Clinical trial NCT03434977
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2018-02-14; Completion date: 2018-03-11
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess the PK of TAK-536 and effect of food on the PK following single oral administration of TAK-536 pediatric formulation in Japanese healthy adult male participants.

Detailed description:
The drug being tested in this study is called TAK-536. TAK-536 is being tested in Japanese healthy adult male participants. This study will look at the PK and effect of food on the PK following single oral administration of TAK-536 pediatric formulation.

The study will enroll 12 healthy participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups and will receive a single oral dose of 10 mg of TAK-536 pediatric formulation with 200 mL of water according to the following treatments in each period during the study.

* Treatment Group A: single oral administration in the morning under fasted condition (Period 1), followed by single oral administration after breakfast (Period 2)
* Treatment Group B: single oral administration after breakfast (Period 1), followed by in the morning under fasted condition (Period 2)

This single-center trial will be conducted in Japan. The overall time to participate in this study is approximately one month. Participants will make five visits to the clinic and be hospitalized for eight days in total.

Arms: arm 1: TAK-536 10 milligram (mg) granule formulation (pediatric formulation), once daily on Day 1 of Period 1 (6 days) in the morning under fasted condition, followed by wash-out (6 days), followed by TAK-536 10 mg granule formulation (pediatric formulation), once daily on Day 1 of Period 2 (6 days) after starting breakfast. arm 2: TAK-536 10 mg granule formulation (pediatric formulation), once daily on Day 1 of Period 1 (6 days) after starting breakfast, followed by wash-out (6 days), followed by TAK-536 10 mg granule formulation (pediatric formulation), once daily on Day 1 of Period 2 (6 days) in the morning under fasted condition.
Interventions: intervention 1: TAK-536
Intervention descriptions: intervention 1: TAK-536 granule formulation

Protocol documents:
Prot_000.pdf: 
 
 
Title: A Randomized, Open-Label, Cross-over Phase 1 Study to Evaluate the Food Effect 
of Single Oral Dose of TAK-536 Pediatric Formulation in Healthy Adult Male Subjects 
 
NCT Number: NCT03434977 
Protocol Approve Date: 08-Dec-2017 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


CONFIDENTIAL
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Open-Label, Cross-over Phase 1 Study to Evaluate the Food Effect of Single 
Oral Dose of TAK-536 Pediatric Formulation in Healthy Adult Male Subjects
A Phase 1 Food Effect Study of TAK-536 Pediatric Formulation
Study Identifier:
Azilsartan-1005
Compound:
TAK-536
Date:
08 December 2017
Version/Amendment 
Number:
Initial Version
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................6
2.0
STUDY SCHEMATIC....................................................................................................9
3.0
SCHEDULE OF STUDY PROCEDURES (PERIOD 1 AND PERIOD 2).....................10
4.0
INTRODUCTION.........................................................................................................11
4.1
Background .............................................................................................................11
4.2
Rationale for the Proposed Study.............................................................................12
4.3
Benefit/Risk Profile .................................................................................................12
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................13
5.1
Hypothesis...............................................................................................................13
5.2
Trial Objectives .......................................................................................................13
5.2.1
Trial Primary Objective...............................................................................13
5.2.2
Trial Secondary Objective...........................................................................13
5.3
Endpoints.................................................................................................................13
5.3.1
Primary Endpoint........................................................................................13
5.3.2
Secondary Endpoints...................................................................................13
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................14
6.1
Trial Design.............................................................................................................14
6.2
Rationale for Trial Design, Dose, and Endpoints......................................................15
6.2.1
Rationale of Trial Design ............................................................................15
6.2.2
Rationale for Dose ......................................................................................15
6.2.3
Rationale for Study Population....................................................................15
6.2.4
Rationale for Washout Period......................................................................15
6.2.5
Rationale for Endpoints...............................................................................15
6.2.6
Critical Procedures Based on Trial Objectives: Timing of Procedures .........16
6.3
Trial Beginning and End/Completion.......................................................................16
6.3.1
Definition of Beginning of the Trial ............................................................16
6.3.2
Definition of End of the Trial......................................................................16
6.3.3
Definition of Trial Discontinuation..............................................................16
6.3.4
Criteria for Premature Termination or Suspension of the Trial.....................17
6.3.5
Criteria for Premature Termination or Suspension of a Site.........................17
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............18
7.1
Inclusion Criteria .....................................................................................................18
7.2
Exclusion Criteria ....................................................................................................18
7.3
Excluded Medications, Supplements, Dietary Products............................................20


