled.  
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 eCRF using the following categories. For subject failure, refer to 
Section 9.1.12. 
1. 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 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%). 
2. Significant Protocol deviation. The discovery after the start of the first dose of study drug 
that the subject failed to meet protocol entry criteria or did not adhere to protocol 
requirements, and continued participation poses an unacceptable risk to the subject’s health. 
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject, 
the subject’s parent or the subject’s legal guardian were unsuccessful. Attempts to contact the 
subject, the subject’s parent or the subject’s legal guardian must be documented in the 
subject’s source documents. 
4. Voluntary withdrawal. The subject (or the subject’s parent or legal guardian) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF. 
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Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to 
an AE should not be recorded in the “voluntary withdrawal” category). 
5. Study termination. The sponsor, IRB, or regulatory agency terminates the study. 
6. 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 
22 mmHg and/or an office sitting diastolic blood pressure is persistently higher by at least 
17 mmHg than the 95th 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 before Week 12 or with the addition of any other antihypertensive drugs 
other than RAS inhibitors during the Treatment Period after Week 12. 
7. 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 (or the subject’s parent or legal guardian) 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 the eCRF. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit. 
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8.0 
CLINICAL STUDY 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 study 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 granules 
(placebo for the Run-in Period) 
White to nearly white granules Contains no TAK-536 in 1 g 
TAK-536 granules 
(active drug for the Treatment Period) 
White to nearly white granules Contains 10 mg of TAK-536 in 1 
g 
 
Manufacturing: Nipro Pharma Corporation 
2. Package and labeling 
• Package 
Study drugs will be dispensed in bottles. 
• Labeling 
Each bottle indicates the following information: the drug is for the study use only, study drug 
name, study number, subject identification number, medication identification number, the 
sponsor’s name and address, batch number, and storage condition, and expiration date. 
8.1.2 
Storage 
The study drugs are to be stored at room temperature (1°C 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 
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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 
TAK-536 granules will be subdivided into sachets by the on-site pharmacist (site designee) at 
each site. The subjects’ parent or the subjects’ legal guardian will be instructed not to store in 
direct sunlight, high temperatures or high humidity. TAK-536 granules should be administered 
immediately after the sachet is torn off. 
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. 
During the Run-in Period, subjects will orally receive the study drug for the Run-in Period once 
daily, before or after breakfast. The placebo study drug during the Run-in Period will be 
provided with equivalent daily amount (mg) as they would receive for TAK-536 0.1 mg/kg dose. 
During the Treatment Period, study drugs will be dosed according to the subject’s body weight. 
After the initial dose (0.1 mg/kg [not exceeding 2.5 mg/day]), subjects will orally receive any of 
TAK-536 0.2 mg/kg (not exceeding 5 mg/day), 0.4 mg/kg (not exceeding 10 mg/day), 0.8 mg/kg 
(not exceeding 20 mg/day) once daily, before or after breakfast. For dose titration method, see 
Section 6.1. 
At Week 12, 24 and 40, subject’s body weight is measured and the dose is adjusted according to 
the body weight. 
The investigator or subinvestigator may select the timing of the study drug administration (ie, 
before or after breakfast) in consideration of subject lifestyle but should not change this timing 
throughout the study. Regular doses on days except for the visits will be administered no later 
than 9:00 AM, regardless of the specified dosing timing (ie, before or after breakfast). The study 
drug should be administered at the almost same time every day throughout the study (acceptable 
range is ± 3hours) except the visit day. In case of a missed dose, the subject should take only one 
dose of the study drug for the day; instructions should be provided to parents or legal guardians 
that the daily dose should not be doubled on account of the missed dose. On the day before a 
scheduled visit, subject must take the study drug 24 hours (acceptable range, 21 to 27 hours) 
before office blood pressure measurement on the following 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. 
The investigator or subinvestigator will confirm whether the subject has taken the study drug or 
not in the morning of each visit. 
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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 eCRFs according to Section10.0. 
Serious adverse events (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 in response to symptoms. 
8.2 
Study Drug Assignment and Dispensing Procedures 
The investigator or subinvestigator will dispense the study drug to subjects according to the 
study procedure. 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee or destroyed at the site. The site will maintain source documents in addition to entering 
data into the interactive response technology system (IRT). 
In case subjects cannot visit the site due to the COVID-19 associated event/issue (e.g. subjects or 
their care givers who tested positive for COVID-19 or is close contact, or site shutdown due to 
COVID-19, etc), additional study drug may be provided to the subjects to cover extended periods 
between on-site visits. Study drug may be shipped directly from investigational sites to subjects’ 
residences by a contracted logistics provider (Direct to Patient [DTP] shipment) or the subject’s 
parent or the subject’s legal guardian may receive directly at investigational site. DTP shipment 
will be performed if the investigator determines that treatment can be continued after confirming 
the subject's condition by phone or using a data communication device and be provided in 
compliance with applicable laws, regulations or temporary emergency measures. The 
investigator's decision must be documented in the source documents. 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs 
The on-site pharmacist (site designee) will receive the pharmacy manual 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 investigator or designee and the on-site pharmacist (site designee) must ensure that the 
sponsor-supplied drug is used in accordance with the protocol and is dispensed only to subjects 
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enrolled in the study. To document appropriate use of sponsor supplied drug, the on-site 
pharmacist (site designee) must maintain records of all sponsor-supplied drug delivery to the site, 
site inventory, dispensation and use by each subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the on-site pharmacist (site designee) must verify the 
contents of the shipments against the packing list. The verifier should ensure that the quantity is 
correct, and the medication is in good condition. If quantity and conditions are acceptable, the 
on-site pharmacist (site designee) should acknowledge the receipt of the shipment in the IRT. If 
there are any discrepancies between the packing list versus the actual product received, the 
sponsor must be contacted to resolve the issue. The packing list should be filed in the 
investigator’s essential document file. 
The on-site pharmacist (site designee) will immediately return unused study drugs to the sponsor 
after the study is closed at the study 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 are described in Section15.2. 
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. 
Consent to participate in the study will be obtained from any subject’s parent or the subject’s 
legal guardian 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 obtained; this subject number will be used throughout the study. 
9.1.2 
Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, race, 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 resolved within 1 year prior to 
signing of informed consent form. 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 the start of Run-in Period (Week -2). 
9.1.3 
Physical Examination Procedure 
A baseline physical examination (defined as the assessment prior to first dose of study drug) will 
consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) 
musculoskeletal system; (9) nervous system; (10) lymph nodes; (11) other. All subsequent 
physical examinations should assess clinically significant changes from the assessment prior to 
first dose examination. 
9.1.4 
Weight, Height and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below: Height is 
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recorded in centimeters without decimal places. Weight is collected in kilograms (kg) with 1 
decimal place. BMI should be derived as: 
Metric: 
BMI = weight (kg)/height (m)2 
Note that although height is reported in centimeters, the formula uses meters for height; meters 
can be determined from centimeters by dividing by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2 
9.1.5 
Vital Sign Procedure 
Vital signs will include office sitting blood pressure (systolic and diastolic) and office sitting 
pulse rate (pulse rate per 1 minute). All office blood pressure will be measured with a blood 
pressure meter provided by the sponsor. 
Office blood pressure should be measured at the time of trough (approximately 21 to 27 hours 
after the latest dose, ie, 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. 
<Arm for measurement> 
The right arm should be used to measure office blood pressure. 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 after the subject has been sitting at 
rest and recorded in the subject source documents and eCRF. These should be measured in a 
sitting position. For subjects who are unable to assume a sitting position, the measurements can 
be obtained while in other positions such as a supine position. In this case, all measurements 
should be conducted in the same position during the study. 
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. Every effort 
should be made to standardize the condition of office blood pressure measurements as possible, 
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such as measurement time, the same blood pressure device should be used, whenever possible, 
by the same investigator, subinvestigator, or study collaborator. 
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. 
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, 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 (including visit at Week 6, when performed), and 
for 1 week from the day before the visit at Week 12 of the Treatment Period. 
The subject should measure blood pressure 2 times in a row with the blood pressure cuff applied 
to the right arm. 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 the eCRF. 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 22 mmHg and/or a home sitting 
diastolic blood pressure which is higher by at least 17 mmHg than the 95th 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. 
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 the sponsor. 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 the medications permitted with conditions (see 7.3.2), the 
daily dosage and unit of concomitant medications until Week 12 must be recorded in the eCRF 
as well. 
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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 form. This includes clinically significant laboratory, ECG, 
or physical examination abnormalities noted at the first test after signing of informed consent 
form, according the judgment of the investigator. The condition (ie, 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 and the maximum total 
volume of blood for the study is approximately 73 mL. The volume of blood will be determined 
at each site. 
Table 9.a lists the tests that will be obtained for each laboratory specimen. 
Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis c 
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 
Estimated 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 
a 
Only for subjects with diabetes mellitus 
b 
The laboratory tests associated with renal parameters and potassium should be performed to confirm the safety 
and tolerability when TAK-536 is titrating (including unscheduled visit). 
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c 
Urine samples will be collected when possible. 
 
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis (acceptable under the fed condition). The results of laboratory tests will be returned to 
the investigator, who is responsible for reviewing and filing these results. 
The laboratory tests associated with renal parameters and potassium should be performed to 
confirm the safety and tolerability when TAK-536 is titrating (including unscheduled visit). 
The following formula proposed by the Committee for Pediatric Chronic Kidney Disease will be 
used to deduce eGFR in Japanese children. 
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 [17] 
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, 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 (refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 
for the appropriate guidance on reporting of abnormal liver function tests). 
If 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 (refer to Section 10.2.3). 
The investigator or subinvestigator is responsible for transcribing laboratory results to the eCRF. 
The investigator will maintain a copy of the reference ranges including the archival records for 
the laboratory used. 
9.1.10 
ECG Procedure 
A resting 12-lead ECG will be measured. The investigator (or a qualified observer at the study 
site) will interpret the ECG using 1 of the following categories: within normal limits, abnormal 
but not clinically significant, or abnormal and clinically significant. The investigator 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. 
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QTc will be calculated by the sponsor using the Fredericia’s formula (QT/RR0.33). 
9.1.11 
Pharmacokinetic Sample Collection 
According to the study schedule (Appendix A), pharmacokinetic sample should be collected 
before study drug administration at one of the 4 visits (Week 2, 4, 8, and 12). Also, if possible, 
pharmacokinetic sample is collected around 2 hours (acceptable time window is 1 to 3 hours) 
after study drug administration at the same visit. At other 3 visits, if possible, pharmacokinetic 
samples are collected before study drug administration and/or around 2 hours (acceptable time 
window is 1 to 3 hours) after study drug administration. 
On the visit of Week 16, pharmacokinetic sample should be collected around 2 hours (acceptable 
time window is 1 to 3 hours) after study drug administration. 
9.1.11.1 
Collection of Plasma for Pharmacokinetic Sampling 
Blood samples (one 1-mL sample per scheduled time) for pharmacokinetic analysis of TAK-536 
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. 
9.1.11.2 
Bioanalytical Method 
Plasma concentrations of TAK-536, M-I, and M-II will be measured by HPLC/MS/MS (high-
performance liquid chromatography with tandem mass spectrometry) at CMIC Pharma Science 
Co., Ltd. 
9.1.12 Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent form. If the subject is 
withdrawn before the start of the Treatment Period, the investigator or subinvestigator should 
complete the eCRF. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
• AE. 
• Screen Failure <specify reason>. 
• Lost to follow-up. 
• Voluntary withdrawal <specify reason>. 
• Study termination. 
• Other <specify reason>. 
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Subject identification numbers assigned to subjects who fail screening should not be reused. 
9.1.13 
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 
Subjects will be required to bring study drug containers/unused study drugs to each dispensing 
site visit. Compliance with study drug (amount of dispense and return) between the visits, 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 (Compliance: <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. 
In unavoidable circumstances (eg, a widespread disease outbreak such as COVID-19 pandemic 
or natural disaster), exceptions may be consulted for alternative visits or assessments for 
conducting subject visits with approval by the Medical Monitor and/or sponsor. 
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. See Section 9.1.12 for procedures for documenting screening failures. 
Procedures to be completed at Screening include: 
• Informed consent. 
• Demographics, medical history, and medication history. 
• Physical examination. 
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• Vital signs. 
• Weight, height. 
• Concomitant medications. 
• Concurrent medical conditions. 
• Screening clinical laboratory tests. 
• Resting 12-lead ECG. 
• AE assessment. 
9.3.2 
Start of the Run-in Period (Week -2) 
The study drug for the Run-in Period (TAK-536 placebo) 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 
for the Run-in Period will be started from the next day. 
Two weeks will be set as the Run-in Period. However, at the earliest, the subjects should enter 
the Treatment Period 1 week after starting to receiving placebo if his/her blood pressures meet 
the inclusion criteria. In addition, for the subjects who are treated with any antihypertensive 
drugs before the Run-in Period, the Run-in Period can 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 9.1.12 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, 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. 
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. 
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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 who terminate the study early 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 measured 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 continued to receive the study drug 
beyond Week 24. 
9.3.6 
Follow-up Period: Week 54 
The follow-up Period will begin the 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 at the end 
of this follow-up period but care should be taken for subject safety. 
9.3.7 
Post Study Care 
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 form 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 test values and ECG findings: 
• Changes in laboratory test values or ECG findings are only considered to be AEs if they are 
judged to be clinically significant (ie, 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 or ECG re-test and/or continued monitoring of an 
abnormal value or finding 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 test 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 form) 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 form 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 concurrent medical condition (eg, asthma, epilepsy) 
any occurrence of an episode should only be captured as an AE if the condition becomes 
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, worsening of the condition 
should only be recorded as an AE if occurring to a greater extent to that which would be 
expected. 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 the start of study drug, 
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…”). 
• If the subject experiences a worsening or complication of an AE after any change in the study 
drug, 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 intensity of AEs: 
• If the subject experiences changes in intensity 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 intensity recorded. 
Preplanned procedures (surgeries or interventions): 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent form 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 recorded 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 form 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 (including seizure and epilepsy) 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis (including interstitial lung disease) 
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 
COVID-19 related disease 
COVID-19 pneumonia 
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered 
as “Important Medical Events” satisfying SAE reporting requirements. 
10.1.4 
AEs of Special Interest (AESI) 
An AE of Special Interest (AESI) (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 and instructions provided for investigator or subinvestigator as to how and when they 
should be reported to Takeda. The list of AESIs in this study is in Section 10.2.1.3 
10.1.5 
Intensity of AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
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10.1.6 
Causality of AEs 
The relationship 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 possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications 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 medications and concurrent treatments. 
10.1.7 
Causality to Study Procedures 
Relationship (causality) to study procedures should be determined for all AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as 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 
investigator or subinvestigator. 
10.1.9 
Stop 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  Frequency 
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 Concerning Study Drug 
• 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. 
• Dose Reduced – the dose was reduced due to the particular AE. 
• Dose Increased – the dose was increased due to the particular AE. 
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• Dose Interrupted – the dose was interrupted due to the particular AE. 
10.1.12  Outcome 
• Recovered/Resolved – Subject returned to first assessment status with respect to the AE. 
• 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”. 
• Resolved/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’s parent or the subject’s legal 
guardian signs the informed consent form. 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. 
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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 stop date. 
3. Frequency. 
4. Intensity. 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study drug(s) (related or not related) (not applicable for the AE that occurred before the study 
drug administration). 
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
7. Action concerning 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. In addition to these risks, hyperkalemia is also known as a risk 
caused by the pharmacological effect of ARB. Hence, the following AEs related to hypotension, 
renal impairment or hyperkalemia will be investigated as AESIs 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. 
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[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. 
[Hyperkalemia-related AE] 
Blood potassium increased, Hyperkalaemia 
If any of these AESIs occur during the Treatment Period or the Follow-up Period, it should be 
reported to the sponsor. 
An AESI eCRF should be completed, and signed by the investigator immediately or within 1 
business day of first onset or notification of the event from the subject, the subject’s parent or the 
subject’s legal guardian. However, as a back-up, if required, the AESI Form should be completed 
and reported to the sponsor (described in the separate contact information list) within 1 business 
day. 
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 eCRF should be completed, and signed by the investigator immediately or within 1 
business day of the first onset or notification of the event from the subject, the subject’s parent or 
legal guardian. However, as a back-up, if required, the SAE Form should be completed and 
reported to the sponsor (described in the separate contact information list) within 1 business day. 
The information should be provided as completely 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 and dose (during the Treatment Period). 
• 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. 
Reporting SAEs that occur before the first dose of study drug will follow the procedure 
described for SAEs. 
10.2.3 
Reporting of Abnormal Liver Function Tests  
If a subject is noted to have ALT or AST >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 Medical Monitor for 
discussion of the relevant subject details and possible alternative etiologies, such as acute viral 
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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 update SAE eCRF or complete a follow-up SAE form 
immediately. Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, 
discharge summary, postmortem results) should be sent to the sponsor, 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/ the 
head of the study site. 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, medical history and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using WHO Drug Dictionary. 
12.1 
CRFs (Electronic) 
Completed eCRFs are required for each subject who signs an informed consent form. 
The sponsor or its designee will supply study 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 e-
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 results of pharmacokinetics conducted at the analytical institute will not be recorded into the 
eCRFs. 
After the lock of the 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 the sponsor or its designee. 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 
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, 
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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 study site and filed with the original in the 
subject’s chart to ensure long term legibility. Furthermore, the investigator and the head of the 
study 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 study 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 study. 
In addition, the investigator and the head of the study 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 prior to first subject enrolled 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 all subjects complete Week 24 and 52 in the Treatment Period, the data until 
Week 24 and 52 in the Treatment Period will be analyzed separately after being locked. 