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7.4
Diet, Fluid, Activity.................................................................................................21
7.4.1
Diet and Fluid .............................................................................................21
7.4.2
Activity.......................................................................................................21
7.5
Documentation of Subject Failure............................................................................22
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................22
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................23
7.8
Subject Replacement................................................................................................23
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................24
8.1
Clinical Study Drug .................................................................................................24
8.1.1
Clinical Study Drug Labeling......................................................................24
8.1.2
Clinical Study Drug Inventory and Storage .................................................24
8.1.3
Randomization Code Creation and Storage .................................................24
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs ........................24
9.0
STUDY PROCEDURES...............................................................................................25
9.1
Administrative Procedures.......................................................................................25
9.1.1
Informed Consent Procedure.......................................................................25
9.1.2
Inclusion and Exclusion ..............................................................................25
9.1.3
Medical History/Demography .....................................................................25
9.1.4
Concomitant Medications............................................................................26
9.2
Clinical Procedures and Assessments.......................................................................26
9.2.1
Full Physical Exam .....................................................................................26
9.2.2
Height and Weight ......................................................................................26
9.2.3
BMI ............................................................................................................26
9.2.4
Vital Signs ..................................................................................................26
9.2.5
12-Lead ECG..............................................................................................27
9.2.6
Study Drug Administration .........................................................................27
9.2.7
AE Monitoring............................................................................................27
9.2.8
Laboratory Procedures and Assessments .....................................................27
9.3
PK Samples .............................................................................................................29
9.3.1
PK Measurements .......................................................................................29
9.3.2
Confinement ...............................................................................................30
10.0
ADVERSE EVENTS ....................................................................................................31
10.1
Definitions and Elements of AEs .............................................................................31
10.1.1
SAEs...........................................................................................................33
10.2
AE Procedures.........................................................................................................34


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10.2.1
Assigning Severity of AEs ..........................................................................34
10.2.2
Assigning Causality of AEs.........................................................................35
10.2.3
Assigning Causality of AEs to Study Procedures.........................................35
10.2.4
Start Date....................................................................................................35
10.2.5
End Date.....................................................................................................35
10.2.6
Pattern of Adverse Event (Frequency).........................................................35
10.2.7
Action Taken With Study Treatment ...........................................................35
10.2.8
Outcome .....................................................................................................36
10.2.9
Collection and Reporting of AEs, SAEs, and Abnormal LFTs.....................36
10.2.10
Safety Reporting to Investigators, IRBs, and Regulatory Authorities...........38
11.0
STATISTICAL METHODS..........................................................................................39
11.1
Statistical and Analytical Plans ................................................................................39
11.1.1
Analysis Sets...............................................................................................39
11.1.2
Analysis of Demography and Other Baseline Characteristics.......................39
11.1.3
PK Analysis ................................................................................................39
11.1.4
Safety Analysis ...........................................................................................40
11.2
Interim Analysis and Criteria for Early Termination ................................................41
11.3
Determination of Sample Size..................................................................................41
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................42
12.1
Study-Site Monitoring Visits ...................................................................................42
12.2
Protocol Deviations..................................................................................................42
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................42
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................43
13.1
IRB Approval ..........................................................................................................43
13.2
Subject Information, Informed Consent, and Subject Authorization .........................43
13.3
Subject Confidentiality ............................................................................................44
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................45
13.4.1
Publication and Disclosure..........................................................................45
13.4.2
Clinical Trial Registration...........................................................................45
13.4.3
Clinical Trial Results Disclosure .................................................................45
13.5
Insurance and Compensation for Injury....................................................................45
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................46
14.1
Administrative Information......................................................................................46
14.1.1
Study Contact Information ..........................................................................46
14.1.2
Investigator Agreement ...............................................................................46


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14.1.3
Study-Related Responsibilities....................................................................46
14.1.4
List of Abbreviations...................................................................................46
15.0
DATA HANDLING AND RECORDKEEPING............................................................47
15.1
eCRFs......................................................................................................................47
15.2
Record Retention .....................................................................................................47
16.0
REFERENCES..............................................................................................................49
17.0
APPENDICES...............................................................................................................51
LIST OF IN-TEXT TABLES
Table 6.a
Dosage, Treatment Condition, and Number of Subjects......................................14
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................20
Table 9.a
Collection of Plasma Samples for PK Analysis ..................................................30
Table 10.a
Takeda Medically Significant AE List................................................................34
LIST OF IN-TEXT FIGURES
Figure 2.a
Schematic of Study Design ..................................................................................9
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................51
Appendix B
Acceptable Time Window for Study Procedure..................................................52


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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical Company Limited
Compound:
TAK-536
Study Identifier: Azilsartan-1005
Phase: 1
Protocol Title: A, Randomized, Open-Label, Crossover Phase 1 Study to Evaluate the Food Effect of Single Oral 
Dose of TAK-536 Pediatric Formulation in Healthy Adult Male Subjects
Trial Design:
This is an open-label, 2×2 crossover study to assess the food effect on the pharmacokinetics (PK) and safety of a single 
oral dose of TAK-536 10 mg granules (contains 10 mg of TAK-536 in 1 g) in Japanese healthy adult male subjects 
under fasted or fed condition in the morning.
Prior to study drug administration in Period 1, eligible subjects will be randomized to either Sequence A or Sequence
B with 1:1 ratio. Subjects will receive TAK-536 either in the morning under fasted condition (fasted overnight for at 
least 10 hours prior to the study drug administration) or in the morning under fed condition (at 30 minutes after starting 
breakfast).
Hospitalization will be for 4 days and 3 nights. At least 6-day washout interval will be placed between the study drug 
administrations in Periods 1 and 2.
Sequences
Number of 
Subjects
Dose of TAK-536
Regimen
Period 1
Period 2
A
6
TAK-536 10 mg granules
(TAK-536 10 mg)
Single oral dose 
under fasted condition
Single oral dose 
under fed condition
B
6
TAK-536 10 mg granules
(TAK-536 10 mg)
Single oral dose 
under fed condition
Single oral dose 
under fasted condition
Trial Primary Objective:
To assess the food effect on the PK following single oral administration of TAK-536 pediatric formulation in Japanese 
healthy adult male subjects
Secondary Objective:
To assess the food effect on the safety of a single oral administration of TAK-536 pediatric formulation in Japanese 
healthy adult male subjects
Trial Subject Population: Japanese healthy adult male subjects
Planned Number of Subjects:
12 subjects (6 for each sequence)
Planned Number of Sites:
1 site
Dose Levels:
Each subject will receive the study drug under one of 
the following treatment conditions in each period.
1.
One sachet of TAK-536 10 mg granules
(TAK-536 10 mg) will be administered orally 
with 200 mL of water in the morning under 
fasted condition (fasted overnight for at least 10 
hours prior to the study drug administration).
2.
One sachet of TAK-536 10 mg granules
(TAK-536 10 mg) will be administered orally 
with 200 mL of water in the morning under fed 
condition (at 30 minutes after starting breakfast).
Route of Administration:
Oral


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Duration of Treatment:
Single dose×2 periods (with at least 6-day washout 
interval)
Planned Trial Duration:
Hospitalization for 4 days and 3 nights+1 day for a
follow-up examination in each period
Criteria for Inclusion:
1.
In the opinion of the investigator or sub-investigator, the subject is capable of understanding and complying with 
protocol requirements.
2.
The subject signs and dates a written informed consent form prior to the initiation of any study procedures.
3.
The subject is a Japanese healthy adult male.
4.
The subject ages 20 to 35 years inclusive at the time of informed consent.
5.
The subject weighs at least 50.0 kg, and has a BMI between 18.5 and 25.0 kg/m2, inclusive, at Screening.
Criteria for Exclusion:
1.
The subject has suspected hypotension with associated physical findings, such as dizziness postural, facial pallor, 
or cold sweats based on evaluation/physical examination at Screening, on the day before the study drug 
administration (Day -1) in Period 1, or up to the study drug administration in Period 1.
2.
The subject has received any study drug within 16 weeks (112 days) prior to the study drug administration in 
Period 1.
3.
The subject has received TAK-536 or TAK-491 in a previous clinical study or as a therapeutic agent.
4.
The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, 
metabolic, gastrointestinal, or endocrine disease or other abnormality, which may impact the ability of the 
subject to participate or potentially confound the study results.
5.
The subject has a hypersensitivity to any component of the formulation of TAK-536 or any angioteosin II 
receptor blockers (ARB).
6.
The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at Screening.
7.
The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 2 
years prior to the Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.
8.
The subject has taken any excluded medications, supplements, dietary products or food products during the time 
periods listed in Section 7.3.
9.
The subject has any current or recent (within 6 months prior to the start of the study drug administration in Period 
1) gastrointestinal diseases that would be expected to influence the absorption of drugs (ie, a history of 
malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent [more than once per week] 
occurrence of heartburn, or any surgical intervention).
10.
The subject has a history of cancer, except the basal cell carcinoma which has been in remission for at least 5 
years prior to Day 1 of Period 1.
11.
The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, 
human immunodeficiency virus (HIV) antibody/antigen, or serological reactions for syphilis at Screening.
12.
The subject has poor peripheral venous access.
13.
The subject has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) or at least 400 mL 
within 12 weeks (84 days) prior to the start of the study drug administration in Period 1.
14.
The subject has undergone whole blood collection of at least 800 mL in total within 52 weeks (364 days) prior to 
the start of the study drug administration in Period 1.
15.
The subject has undergone blood component collection within 2 weeks (14 days) prior to the start of the study 
drug administration in Period 1.
16.
The subject has an abnormal (clinically significant) ECG at Screening or prior to the study drug administration in 
Period 1.
17.
The subject has abnormal laboratory values that suggest a clinically significant underlying disease, or subject 