13.1.1 
Analysis Sets 
13.1.1.1 
Safety Analysis Set 
The safety analysis set will consist of all subjects who were enrolled and received at least 1 dose 
of study drug for the Treatment Period. Subjects in this analysis set will be used for 
demographic, baseline characteristics, and safety summaries. 
13.1.1.2 
Full Analysis Set 
The full analysis set (FAS) will consist of all subjects who were enrolled and received at least 1 
dose of study drug for the Treatment Period. Subjects in this analysis set will be used for efficacy 
summaries. The definition of FAS is same as the safety analysis set in this study. 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized using the safety analysis 
set. 
13.1.3 
Efficacy Analysis 
(1) Secondary endpoints and analytical methods 
[Secondary endpoints] 
Change from baseline in office trough sitting diastolic and systolic blood pressure, proportion of 
subjects who achieve the target blood pressure at Week 12 and 52 (LOCF) 
The short term efficacy and long term efficacy will be mainly evaluated by Week 12 (LOCF) and 
Week 52 (LOCF), respectively. 
[Analytical methods] 
The analyses discussed below will be conducted with the FAS. 
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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 pointand 
Week 12 and 52 (LOCF). The case plots will be also provided. 
Summary statistics and 2-sided 95% confidence intervals for mean values will be calculated 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 and Week 12 and 52 (LOCF) during the Treatment Period.  
The proportion of subjects who achieve the target blood pressure at each time point and Week 12 
and 52 (LOCF) during the Treatment Period will be summarized with blood pressure values 
measured under stable condition.  
In the analysis of Week 12 (LOCF), the above analysis will be conducted with data which are 
obtained before dosage of the medications permitted with conditions (see Section 7.3.2) is 
changed in the Treatment Period. 
(2) Confidence coefficient 
Confidence coefficient: 0.95 (2-sided estimates) 
13.1.4 
Pharmacokinetic Analysis 
[Secondary endpoints] 
Plasma concentrations of TAK-536 
[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 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, and pharmacokinetic parameters (eg, 
Cmax and AUC) in the subjects will be estimated, if possible. An analysis plan and results will be 
provided separately from those of this study. 
13.1.5 
Safety Analysis 
Primary endpoints and analytical methods 
[Primary endpoints] 
• AEs 
• Resting 12-lead ECG parameters 
• Anthropometric measurements (weight, height, and BMI]) 
• Laboratory test values 
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• Vital sign measurements (office sitting 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 TEAE is defined as any AE occurring after the start of TAK-536 administration, and until the 
end of Follow-up Period (or the test performed at early termination). 
The incidence of TEAEs listed below will be analyzed. TEAEs will be coded using 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) Resting 12-lead ECG parameters, anthropometric measurements (weight, height, and BMI), 
laboratory test values, and vital sign measurements (office sitting 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. The number and percentage of Markedly Abnormal Values 
(MAV) for serum chemistry will be provided. 
13.2 
Interim Analysis and Criteria for Early Termination 
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 after being locked. This analysis is not intended to 
inform the trial for any decisions such as to continue or discontinue this study. 
13.3 
Determination of Sample Size 
Total of 10 subjects to enter the Treatment Period.  
[Rationale for Determination of Sample Size] 
Total of 10 subjects to enter the Treatment Period was set in consideration of feasibility. 
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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 head of the study 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 
sponsor’s 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 or 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. Should other unavoidable 
circumstances arise (eg, a widespread disease outbreak such as the COVID-19 pandemic or 
natural disaster) that will require deviation from protocol-specified procedures, the investigator 
should consult with the sponsor or designee (and IRB, as required) to determine the appropriate 
course of action. Deviations from the protocol-specified procedures will be recorded as related to 
COVID-19. There will be no exemptions (a prospectively approved deviation) from the inclusion 
or exclusion criteria. In the event of a deviation or change, the principal investigator should 
notify the sponsor and the head of the study 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 study 
site as soon as possible and an approval from IRB should be obtained. 
The investigator or subinvestigator should document all protocol deviations. 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 
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the study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and head of the study 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 (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix 
B. The principles of Helsinki are addressed through the protocol and through appendices 
containing requirements for informed consent and investigator responsibilities. 
15.1 
IRB 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 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 must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB approval must refer to the study by exact protocol title, number, and 
version date; identify versions of other documents (eg, informed consent form) reviewed; and 
state the approval date. The sponsor will notify site once the sponsor has confirmed the adequacy 
of site regulatory documentation. Until the site receives notification no protocol activities, 
including screening may occur. 
Study 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 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, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form describes the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
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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 form. The informed consent form must be approved by both of the IRB and sponsor 
prior to use. 
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 detailed elements of the informed consent form to a subject’s parent or the 
subjects’ legal guardian. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB. 
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. 
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. The investigator must also sign and date 
the informed consent form at the time of consent and prior to subject entering into the study. 
Once signed, the original informed consent form 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 in the subject’s medical record. Copies of the 
signed informed consent form shall be given to the subject’s parent, or the subject’s legal 
guardian. 
All revised informed consent forms must be reviewed and signed by the relevant subject’s parent 
or the subject’s legal guardian in the same manner as the original informed consent. The date the 
revised consent was obtained should be recorded in the subject’s medical record, and the 
subject’s parent, or legal guardian should receive a copy of the revised informed consent form. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth 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 the monitor or the sponsor’s designee, representatives 
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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’s parent, or the subject’s legal guardian as part of the informed consent process (see 
Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s 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 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 needs 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 registerall 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with facility names, 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 and/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 study 
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subjects. Refer to the study site agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator or subinvestigator has questions 
regarding this policy, he or she should contact the sponsor or sponsor’s designee. 
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16.0 
REFERENCES 
1. Kikuchi T, Nagasaki K, Hiura M, Tanaka Y, Ogawa Y, Uchiyama M. Examination of the 
usefulness of blood pressure test in children with obesity. Himan-Kenkyu. 2005;11(1):69-73. 
2. The Japanese Society for Pediatric Nephrology. The Clinical guideline for Pediatric Renal 
Vascular Hypertension 2017. Shindan to Chiryo Sha; 2017. 
3. The Japanese Circulation Society. JCS 2018 Guideline on the Clinical Examination for 
Decision Making of Diagnosis and Drug therapy in Pediatric Patients with Congenital Heart 
Disease and Cardiovascular Disorder (JCS 2018 Yasukochi). Available from: j-
circ.or.jp/guideline/index.htm. Accessed September 2020 
4. Uchiyama M. Childhood and juvenile hypertension: VII. Blood pressure management to 
prevent complications and organ damage. Nippon Rinsho. 2004;62 (3):399-402. 
5. Matsuoka H. Diagnosis and treatment of hypertension: III. Treatment of Hypertension 
UPDATE 4. Antihypertensive Targets and Therapeutic Effects. The 118th Symposium of the 
Japanese Medical Association. 
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 2019). Tokyo: The Japanese Society of Hypertension; 2019. 
7. Japanese Society of Nephrology. Evidence-based Clinical Practice Guideline for CKD 2013. 
Tokyo Igakusha; 2013. 
8. The Japanese Society for Pediatric Endocrinology. 1. Standard Height and Weight: 
Assessment of body size in Japanese children. Available from: 
jspe.umin.jp/medical/jspe_test/medical/taikaku.html. Accessed September 2020. 
9. Principles for Clinical Evaluation of New Antihypertensive Drugs. (Notification No. 
0128001 of the Evaluation and Licensing Division, PFSB dated January 28, 2002)  
10. Flynn JT, Pasko DA. Calcium channel blockers: pharmacology and place in therapy of 
pediatric hypertension. Pediatr Nephrol. 2000 Dec;15(3-4):302-16. 
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. Japanese Society of Nephrology. Evidence-based Clinical Practice Guideline for CKD 2018. 
Tokyo Igakusha; 2018. 
14. Frazier KS. Species Differences in Renal Development and Associated Developmental 
Nephrotoxicity. Birth Defects Res. 2017; 109(16): 1243-56. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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15. Yanase T, Tajima T, Katabami T, Iwasaki T, Tanahashi Y, Sugawara A, et al. Diagnosis and 
treatment of adrenal insufficiency including adrenal crisis: a Japanese Endocrine Society 
clinical practice guideline. Endocrine Journal. 2016;63 (9):765-84. 