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CONFIDENTIAL
with the following laboratory abnormalities at Screening or prior to the study drug administration in Period 1: 
ALT and/or AST >1.5× the upper limits of normal (ULN).
18.
The subject who, in the opinion of the investigator or sub-investigator, is unlikely to comply with the protocol or 
is unsuitable for any other reason.
Criteria for Evaluation and Analyses:
Primary endpoints
PK: Plasma concentrations and PK parameters of unchanged TAK-536 (Cmax, tmax, AUClast, AUC∞, t1/2z, MRT, λz, 
CL/F, and Vz/F).
Secondary endpoints
Safety: Adverse events (AEs), vital signs (sitting blood pressure, sitting pulse rate and body temperature), weight, 
laboratory test results (hematology, serum chemistry, and urinalysis), and resting 12-lead ECGs.
Statistical Considerations:
PK:
The following statistical analyses will be performed on the PK analysis set:
For plasma concentration of unchanged TAK-536, descriptive statistics will be provided by time point for each 
treatment condition (fed and fasted condition). In addition, the plasma concentration-time profiles will be provided 
with both conditions on the same graph.
For PK parameters, descriptive statistics will be provided by each treatment condition.
The difference in the least square means between treatment conditions (fed - fasted) and the two-sided 90% confidence 
interval (CI) will be provided using a crossover analysis of variance (ANOVA) model. The ANOVA model will 
include log-transformed (natural log) PK parameters other than tmax as dependent variable, and treatment condition, 
group, and period as independent variables. For non-natural log transformed tmax, same analyses will be performed.
Safety:
The following statistical analyses will be performed on the safety analysis set:
A treatment emergent adverse event (TEAE) is defined as an event whose date of onset occurs on or after the start of 
study drug administration.
The frequency distribution will be provided for all TEAEs, drug-related TEAEs, intensity of all TEAEs, intensity of 
drug-related TEAEs, TEAEs leading to study drug discontinuation and serious TEAEs by treatment condition. TEAEs 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. The frequency 
distribution will be provided using the system organ class and the preferred term for each treatment condition.
For continuous variables of clinical laboratory tests and other safety measurements, the observed values and the 
changes from baseline will be summarized by treatment condition for each time point using descriptive statistics. Case 
plots for the observed values will also be provided for each treatment condition. For categorical variables, shift tables 
showing the number of subjects in each category at baseline and each post-baseline visit will be provided for each 
treatment condition.
Sample Size Justification:
A total of 12 subjects, with 6 subjects in each sequence were considered the sufficient sample size to evaluate the PK
and safety of TAK-536. The sample size is not based on statistical consideration.


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2.0
STUDY SCHEMATIC
Figure 2.a
Schematic of Study Design
Element
Screening
Treatment (TAK-536 10 mg Pediatric Formulation)
Period 1 and Period 2*
Day
Day -28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
…
Day 6
Visit
Hospitalization
Visit
Content
Informed 
Consent, 
Screening
Admission
Study Drug 
Administration
Discharge
Follow-up 
Examination
*: There will be at least 6-day washout interval between the study drug administrations in Periods 1 and 2. The 
examinations scheduled on the day before the study drug administration (Day -1) in Period 2 can be replaced with the 
follow-up examinations (Day 6) in Period 1, provided that they are scheduled on the same day.