16. The Japanese Society for Pediatric Nephrology: Practical guideline for pediatric idiopathic 
nephrotic syndrome. Shindan to Chiryo Sha; 2013 
17. 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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SAP_001.pdf: 
Statistical Analysis Plan 
NCT Number: NCT04668157 
Title: A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, 
Efficacy and Pharmacokinetics of TAK-536 in Pediatric Subjects from 2 to Less Than 6 
Years of Age with Hypertension 
Study Number: Azilsartan-3004 
Document Version and Date: Version 2.0 / 06-Jun-2023 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 


STATISTICAL ANALYSIS PLAN 
Study Number: Azilsartan-3004 
Study Title: A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, 
Efficacy and Pharmacokinetics of TAK-536 in Pediatric Subjects from 2 to Less Than 6 Years of 
Age with Hypertension 
Phase: 3 
Version: 2.0 
Date: 06-Jun-2023 
Prepared by: 
 
Based on: 
Protocol Version:  Version 2.0/Amendment 1 
Protocol Date: 21 February 2023 
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Statistical Analysis Plan Final 
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REVISION HISTORY 
Version 
Approval Date 
Primary Rationale for Revision 
Original version 
01-Feb-2021
Not Applicable 
Version 2.0 
06-Jun-2023
To add some analysis 
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Statistical Analysis Plan Final 
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TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................6 
1.1 
Objectives ......................................................................................................................6 
1.1.1 
Primary Objective ..................................................................................................6 
1.1.2 
Secondary Objective(s) .........................................................................................6 
1.2 
Endpoints .......................................................................................................................6 
1.2.1 
Primary Endpoint(s) ..............................................................................................6 
1.2.2 
Secondary Endpoint(s) ..........................................................................................6 
1.3 
Estimand(s) ....................................................................................................................7 
2.0 
STUDY DESIGN.................................................................................................................7 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................10 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................10 
5.0 
ANALYSIS SETS .............................................................................................................10 
5.1 
Safety Analysis Set ......................................................................................................10 
5.2 
Full Analysis Set ..........................................................................................................11 
6.0 
STATISTICAL ANALYSIS .............................................................................................11 
6.1 
General Considerations ................................................................................................11 
6.1.1 
Analysis Approach for Continuous Variables .....................................................12 
6.1.2 
Analysis Approach for Binary Variables ............................................................12 
6.2 
Disposition of Subjects ................................................................................................12 
6.2.1 
Study Information ................................................................................................12 
6.2.2 
Screen Failures ....................................................................................................12 
6.2.3 
Subject Eligibility ................................................................................................13 
6.2.4 
Number of Subjects Who Entered the Treatment Period by Site ........................13 
6.2.5 
Disposition of Subjects ........................................................................................14 
6.2.5.1 
Treatment of Subjects .................................................................................14 
6.2.5.2 
Disposition of Subjects ...............................................................................14 
6.2.6 
Protocol Deviations and Analysis Sets ................................................................15 
6.2.6.1 
Protocol Deviations .....................................................................................15 
6.2.6.2 
Analysis Sets ...............................................................................................15 
6.3 
Demographic and Other Baseline Characteristics .......................................................16 
6.3.1 
Demographics and Other Baseline Characteristics .............................................16 
6.3.2 
Medical History and Concurrent Medical Conditions .........................................17 
6.4 
Medication History and Concomitant Medications .....................................................18 
6.5 
Efficacy Analysis .........................................................................................................19 
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6.5.1 
Secondary Endpoint(s) Analysis .........................................................................19 
6.5.1.1 
Derivation of Endpoint(s) ...........................................................................19 
6.5.1.2 
Main Analytical Approach ..........................................................................19 
6.5.2 
Subgroup Analyses ..............................................................................................20 
6.6 
Safety Analysis ............................................................................................................21 
6.6.1 
Adverse Events ....................................................................................................21 
6.6.1.1 
Overview of Treatment-Emergent Adverse Events ....................................21 
6.6.1.2 
Displays of Treatment-Emergent Adverse events.......................................22 
6.6.1.3 
Displays of Pretreatment Events .................................................................24 
6.6.1.4 
Displays of Run-in Adverse Events ............................................................24 
6.6.2 
Adverse Events of Special Interest ......................................................................24 
6.6.3 
Clinical Laboratory Evaluations ..........................................................................25 
6.6.3.1 
Hematology and Serum Chemistry .............................................................25 
6.6.3.2 
Urinalysis ....................................................................................................26 
6.6.4 
Vital Signs ...........................................................................................................27 
6.6.5 
12-Lead ECGs .....................................................................................................28
6.6.6 
Extent of Exposure and Compliance ...................................................................29 
6.6.6.1 
Extent of Exposure and Compliance ...........................................................29 
6.6.6.2 
Dose Corresponding to Each Visit Assessment ..........................................29 
6.6.6.3 
Dose Escalation ...........................................................................................30 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses .................................30 
6.7.1 
Pharmacokinetic Analysis ...................................................................................30 
6.8 
Interim Analyses ..........................................................................................................31 
7.0 
REFERENCES ..................................................................................................................31 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................31 
9.0 
APPENDIX ........................................................................................................................31 
9.1 
Changes From the Previous Version of the SAP .........................................................31 
9.2 
Data Handling Conventions .........................................................................................34 
9.2.1 
Definition of Baseline ..........................................................................................34 
9.2.2 
Definition of Visit Windows ...............................................................................34 
9.2.3 
AEs of Special Interest ........................................................................................36 
9.2.4 
Criteria for Markedly Abnormal Values .............................................................36 
9.3 
Analysis Software ........................................................................................................37 
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ABBREVIATIONS 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARB 
angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
BMI 
Body mass index 
BUN 
blood urea nitrogen 
CCB 
calcium channel blocker 
CI 
confidence interval 
CRF 
case report form 
COVID-19 
coronavirus disease 2019  
DRI 
direct renin inhibitors 
ECG 
electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
LLN 
lower limit of normal 
LDH 
lactate dehydrogenase 
LOCF 
last observation carried forward 
MAV 
markedly abnormal value 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
Preferred Term (MedDRA) 
PTE 
pretreatment event 
Q1 
25th percentile 
Q3 
75th percentile 
RAS 
renin-angiotensin-system 
SD 
standard deviation 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
To evaluate the safety of TAK-536 in pediatric subjects with hypertension aged 2 to less than 6 
years 
1.1.2 
Secondary Objective(s) 
To evaluate the efficacy and pharmacokinetics of TAK-536 in pediatric subjects with 
hypertension aged 2 to less than 6 years 
1.2 
Endpoints 
1.2.1 
Primary Endpoint(s) 
Safety: 
•
Adverse events (AEs)
•
Resting 12-lead electrocardiogram (ECG) parameters
•
Anthropometric measurements (weight, height, and body mass index [BMI])
•
Laboratory test values
•
Vital sign measurements (office sitting pulse rate* and home sitting blood pressure*)
*These should be measured in a sitting position. For subjects who are unable to assume a
sitting position, blood pressure measurements can be obtained while in other positions such
as a supine position. In this case, all measurements should be conducted in the same position
during the study.
1.2.2 
Secondary Endpoint(s) 
Efficacy: 
•
Change from baseline in office trough sitting diastolic and systolic blood pressure at Week
12 and 52 (last observation carried forward [LOCF])
•
Proportion of subjects who achieve the target blood pressure at Week 12 and 52 (LOCF)
Note: The target blood pressure is <95th percentile for essential hypertension and <90th 
percentile for subjects with secondary hypertension. The values are shown in Table 1. 
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Table 1 
Reference Blood Pressure Values of Children by Gender and Age 
Age (years) 
Male 
Female 
90th 
95th 
95th 
+ 12 mmHg
90th 
95th 
95th 
+ 12 mmHg
2 
102/56 
106/59 
118/71 
103/60 
106/64 
118/76 
3 
103/59 
107/62 
119/74 
104/62 
108/66 
120/78 
4 
105/62 
108/66 
120/78 
106/65 
109/69 
121/81 
5 
106/65 
109/69 
121/81 
107/67 
110/71 
122/83 
6 
107/68 
111/71 
123/83 
108/69 
111/72 
123/84 
Systolic/diastolic blood pressures (mmHg), Guidelines on the Clinical Examination for Decision Making of 
Diagnosis and Drug Therapy in Pediatric Patients with Cardiovascular Diseases and Cardiovascular Disorder by 
the Japanese Circulation Society (JCS2018) [3] 
The 90th and 95th indicate 90th and 95th percentile, respectively. 
Pharmacokinetics: 
Plasma concentrations of TAK-536 
1.3 
Estimand(s) 
Not Applicable. 
2.0 
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 with hypertension aged 2 to less than 6 years. 
The study consists of a 2-week Run-in Period, a 52-week Treatment Period, and a 2-week 
Follow-up Period (56 weeks in total). 
Screening and Run-in Period: 
Subjects eligible at screening will begin 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. However, at the earliest, the subjects should 
enter the Treatment Period 1 week after starting to receive placebo if his/he blood pressures 
meet the inclusion criteria. In addition, for the subjects who are treated with any 
antihypertensive drugs before the Run-in Period, the Run-in Period can be extended up to 
4 weeks if blood pressures do not meet the inclusion criteria. 
Subjects who were treated with renin-angiotensin-system (RAS) inhibitors (ACE inhibitors, ARB 
and direct renin inhibitors [DRI]) must discontinue these medications at the start of the Run-in 
Period. 
Subjects who were 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 
 
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study drug if the subjects are considered to need the additional treatment for hypertension in the 
Treatment Period by the investigator or subinvestigator. The dose of the antihypertensive drug 
used before the Run-in period should be the same once the Run-in period starts.  
If termination of antihypertensive drugs other than RAS inhibitors requires a gradual down-
titration, this can be accomplished while subjects are in the Run-in Period. In the case of the 
down-titration, the antihypertensive drugs should be discontinued at least 1 week (7 days) before 
the start of the Treatment Period. Antihypertensives, in particular beta-blockers (BBs), should be 
tapered off gradually, as it may cause withdrawal syndrome, in which symptoms such as 
palpitations, restlessness, hypertension, headache would be observed upon abrupt 
discontinuation. 
Treatment Period: 
Study drugs will be dosed according to the subject’s body weight. In the Treatment Period, the 
initial dose of TAK-536 will be 0.1 mg/kg (not exceeding 2.5 mg/day). After the initial dose, 
TAK-536 will be titrated to 0.2 mg/kg (not exceeding 5 mg/day), 0.4 mg/kg (not exceeding 
10 mg/day), and 0.8 mg/kg (not exceeding 20 mg/day) if the subjects do not achieve the target 
blood pressure and no concerns are found in safety and tolerability. The target blood pressure is 
<95th percentile for essential hypertension and <90th percentile for subjects with secondary 
hypertension (Table 1)  
TAK-536 will be titrated at the visits of Weeks 2, 4, or 8. 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. Even if the dose is not titrated to the maximum 
dose (0.8 mg/kg) by Week 8, TAK-536 may be titrated to 0.2 mg/kg, 0.4 mg/kg, or 0.8 mg/kg in a 
stepwise order after Week 8 if the subjects do not achieve the target blood pressure and there are 
no concerns regarding safety and tolerability.  
During the Treatment Period before Week 12, change in the dosage of any concomitant 
antihypertensive drug is not allowed in the subjects who are treated with a single 
antihypertensive drug other than RAS inhibitors. TAK-536 dose can be reduced to 0.4 mg/kg, 
0.2 mg/kg, or 0.1 mg/kg at the investigator’s or subinvestigator’s discretion if there are any 
concerns in safety and tolerability with upward titration of TAK-536 (ie, in case of occurring any 
AEs associated with titration of TAK-536). 
During the Treatment Period after Week 12, when the subjects do not achieve the target blood 
pressure with the maximum dose (0.8 mg/kg) 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. TAK-536 dose 
can be reduced to 0.4 mg/kg, 0.2 mg/kg, or 0.1 mg/kg at the investigator’s or subinvestigator’s 
discretion if there are any concerns in safety and tolerability with upward titration of TAK-536 
(ie, in case of occurring any AEs associated with titration of TAK-536). When the 
antihypertensive drugs require dose reduction or interruption because of concerns in safety and 
tolerability with titration, dosing of the antihypertensive drugs other than TAK-536 should be 
 
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reduced or interrupted first. Thereafter, dose reduction or interruption of TAK-536 should be 
considered. 
Follow-up Period: 
Follow-up Period will last 2 weeks from the day following the final dose of TAK-536, that is at 
Week 54 after the start of the Treatment Period. Safety will be evaluated up to that time. 
Sites will employ all efforts to see subjects in the clinic for assessments. In unavoidable 
circumstances (eg, a widespread disease outbreak such as the coronavirus disease 2019 
[COVID-19] pandemic or natural disaster), exceptions may be consulted for alternative visits or 
assessments for conducting subject visits with approval by the Medical Monitor and/or sponsor. 
Such instances will be documented in the study records as related to COVID-19. 
A schematic of the study design is included as Figure 1. A schedule of assessments is listed in 
Appendix A in the protocol. 
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5.2 
Full Analysis Set 
The full analysis set (FAS) will consist of all subjects who were enrolled and received at least 1 
dose of study drug for the Treatment Period. Subjects in this analysis set will be used for efficacy 
summaries.  
6.0 
STATISTICAL ANALYSIS 
6.1 
General Considerations 
•
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 start of TAK-536
administration, and until the end of Follow-up Period (or the test performed at early termination)
•
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
•
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
•
Study Drug Compliance for 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
•
Office trough sitting diastolic and systolic blood pressures on each measuring day: The mean
of 3 values with rounding to integer on a given measuring day is used as the representative
value of that measuring day. If only 2 measurements are obtained on a given measuring day,
the mean of the 2 values is used. If only one measurement is obtained on a given measuring
day, that value is used.
•
Achievement of target blood pressure on each measuring day: Subjects are determined to have
achieved their target blood pressures if their office trough sitting diastolic/systolic blood
pressures are the <95th percentile (both diastolic and systolic) shown in Table 1 for essential
hypertension or <90th percentile (both diastolic and systolic) shown in Table 1 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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Statistical Analysis Plan Final 
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•
Disease duration (years): (Date of informed consent [year and month] − date of onset [or
diagnosis] of underlying disease [year and month]) / 12
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])
6.1.1 
Analysis Approach for Continuous Variables 
Continuous variables will be summarized using the descriptive statistics (n, mean, standard 
deviation [SD], minimum, Q1, median, Q3, and maximum) unless stated otherwise in the section 
specific to an endpoint. The confidence intervals of the mean will be calculated using t-
distribution. 
6.1.2 
Analysis Approach for Binary Variables 
Binary and categorical variables will be summarized using the number and percentage of 
subjects unless stated otherwise in the section specific to an endpoint. The confidence intervals 
of the proportion will be calculated using Clopper-Pearson method. 
6.2 
Disposition of Subjects 
6.2.1 
Study Information 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variables: 
Date of First Subject Signed Informed Consent Form 
Date of Last Subject’s Last Visit/Contact 
MedDRA Version 
WHO Drug Version 
SAS Version Used for Creating the Datasets 
Analytical Methods: 
(1) Study Information
Study information shown in the analysis variables section will be provided.
6.2.2 Screen Failures 
Analysis Set: 
All Subjects Who Did Not Enter the Treatment Period 
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Statistical Analysis Plan Final 
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Analysis Variables: 
Age (years) at Informed Consent [2, 3, 4, 5] 
Gender 
[Male, Female] 
Analytical Methods: 
(1) Screen Failures
Frequency distributions for categorical variables and descriptive statistics for
continuous variables will be provided.
6.2.3 Subject Eligibility 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variables: 
Eligibility Status 
[Eligible for Entrance into the Treatment Period, Not Eligible for 
Entrance into the Treatment Period] 
Primary Reason for Subject Not Being Eligible 
[Adverse Event, Lost to Follow-up, 
Screen Failure, Study Termination by Sponsor, Withdrawal by Subject, Other] 
Analytical Methods: 
(1) Eligibility for Entrance into the Treatment Period
Frequency distributions will be provided. When calculating percentages for the
primary reasons for subject not being eligible, the total number of ineligible subjects
will be used as the denominator.
6.2.4 Number of Subjects Who Entered the Treatment Period by Site 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variables: 
Status of Entrance into the Treatment Period 
[Entered] 
Category: 
Site 
[Site numbers will be used as categories] 
Analytical Methods: 
(1) Number of Subjects Who Entered the Treatment Period by Site
Frequency distribution will be provided by site.
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6.2.5 Disposition of Subjects 
6.2.5.1 
Treatment of Subjects 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variables: 
Study Drug Administration Status [Eligible but Not Treated] 
Reason for Not Being Treated 
[Adverse Event, Lack of Efficacy, Lost to Follow-
up, Protocol Deviation, Study Terminated by Sponsor, Voluntary Withdrawal, Other] 
Analytical Methods: 
(1) Treatment of Subjects
Frequency distributions will be provided. When calculating percentages for the reasons
for not being treated, the total number of subjects not treated by the study drug will be
used as the denominator. When calculating percentages for the reasons for
discontinuation, the total number of subjects who prematurely discontinued will be
used as the denominator.
6.2.5.2 
Disposition of Subjects 
Analysis Set: 
All Subjects Who administered the Study Drug 
Analysis Variables: 
Completed study treatment [Completed, Discontinued] 
Reason for Discontinuation of Study Treatment [Adverse Event, Death, Lack of 
Efficacy, Lost to Follow-up, Protocol Deviation, Study Terminated by Sponsor, 
Voluntary Withdrawal, Other] 
Completed study 
[Completed, Discontinued] 
Reason for Discontinuation of Study 
[Adverse Event, Death, Lack of Efficacy, 
Lost to Follow-up, Protocol Deviation, Study Terminated by Sponsor, Voluntary 
Withdrawal, Other] 
Analytical Methods: 
(1) Disposition of Subjects
Frequency distributions will be provided. When calculating percentages for the reasons
for not being treated, the total number of subjects not treated by the study drug will be
used as the denominator. When calculating percentages for the reasons for
discontinuation, the total number of subjects who prematurely discontinued will be
used as the denominator.
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6.2.6 Protocol Deviations and Analysis Sets 
6.2.6.1 Protocol Deviations 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variables: 
Significant Protocol Deviation 
[Categories by Takeda Controlled Terminology] 
Analytical Methods: 
(1) Protocol Deviations
The significant protocol deviations are defined as major or critical ones based on the
Protocol Deviations Management Plan.