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3.0
SCHEDULE OF STUDY PROCEDURES (PERIOD 1 AND PERIOD 2)
Screening
Treatment (a)
(Period 1 and Period 2)
Study Day:
Days -28 to -2
(Screening)
Day -1
(Admission) Day 1 Day 2
Day 3
(Discharge)
Early 
Termination
Day 6 (b)
(Follow-up)
Hospitalization
X
X
X
X
Informed consent
X
Inclusion/exclusion criteria (c)
X
X
Demographics and medical 
history
X
Medication history
X
Physical examination (d)
X
X
X
X
X
X
X
Vital signs (e)
X
X
X
X
X
X
Weight, BMI and height (f)
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
12-lead ECG (g)
X
X
X
X
X
Laboratory tests (h)
X
X
X
X
X
X
Urine drug and alcohol screen
tests
X
Immunology tests
X
Study drug administration
X
Plasma concentrations (i)
X
X
X
X (j)
AE assessment (k)
X
X
X
X
X
X
X
(a)
There will be at least 6-day washout interval between the study drug administrations in Periods 1 and 2.
(b)
The examinations scheduled on the day before the study drug administration (Day -1) in Period 2 can be replaced with the 
follow-up examinations (Day 6) in Period 1, provided that they are scheduled on the same day.
(c)
Check of the inclusion/exclusion criteria will be done at Screening and before the study drug administration in Period 1 and 
not be done in Period 2.
(d)
Physical examination will be performed at Screening, Day -1, predose, 4, 24, 48 hours postdose and Day 6.
(e)
The sitting blood pressure (resting more than 5 minutes), sitting pulse rate, and body temperature (axillary) will be measured 
at Screening, predose, 4, 24, 48 hours postdose and Day 6.
(f)
Weight will be measured at Screening, predose, 48 hours postdose and Day 6. Height will be measured only at Screening for 
calculation of BMI.
(g)
The 12-lead ECG will be measured at Screening, predose, 48 hours postdose and Day 6.
(h)
Laboratory tests include hematology, serum chemistry, and urinalysis. Blood samples will be collected at Screening, predose,
24, 48 hours postdose and Day 6 after fasting for at least 8 hours.
(i)
PK blood samples will be collected at predose (from waking-up to immediately before the study drug administration) and 0.5, 
1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, and 48 hours postdose.
(j)
Measured only if the subject discontinues the study within 48 hours after the study drug administration.
(k)
The collection of AEs will commence from the time the subject signs the informed consent at Screening and continue until the 
follow-up examination in Period 2.


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4.0
INTRODUCTION
4.1
Background
Hypertension develops not only in adults, but also in children and adolescents. While there are few 
epidemiological reports about the number of pediatric patients with hypertension in Japan, it is
reported that hypertension is detected in 0.1% to 1% among elementary-school and
junior-high-school students and in about 3% among high-school students in health checkups for
Japanese children [1][2]. According to the 2013 Population Estimates, the number is estimated to
be 11 million in elementary-school and junior-high-school students (6 to 15 years) and 3.6 million
in high-school students (16 to 18 years) [3]. Therefore, based on the morbidity rate of hypertension
in health checkups above, the number of pediatric patients with hypertension is estimated to be 100
to 200 thousand (10 to 110 thousand in elementary-school and junior-high-school students and 110
thousand in high-school students).
Pediatric hypertension is classified into essential hypertension and secondary hypertension as
described for adults. Although essential hypertension in children is generally mild, such patients
are at a high risk of cardiovascular disease including left ventricular hypertrophy and carotid
intima-media wall thickening as well as organ damage, eg, renal dysfunction [4][5]. Furthermore,
essential hypertension in children can highly track into adult essential hypertension with patients’ 
growth [6]. The possibility of secondary hypertension, in contrast, increases with a younger age 
and the majority cases are severe. Hypertension caused by renal diseases (renal hypertension) 
accounts for 60% to 80% of children with secondary hypertension, and chronic renal failure 
requires particular attention. Therefore, it is necessary to prevent deterioration of renal function 
and progression of organ damage.
Moreover, hypertension persisting from childhood is likely to cause cardiovascular diseases and
organ damage including renal dysfunction, thereby markedly affecting the patient’s quality of life
(QOL) and prognosis not only in childhood but also in future. Therefore, it is highly important to
manage blood pressure in the early stage.
The Japanese Society of Hypertension Guidelines for the Management of Hypertension 2014
(JSH2014) [7] recommends that drug therapy should be considered after non-pharmacological
interventions (dietary and exercise therapy) are primarily performed since essential hypertension
in children is often mild. For patients with secondary hypertension and patients with target organ
damage, diabetes mellitus, or chronic kidney disease (CKD), drug therapy is highly recommended
to prevent the development and progression of organ damage.
JSH2014 [7] and the Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular
Diseases by the Japanese Circulation Society 2012 [8] recommend ARBs, angiotensin converting 
enzyme (ACE) inhibitors and calcium channel blockers as first-choice drugs for pediatric patients. 
In particular, more strict blood pressure management is recommended for essential hypertension 
with CKD or diabetes mellitus than that for hypertension without complications. Hypertension 
with such complications is recommended to be treated with ARBs having antiproteinuric effects 
and inhibitory effects of CKD progression in addition to ACE inhibitors.