Frequency distribution will be provided for each deviation category. A subject who has
several deviations will be counted once in each appropriate category. A subject who
has several deviations that can be classified into the same category will be counted
only once.
A listing of all protocol deviations (not only major or critical, but also minor ones) will
be provided with the severity and the category by Takeda Controlled Terminology and
Protocol Deviations Management Plan.
6.2.6.2 Analysis Sets 
Analysis Set: 
All Subjects Who Administered the Study Drug 
Analysis Variables: 
Handling of Subjects 
[Subject Evaluability List] 
Analysis Sets 
Full Analysis Set 
[Included] 
Safety Analysis Set 
[Included] 
Analytical Methods: 
(1) Subjects Excluded from Analysis Sets
(2) Analysis Sets
Frequency distributions will be provided. For (1), a subject who has several reasons for
exclusion will be counted once in each appropriate category. A subject who has several
reasons for exclusion that can be classified into the same category will be counted only
once.
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6.3 
Demographic and Other Baseline Characteristics 
6.3.1 
Demographics and Other Baseline Characteristics 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Age (years) at Informed Consent [2, 3, 4, 5] 
Age (years) at Week 0 
[2, 3, 4, 5]  
Gender 
[Male, Female] 
Height (cm) at Week 0 
[Min≤ - <80, 80≤ - <90, 90≤ - <100, 100≤ - <110, 110≤ - 
<120, 120≤ - ≤Max] 
Weight (kg) at Week 0 
[Min≤ - <10.0, 10.0≤ - <15.0, 15.0≤ - <20.0, 20.0≤ - <25.0, 
25.0≤ - ≤Max] 
BMI (kg/m2) at Week 0 
[Min≤ - <15.0, 15.0≤ - <18.0, 18.0≤ - <21.0, 21.0≤ - <24.0, 
24.0≤ - <27.0, 27.0≤ - ≤Max] 
Disease duration (years) 
[Min≤ - <0.5, 0.5≤ - <1.0, 1.0≤ - <1.5, 1.5≤ - <2.0, 2.0≤ - 
<2.5, 2.5≤ - <3.0, 3.0≤ - ≤Max] 
Type of hypertension [Essential hypertension, Secondary hypertension] 
Drug 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 [Yes, No] 
CCB 
[Yes, No] 
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Diuretics 
[Yes, No] 
Alpha-blockers 
[Yes, No] 
Beta-blockers 
[Yes, No] 
Other 
[Yes, No] 
Steroids at the start of Treatment Period [Yes, No] 
Central nervous system stimulants or non-central nervous system stimulants at the start 
of Treatment Period [Yes, No] 
Office sitting blood pressure (systolic) (mmHg) at Week 0 
[Min≤ - <110, 110≤ - 
<120, 120≤ - <130, 130≤ - <140, 140≤ - <Max] 
Office sitting blood pressure (diastolic) (mmHg) at Week 0 
[Min≤ - <70, 70≤ - 
<80, 80≤ - <90, 90≤ - <100, 100≤ - <Max] 
eGFR (mL/min/1.73 m2) at Week 0 
[Min≤ - <30, 30≤ - <60, 60≤ - <90, 90≤ - 
<Max] 
Analytical Methods: 
(1) Summary of Demographics
Frequency distributions for categorical variables and descriptive statistics for
continuous variables will be provided.
Age at Week 0 is defined as the age at date of the first study drug administration for
the Treatment Period.
6.3.2 
Medical History and Concurrent Medical Conditions 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
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) 
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Analytical Methods: 
(1) Underlying Diseases of Disease Induced Secondary Hypertension by System Organ
Class and Preferred Term
(2) Underlying Diseases of Disease Induced Secondary Hypertension by System Organ
Class and Preferred Term by Steroids at the Start of Treatment Period
(3) Medical History by System Organ Class and Preferred Term
(4) Concurrent Medical Conditions by System Organ Class and Preferred Term
Frequency distributions will be provided. MedDRA dictionary will be used for coding.
Summaries will be provided using SOC and PT, where SOC will be sorted
alphabetically and PT will be sorted in decreasing frequency. 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.
6.4 
Medication History and Concomitant Medications 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Medication History 
Concomitant Medications [antihypertensive drugs, steroids, central nervous system 
stimulants or non-central nervous system stimulants, others] 
Analytical Methods: 
(1) Medication History by Preferred Medication Name
(2) Concomitant Medications by Drug Categories and Preferred Medication Name
(3) Antihypertensive Drugs Except for RAS inhibitors by Drug Categories and Preferred
Medication Name in Treatment Period
Frequency distributions will be provided. WHO Drug dictionary will be used for 
coding. Summaries will be provided using preferred medication name and sorted in 
decreasing frequency based on the number of reports. A subject who has been 
administered several medications with the same preferred medication name will be 
counted only once for that preferred medication name. 
The concomitant medications will be categorized based on the observed data. 
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6.5 
Efficacy Analysis 
6.5.1 
Secondary Endpoint(s) Analysis 
6.5.1.1 
Derivation of Endpoint(s) 
Refer to section 6.1. 
6.5.1.2 
Main Analytical Approach 
Analysis Set: 
Full Analysis Set 
Analysis Variables: 
Office trough sitting diastolic blood pressure 
Office trough sitting systolic blood pressure 
Proportion of subjects who achieved the target blood pressure 
Visit: 
Week 0, 2, 4, 8, 12, 16, 20, 24, 32, 40, 52, 54 (Follow-up), Week 12 (LOCF), Week 52 
(LOCF) 
Analytical Methods: 
(1) Summary of observed value and change from baseline for office trough sitting
diastolic and systolic blood pressure by visit
Descriptive statistics and 95% CI for mean values of observed values and changes
from baseline will be provided by visit. Means and standard deviations will be
plotted.
(2) Case plot of observed value office trough sitting diastolic and systolic blood
pressure over time for each subject
The case plots of observed value over time for each subject will be presented.
(3) Summary of observed value and change from baseline for office trough sitting
diastolic and systolic blood pressure in Week 12 (LOCF) with data which are
obtained before dosage of the medications permitted with conditions in protocol
section 7.3.2 is changed.
Descriptive statistics and 95% CI for mean values of observed values and changes
from baseline will be provided in Week 12 (LOCF). The time window in section
9.2.2 will be applied for the data which are obtained until the day of dosage of the
medications permitted with conditions in protocol section 7.3.2 is changed.
(4) Proportion of subjects who achieved the target blood pressure by visit
Frequency distributions and 95% CI of proportions will be provided by visit.
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(5) Proportion of subjects who achieved the target blood pressure in Week 12 (LOCF)
with data which are obtained before dosage of the medications permitted with
conditions in protocol section 7.3.2 is changed.
Frequency distributions and 95% CI of proportions will be provided in Week 12
(LOCF). The time window in section 9.2.2 will be applied for the data which are
obtained until the day of dosage of the medications permitted with conditions in
protocol section 7.3.2 is changed.
6.5.2 
Subgroup Analyses 
Analysis Set: 
Full Analysis Set 
Analysis Variables: 
Change from baseline for office trough sitting diastolic blood pressure 
Change from baseline for office trough sitting systolic blood pressure 
Proportion of subjects who achieved the target blood pressure 
Visit: 
Week 12 (LOCF), Week 52 (LOCF) 
Subgroups: 
Age (years) at Informed Consent [Min≤3, 4≤Max] 
Gender 
[Male, Female] 
Weight (kg) at Week 0 
[Min≤ - <15.0, 15.0≤ - ≤Max] 
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 
[Yes, No] 
Steroids at the start of Treatment Period [Yes, No] 
Central nervous system stimulants or non-central nervous system stimulants at the start 
of Treatment Period [Yes, No] 
eGFR (mL/min/1.73 m2) 
[Min≤ - <60, 60≤ - <90, 90≤ - ≤Max] 
Analytical Methods: 
(1) Summary of change from baseline for office trough sitting diastolic and systolic
blood pressure by visit by each stratum
Descriptive statistics and 95% CI for mean values of observed values and changes
from baseline will be provided by visit by each subgroup.
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(2) Proportion of subjects who achieved the target blood pressure by visit by each
stratum
Frequency distributions and 95% CI of proportions will be provided by visit by
each subgroup.
6.6 
Safety Analysis 
6.6.1 
Adverse Events 
6.6.1.1 
Overview of Treatment-Emergent Adverse Events 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
TEAE 
Categories: 
Relationship to Study Drug [Related, Not Related] 
Intensity 
[Mild, Moderate, Severe] 
Analytical Methods: 
The following summaries will be provided. 
(1) Overview of Treatment-Emergent Adverse Events
1)
All Treatment-Emergent Adverse Events (number of events, number and
percentage of subjects)
2)
Relationship of Treatment-Emergent Adverse Events to study drug (number of
events, number and percentage of subjects)
3)
Intensity of Treatment-Emergent Adverse Events (number of events, number and
percentage of subjects)
4)
Treatment-Emergent Adverse Events leading to study drug discontinuation
(number of events, number and percentage of subjects)
5)
Serious Treatment-Emergent Adverse Events (number of events, number and
percentage of subjects)
6)
Relationship of Serious Treatment-Emergent Adverse Events to study drug
(number of events, number and percentage of subjects)
7)
Serious Treatment-Emergent Adverse Events leading to study drug
discontinuation (number of events, number and percentage of subjects)
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8)
Treatment-Emergent Adverse Events resulting in death (number of events,
number and percentage of subjects)
TEAEs will be counted according to the rules below. 
Number of subjects 
•
Summaries for 2) and 6)
A subject with occurrences of TEAE in both categories (i.e., Related and Not Related)
will be counted once in the Related category.
•
Summary for 3)
A subject with multiple occurrences of TEAE will be counted once for the TEAE with
the maximum toxicity grade.
•
Summaries other than 2), 3), and 6)
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.
6.6.1.2 
Displays of Treatment-Emergent Adverse events 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
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 Methods: 
The following summaries will be provided using frequency distribution. 
TEAEs will be coded using the MedDRA and will be summarized using SOC and PT. 
SOC will be sorted alphabetically and PT 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 System Organ Class only or PT only. 
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(1) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
(2) Treatment-Emergent Adverse Events by System Organ Class
(3) Treatment-Emergent Adverse Events by Preferred Term
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(5) Intensity of Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ
Class, and Preferred Term
(7) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by
System Organ Class and Preferred Term
(8) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred
Term
(9) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
Over Time
(10) Non-serious Treatment-Emergent Adverse Events whose incidence summarized by
PT is ≥2% by SOC and PT
The frequency distribution will be provided according to the rules below. 
Number of subjects 
•
Summary tables other than (5), (6) and (9)
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted
only once in that SOC or PT. Percentages will be based on the number of subjects in
the safety analysis set.
•
Summary tables for (5) and (6)
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. Percentages will be based on the
number of subjects in the safety analysis set.
•
Summary table for (9)
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 percentages for each time interval, the number of subjects at risk
(i.e., subjects who either have an exposure or have an occurrence of TEAE, during or
after the corresponding time interval) will be used as the denominator. The number of
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subjects whose onset of any one of the TEAEs is within the time interval will be used 
as the numerator. 
6.6.1.3 
Displays of Pretreatment Events 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variables: 
PTE 
Analytical Methods: 
The following summaries will be provided using frequency distribution according to 
section 6.6.1.2. 
(1) Pretreatment Events by System Organ Class and Preferred Term
(2) Serious Pretreatment Events by System Organ Class and Preferred Term
6.6.1.4 
Displays of Run-in Adverse Events 
Analysis Set: 
All subjects who received the study drug for the Run-in Period 
Analysis Variables: 
AEs during the Run-in Period 
Analytical Methods: 
The following summaries will be provided using frequency distribution according to 
section 6.6.1.2. 
(1) Run-in Adverse Events by System Organ Class and Preferred Term
(2) Serious Run-in Adverse Events by System Organ Class and Preferred Term
6.6.2 
Adverse Events of Special Interest 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Hypotension-related TEAE 
Renal dysfunction-related TEAE 
Hyperkalemia-related TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
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Analytical Methods: 
The following summaries will be provided using frequency distribution according to 
section 6.6.1.2. 
(1) Hypotension-related Treatment-Emergent Adverse Events by System Organ Class
and Preferred Term
(2) Drug-Related Hypotension-related Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
(3) Renal dysfunction-related Treatment-Emergent Adverse Events by System Organ
Class and Preferred Term
(4) Drug-Related Renal dysfunction-related Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(5) Hyperkalemia-related Treatment-Emergent Adverse Events by System Organ Class
and Preferred Term
(6) Drug-Related Hyperkalemia-related Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
Hypotension-related TEAE, Renal dysfunction-related TEAE and Hyperkalaemia-
related TEAE are defined in section 9.2.3. 
6.6.3 
Clinical Laboratory Evaluations 
6.6.3.1 
Hematology and Serum Chemistry 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Hematology 
Red blood cell, White blood cell count with differential (%) (neutrophil, basophil, 
eosinophil, lymphocyte, monocyte), Hemoglobin, Hematocrit, Platelets 
Serum Chemistry 
ALT, Albumin, Alkaline phosphatase, AST, Bilirubin (Total bilirubin), Blood urea 
nitrogen (BUN), Calcium, Chloride, Creatinine, Creatine kinase, Cystatin C, 
Estimated Glomerular Filtration Rate (eGFR), Gamma-Glutamyl transferase (GGT), 
Glucose, Cholesterol (Total cholesterol), Triglyceride, Phosphate, Potassium, 
Sodium, Protein (Total protein), Lactate dehydrogenase (LDH) 
Categories: 
Results of determination based on normal reference range 
[Low, Normal, High] 
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Visit: 
Week 0, 2, 4, 8, 12, 24, 52 
Analytical Methods: 
The following summaries will be provided. 
(1) Summary of Laboratory Test Results and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline will be provided
by visit.
(2) Case Plots
Plots over time for each subject will be presented.
(3) Summary of Shifts of Laboratory Test Results by Visit
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided.
For each laboratory test, the laboratory values will be classified as “Low”, “Normal” or
“High” relative to the normal reference range. The shift tables will be based on these
classifications.
(4) Number and Percentage of Subjects with Markedly Abnormal Values of Serum
Chemistry
Overall frequency distributions of MAV during treatment period will be provided. If a 
laboratory parameter has both lower and upper MAV criteria, analysis will be 
performed for each. Further details are given in section 9.2.4. 
6.6.3.2 
Urinalysis 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Quantitative tests 
Protein, Creatinine, Albumin, Protein/creatinine ratio, Albumin/creatinine ratio, 
Specific Gravity 
Qualitative tests 
Glucose 
[-,  +-,  1+,  2+,  3+,  4+, 5+] 
pH 
[Min <= - <= 8.0, 8.0 < - <= Max] 
Protein  
[-,  +-,  1+,  2+,  3+,  4+, 5+] 
Occult blood [-,  +-,  1+,  2+,  3+,  4+, 5+] 
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Ketones 
[-,  +-,  1+,  2+,  3+,  4+, 5+] 
Visit: 
Week 0, 2, 4, 8, 12, 24, 52 
Analytical Methods: 
For quantitative tests, summaries (1), (2) and (3) will be provided. 
For qualitative tests, summaries (4) will be provided. 
(1) Summary of Laboratory Test Results and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline will be provided
by visit.
(2) Case Plots
Plots over time for each subject will be presented.
(3) Summary of Shifts of Laboratory Test Results by Visit
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided.
For each laboratory test, the laboratory values will be classified as “Low”, “Normal” or
“High” relative to the normal reference range. The shift tables will be based on these
classifications.
(4) Number of Subjects in Categories of Urine Laboratory Test Results by Visit
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided.
6.6.4 
Vital Signs 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Height, Weight, BMI 
Office sitting pulse rate 
Home sitting systolic and diastolic blood pressures 
Visit: 
Weight: Week 0, 12, 24, 40, 52 
Height, BMI: Week 0, 24, 52 
Office sitting pulse rate: Week 0, 2, 4, 8, 12, 16, 20, 24, 32, 40, 52 
Home sitting systolic and diastolic blood pressures: Week 0, 2, 4, 8, 12 
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Analytical Methods: 
The following summaries will be provided. 
(1) Summary of Vital Signs and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline will be provided
by visit.
(2) Case Plots
Plots over time for each subject will be presented.
6.6.5 
12-Lead ECGs 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Heart Rate 
PR Interval 
RR Interval 
QRS Interval 
QT Interval 
QTcF Interval 
Interpretation 
[Within Normal Limits, Abnormal but not Clinically Significant, 
Abnormal and Clinically Significant] 
Visit: 
Screening, Week 12, 24, 52 
Analytical Methods: 
For each variable other than 12-lead ECG interpretations, summaries (1) and (2) will 
be provided. 
For 12-lead ECG interpretation, summary (3) will be provided. 
(1) Summary of ECG Parameters and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline (screening) will
be provided by visit.
(2) Case Plots
Plots over time for each subject will be presented.
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(3) Summary of Shift of 12-lead ECG Interpretation by Visit
Shift table showing the number of subjects in each category at baseline (screening) and
each post-baseline visit will be provided.
6.6.6 
Extent of Exposure and Compliance
6.6.6.1 
Extent of Exposure and Compliance 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Duration of Exposure to Study Drug for Treatment Period (days) [1≤ - ≤84, 85≤ - ≤168, 
169≤ - ≤252, 253≤ - ≤336, 337≤ - ≤420, 421≤ - ≤Max] 
Study Drug Compliance for Treatment Period (%) 
[Min≤ - <70.0, 70.0≤ - <80.0, 
80.0≤ - <90.0, 90.0≤ - ≤Max] 
Analytical Methods: 
(1) Study Drug Exposure and Compliance
Frequency distributions for categorical variables and descriptive statistics for
continuous variables will be provided.