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While a number of antihypertensive drugs for adults are available in Japan, only 4 drugs are
indicated for hypertension in children, valsartan being the only ARB among them. Only one drug
among ACE inhibitors is indicated for patients younger than 6 years old. Furthermore, none of the
approved drugs have formulations designed for pediatric patients. Therefore, treatment options for
pediatric patients with hypertension are not sufficient.
TAK-536 (azilsartan) is a novel ARB produced by Takeda Pharmaceutical Company Limited
(TPC) and was approved for the treatment of adult hypertension under the product name of Azilva
tablets 20 mg and 40 mg in January 2012. A supplementary new drug application was filed for the
additional registration of Azilva tablet 10 mg, which was approved in March 2014. TAK-536 is
superior to the existing ARBs (candesartan) in antihypertensive effect and the persistence, while
being safe and well tolerated. It is now widely used by adult patients with hypertension.
Thus, to resolve the unmet needs in the present treatment of pediatric hypertension, it is important
to develop pediatric formulations of TAK-536, whose clinical usefulness for adult patients with
hypertension is established, and to provide them for pediatric patients.
4.2
Rationale for the Proposed Study
Clinical Pharmacokinetic Studies of Pharmaceuticals [9] specifies that the effects of food on 
gastrointestinal absorption should be evaluated since absorption from the gastrointestinal tract is 
likely to be affected by food in the case of study drugs that are administered orally. Therefore, this 
study was designed to evaluate the food effect on the pharmacokinetics and safety of TAK-536
after administration of the TAK-536 pediatric formulation.
This protocol has been prepared in accordance with Good Clinical Practice (GCP).
4.3
Benefit/Risk Profile
There will be no benefit to subjects in this study other than receiving physical examinations and
obtaining information about their general health. Instead, patients with pediatric hypertension may 
benefit in the future from what can be learned in this study.
Although subjects who participate in this study will have risks of adverse events and others
associated with administration of the study drug, they will be informed about possible risk with the 
informed consent form before participation of this study, and are free to withdraw from the study 
at any time without giving a reason (Section 13.2).
Clinical safety information is provided in clinical results in adults and package insert. For further 
information on TAK-536, please refer to the Investigator’s Brochure.


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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study was designed based on the following hypothesis:

No major differences between fasted and fed conditions in the pharmacokinetics (PK) and 
safety will be found after the single oral dose of TAK-536 pediatric formulation. No clinically 
significant food-effect will be found.
5.2
Trial Objectives
5.2.1
Trial Primary Objective
To assess the food effect on the PK following single oral administration of TAK-536 pediatric 
formulation in Japanese healthy adult male subjects
5.2.2
Trial Secondary Objective
To assess the food effect on the safety of a single oral administration of TAK-536 pediatric 
formulation in Japanese healthy adult male subjects
5.3
Endpoints
5.3.1
Primary Endpoint
PK: Plasma concentrations and PK parameters of unchanged TAK-536 (Cmax, tmax, AUClast, 
AUC∞, t1/2z, MRT, λz, CL/F, and Vz/F)
5.3.2
Secondary Endpoints 
Safety: Adverse events (AEs), vital signs (sitting blood pressure, sitting pulse rate, and body 
temperature), weight, laboratory test results (hematology, serum chemistry, and 
urinalysis), and resting 12-lead ECGs.