6.6.6.2 
Dose Corresponding to Each Visit Assessment 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Dose (mg/kg) 
[0.1, 0.2, 0.4, 0.8] 
Visit: 
Week 0, 2, 4, 8, 12, 16, 20, 24, 32, 40, and End of Treatment Period 
Analytical Methods: 
(1) Dose on The One Day before Visit
Frequency distributions will be provided.
For the dose at Week 0, the dose on the day of first study drug administration for the
Treatment Period will be used. For the dose at Week 2, 4, 8, 12, 20, 24, 32 and 40, the
dose on one day before the visit day will be used. For the dose at end of Treatment Period,
the dose at the date of the last study drug administration for the Treatment Period will
be used.
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6.6.6.3 
Dose Escalation 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Dose (mg/kg) 
[0.1, 0.2, 0.4, 0.8] 
Visit: 
Week 0, 2, 4, 8, 12, 16, 20, 24, 32, 40, and End of Treatment Period 
Analytical Methods: 
(1) Dose by Visit
Frequency distributions will be provided.
For the dose at Week 0, the dose on the day of first study drug administration for the
Treatment Period will be used. For the dose at Week 2, 4, 8, 12, 20, 24, 32 and 40, the
dose on the visit day will be used. For the dose at end of Treatment Period, the dose at
the date of the last study drug administration for the Treatment Period will be used.
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses
6.7.1 
Pharmacokinetic Analysis 
Analysis Set: 
Subjects who have adequately measured plasma concentration of TAK-536 in FAS 
Analysis Variable(s): 
Plasma Concentrations of TAK-536, M-I and M-II 
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, Week 16 postdose, 
Analytical Method(s): 
The following summaries will be provided. The scheduled visit will be used. Any 
hours after dose (0.25 hours, 0.5 hours etc.) will be handled as “postdose”. 
(1) Summary of Plasma Concentrations by Visit
Descriptive statistics will be provided by visit.
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6.8 
Interim Analyses 
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 after being locked. This analysis is not intended to 
inform the trial for any decisions such as to continue or discontinue this study. 
7.0 
REFERENCES 
Not applicable. 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
No changes to protocol planed analyses. 
9.0 
APPENDIX 
9.1 
Changes From the Previous Version of the SAP 
Section 
Before Change 
After Change 
Reason 
6.1 
Office trough sitting 
diastolic and systolic 
blood pressures on each 
measuring day: The mean 
of 3 values on a given 
measuring day is used as 
the representative value of 
that measuring day. 
Office trough sitting diastolic and 
systolic blood pressures on each 
measuring day: The mean of 3 values 
with rounding to integer on a given 
measuring day is used as the 
representative value of that 
measuring day. If only 2 
measurements are obtained on a 
given measuring day, the mean of the 
2 values is used. If only one 
measurement is obtained on a given 
measuring day, that value is used. 
To clarify 
the 
calculation 
6.1.1 
The confidence intervals of the mean 
will be calculated using t-
distribution. 
To specify 
the method 
6.1.2 
The confidence intervals of the 
proportion will be calculated using 
Clopper-Pearson method. 
To specify 
the method 
6.2.2 
Age at Informed Consent 
(years) 
Age (years) at Informed Consent 
Correction 
6.2.6.1 
Significant Protocol 
Deviation [Entry Criteria, 
Concomitant Medication, 
Significant Protocol Deviation 
[Categories by Takeda Controlled 
Terminology] 
To change 
the analysis 
category 
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Statistical Analysis Plan Final 
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Procedure Not Performed 
Per Protocol, Study 
Medication, Withdrawal 
Criteria, Major GCP 
Violations] 
6.2.6.1 
The significant protocol deviations 
are defined as major or critical ones 
based on the Protocol Deviations 
Management Plan. 
To clarify 
6.2.6.1 
A listing of all protocol deviations 
(not only major or critical, but also 
minor ones) will be provided with 
the severity and the category by 
Takeda Controlled Terminology and 
Protocol Deviations Management 
Plan. 
To clarify 
6.3.1 
Age (years) at Week 0 [2, 3, 4, 5] 
To add this 
analysis 
6.3.1 
Disease duration (years) 
[Min≤ - <0.5, 0.5≤ - <1.0, 
1.0≤ - <1.5, 1.5≤ - <2.0, 
2.0≤ - <2.5, 2.5≤ - <3.0, 
3.0≤ - <Max] 
Disease duration (years) [Min≤ - 
<0.5, 0.5≤ - <1.0, 1.0≤ - <1.5, 1.5≤ - 
<2.0, 2.0≤ - <2.5, 2.5≤ - <3.0, 3.0≤ - 
≤Max] 
Correction 
6.3.1 
Drug Induced Hypertension [Yes, 
No] 
To add this 
analysis 
6.3.1 
eGFR (mL/min/1.73 m2) 
[Min≤ - <30, 30≤ - <60, 
60≤ - <90, 90≤ - <Max] 
eGFR (mL/min/1.73 m2) at Week 0 
[Min≤ - <30, 30≤ - <60, 60≤ - <90, 
90≤ - <Max] 
To clarify 
6.3.1 
Age at Week 0 is defined as the age 
at date of the first study drug 
administration for the Treatment 
Period. 
To clarify 
6.3.2 
(1) Underlying Diseases of
Secondary Hypertension
by System Organ Class
and Preferred Term
(2) Underlying Diseases of
Secondary Hypertension
(1) Underlying Diseases of Disease
Induced Secondary Hypertension by
System Organ Class and Preferred
Term
(2) Underlying Diseases of Disease
Induced Secondary Hypertension by
To clarify 
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Statistical Analysis Plan Final 
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by System Organ Class 
and Preferred Term by 
Steroids at the Start of 
Treatment Period 
System Organ Class and Preferred 
Term by Steroids at the Start of 
Treatment Period 
6.4 
(3) Antihypertensive Drugs Except
for RAS inhibitors by Drug
Categories and Preferred Medication
Name in Treatment Period
To add this 
analysis 
6.5.2 
Age (years) at Informed 
Consent [<3, >4] 
eGFR (mL/min/1.73 m2) 
[Min≤ - <60, 60≤ - <89, 
90≤ - ≤Max] 
Age (years) at Informed Consent 
[Min≤3, 4≤Max] 
eGFR (mL/min/1.73 m2) [Min≤ - 
<60, 60≤ - <90, 90≤ - ≤Max] 
Correction 
6.6.1.4 
(1) Pretreatment Events by
System Organ Class and
Preferred Term
(2) Serious Pretreatment
Events by System Organ
Class and Preferred Term
(1) Run-in Adverse Events by
System Organ Class and Preferred
Term
(2) Serious Run-in Adverse Events
by System Organ Class and Preferred
Term
Correction 
6.6.6.2 
Dose Escalation 
Dose Corresponding to Each Visit 
Assessment 
To clarify 
this analysis 
6.6.6.2 
(1) Dose by Visit
Dose on The One Day before Visit 
To add this 
analysis 
6.6.6.3 
Added this section 
To add this 
analysis 
9.2.2 
Updated Table 2, and added “*3 If 
there would be a value that can be 
used as both of Week 52 and Week 
54 (Follow-up Period) by applying 
the above rule, the value will be used 
only as Week 52.” 
Correction 
9.2.2 
Next, based on Table 3, 
the mean of the 
representative values  on 
each measuring day within 
each time window will be 
used as the values for each 
visit. 
Next, based on Table 3, the mean of 
the representative values with 
rounding to integer on each 
measuring day within each time 
window will be used as the values 
for each visit. 
To clarify 
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Statistical Analysis Plan Final 
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9.2 
Data Handling Conventions 
9.2.1 
Definition of Baseline 
Baseline values are defined as the last observed value before the first dose of study drug for 
Treatment Period. 
9.2.2 
Definition of Visit Windows  
For efficacy endpoints in section 6.5, the below time windows will be applied. 
When calculating Study Day relative to a reference date (i.e., date of first dose for Treatment 
Period [Day 1]) , if the date of the observation is on the same date or after the reference date, it 
will be calculated as: date of observation - reference date + 1; otherwise, it will be calculated as: 
date of observation - reference date. Hence, reference day is always Day 1 and there is no Day 0. 
When calculating Follow-up Day relative to a reference date (i.e., date of last dose [Follow-up 
Day 0]), it will be calculated as: date of observation - reference date. Hence, reference day is 
always Follow-up Day 0.  
All evaluable data (i.e., non-missing data) will be handled according to the following rules. 
For each visit, observation obtained in the corresponding time window will be used. If more than 
one observation lies within the same time window, the observation with the closest Study Day to 
the scheduled Study Day will be used. If there are two observations equidistant to the scheduled 
Study Day, the later observation will be used. This does not apply to Week 12 (LOCF) and Week 
52 (LOCF).  
For Week 12 (LOCF) and Week 52 (LOCF), the last observation obtained in the corresponding 
time window will be used. 
 
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