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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design
This is an open-label, 2×2 crossover study to assess the food effect on the PK and safety of a single 
oral dose of TAK-536 pediatric formulation in Japanese healthy adult male subjects under fasted 
or fed condition in the morning.
The dosage, treatment condition, and number of subjects are shown in Table 6.a. Each subject will 
receive the study drug under one of the following treatment conditions in each period.
1. One sachet of TAK-536 10 mg granules (TAK-536 10 mg) will be administered orally with 
200 mL of water in the morning under fasted condition (fasted overnight for at least 10 hours 
prior to study drug administration).
2. One sachet of TAK-536 10 mg granules (TAK-536 10 mg) will be administered orally with 
200 mL of water in the morning under fed condition (at 30 minutes after starting breakfast).
Table 6.a
Dosage, Treatment Condition, and Number of Subjects
Sequences
Number of 
Subjects
Dose of TAK-536
Regimen
Period 1
Period 2
A
6
TAK-536 10 mg Granules
(TAK-536 10 mg)
Single oral dose 
under fasted condition
Single oral dose 
under fed condition
B
6
TAK-536 10 mg Granules
(TAK-536 10 mg)
Single oral dose 
under fed condition
Single oral dose 
under fasted condition
Subjects will be screened for enrollment from 4 weeks (28 days) to 2 days (the day before
admission) before the study drug administration (Day -28 to Day -2) in Period 1. Subjects will be 
admitted to the study site on the day before the study drug administration (Day -1) in both Periods 
1 and 2, and will be hospitalized under medical supervision for 4 days (until 48 hours after the 
study drug administration). They will undergo daily examinations and observations from the day 
before the study drug administration (Day -1) during their hospitalization according to the study 
schedule specified in Section 3.0, and will be discharged from the study site on Day 3 after
confirmation of safety by the investigator or sub-investigator. Subjects will return to the study site 
for follow-up examinations on Day 6. At least 6-day washout interval will be placed between the 
study drug administrations in Periods 1 and 2.
Subjects will visit the study site 5 times, including the visit for screening examinations, in this 
study. They will be hospitalized for a total of 8 days in Periods 1 and 2 (refer to Section 2.0 for a 
schematic of the study design).
The examinations scheduled on the day before the study drug administration (Day -1) in Period 2 
can be replaced with the follow-up examinations (Day 6) in Period 1, if they are scheduled on the 
same day. If this is the case, the subject will visit the study site 4 times in this study.


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6.2
Rationale for Trial Design, Dose, and Endpoints
6.2.1
Rationale of Trial Design
In accordance with Clinical Pharmacokinetic Studies of Pharmaceuticals [9], a 2-period,
2-treatment, crossover design, which allows food effect evaluation on PK and safety with minimal 
effect on inter-subject variation, was selected for this study.
6.2.2
Rationale for Dose
TAK-536 pediatric formulation, 1% film-coated granules, is being developed for pediatric patients
younger than 6 years old who have a difficulty in swallowing tablets. Generally, maximum amount 
of the pediatric granule formulation which pediatric patients can take orally at one time is 
estimated to be 1 g, equivalent to 10 mg of TAK-536 based on 1% concentration of TAK-536. It is 
assumed that many patients will take 10 mg of TAK-536 at a maximum. Guidance for Industry 
Food-Effect Bioavailability and Fed Bioequivalence Studies by FDA[10] recommends to 
investigate the food effect with an estimated maximum dose. Considering the above, 10 mg is 
selected as the dose of this study.
6.2.3
Rationale for Study Population
The study population will be healthy adult males in accordance with the Guidance on Clinical
Investigation of Medicinal Products in the Pediatric Population [11] and Clinical Pharmacokinetic 
Studies of Pharmaceuticals [9].
6.2.4
Rationale for Washout Period
When a single oral dose of TAK-536 10 mg was administered under fasted condition to Japanese 
healthy adult subjects, plasma concentration of unchanged TAK-536 was 9 ng/mL at 72 hours 
after the administration in the subject with the highest plasma TAK-536 level. It was assumed that 
the plasma unchanged TAK-536 level would be below the lower limit of quantification 
(<1 ng/mL) at 6 days (3 days after the time point of Cmax) after the administration based on the 
half-life of TAK-536 (about 13 hours). The Japanese Guideline for Bioequivalence Studies of 
Generic Products [12] recommends that there should be a washout period at least 5 times longer 
than the apparent half-life of the investigational drug between the two treatments to be compared 
within subjects. Thus, the washout period in this study was set as 6 days (144 hours), which is 
more than 5 times longer than the apparent elimination half-life of TAK-536.
6.2.5
Rationale for Endpoints
6.2.5.1
Rationale for Pharmacokinetic Endpoints
The plasma concentration of unchanged TAK-536 will be evaluated to determine the food effect
on PK after the administration of TAK-536. The plasma concentration will be evaluated until 48 
hours postdose for TAK-536, the time point when its AUClast is expected to be over 80% of its
AUC∞.


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6.2.5.2
Rationale for Safety Endpoints
AEs, vital signs, resting 12-lead ECGs, weight and laboratory test results are set as standard 
endpoints used for assessing safety in clinical pharmacology studies.
6.2.6
Critical Procedures Based on Trial Objectives: Timing of Procedures
For this study, the collection of blood samples for TAK-536 PK is the critical procedure since PK 
is set as the primary endpoint. The examination regarding safety is also the critical procedure since 
safety is set as the secondary endpoint. Critical procedures are listed below:

At any postdose time point, the blood samples for TAK-536 PK need to be collected as close to 
the nominal time point as possible.

The other procedures should be completed as close to the nominal time as possible, either 
before or after these nominal times.

When ECG and/or vital signs measurements are scheduled at the same time as PK sampling,
the blood draw will take priority and ECG and/or vital signs will be obtained within an
acceptable time window (see Appendix B).

The order of priority can be changed during the study with joint agreement of the investigator
and the Sponsor.

Any unscheduled procedures required for the urgent evaluation of safety concerns, regardless 
of the content of procedures, will take precedence over all routine scheduled procedures.
6.3
Trial Beginning and End/Completion
6.3.1
Definition of Beginning of the Trial
The overall study begins when the first subject signs the trial’s informed consent form.
6.3.2
Definition of End of the Trial
The overall trial ends when the last subject completes the last planned or follow-up
visit/interaction associated with a planned visit, discontinues from the trial or is lost to follow-up 
(ie, the investigator is unable to contact the subject).
6.3.3
Definition of Trial Discontinuation
Study discontinuation due to non-safety-related reasons, such as:

A finding (eg, PK, pharmacodynamics, efficacy, biologic targets) from the other nonclinical or 
clinical studies results with the study drug in the study discontinuation for non-safety related 
reasons.

Data from drugs classified in the same class, or methodologies used in this study become 
available and results in the study being stopped for a non-safety related reason.


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
Study discontinuation due to non-scientific and non-safety-related reasons, such as slow 
enrollment.
Study discontinuation due to safety reasons, such as:

Early termination due to unanticipated concerns of safety to the subjects arising from the other 
clinical or nonclinical studies with the study drug.

Early termination due to unanticipated concerns of safety observed in the other drugs classified 
in the same class.
6.3.4
Criteria for Premature Termination or Suspension of the Trial
6.3.4.1
Criteria for Premature Termination or Suspension of Trial
The study will be completed as planned unless 1 or more of the following criteria are met that 
require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of GCP that compromises the ability to achieve the primary study 
objective or compromises subject safety.
6.3.4.2
Procedure for Premature Termination or Suspension of the Trial
In the event that the Sponsor, an institutional review board (IRB), or a regulatory authority elects 
to terminate or suspend the study, 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.
6.3.5
Criteria for Premature Termination or Suspension of a Site
6.3.5.1
Criteria for Premature Termination or Suspension of a Site
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.5.2
Procedures for Premature Termination or Suspension of a Site
In the event that the Sponsor, an IRB, or a regulatory authority elects to terminate or suspend of the 
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
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 sub-investigator, the subject is capable of understanding 
and complying with protocol requirements.
2. The subject signs and dates a written informed consent form prior to the initiation of any study 
procedures.
3. The subject is a Japanese healthy adult male.
4. The subject ages 20 to 35 years inclusive at the time of informed consent.
5. The subject weighs at least 50.0 kg, and has a BMI between 18.5 and 25.0 kg/m2, inclusive, at 
Screening.
[Justification of Inclusion Criteria]
1. to 4. These are the standard inclusion criteria used in clinical pharmacology studies.
5. In accordance with “Law Enforcement Regulation on Securing a Stable Supply of Safe Blood 
Products,” the Ministry of Health and Welfare Ordinance No.22 [13], which recommends against 
collecting 400 mL blood from individuals weighing less than 50.0 kg because of its possible 
harmful effects on health, subjects in this study should weigh at least 50.0 kg. The acceptable BMI 
range is based on the diagnostic criteria for obesity proposed by the Japan Society for the Study of 
Obesity [14].
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 suspected hypotension with associated physical findings, such as dizziness 
postural, facial pallor, or cold sweats based on evaluation/physical examination at Screening, 
on the day before the study drug administration (Day -1) in Period 1, or up to the study drug 
administration in Period 1.
2. The subject has received any study drug within 16 weeks (112 days) prior to the study drug 
administration in Period 1.
3. The subject has received TAK-536 or TAK-491 in a previous clinical study or as a therapeutic 
agent.
4. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality, which 
may impact the ability of the subject to participate or potentially confound the study results.
5. The subject has a hypersensitivity to any component of the formulation of TAK-536 or any 
ARB.


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6. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at 
Screening.
7. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 2 years prior to the Screening visit or is unwilling to agree to abstain from alcohol 
and drugs throughout the study.
8. The subject has taken any excluded medications, supplements, dietary products or food 
products during the time periods listed in Section 7.3.
9. The subject has any current or recent (within 6 months prior to the start of the study drug 
administration in Period 1) gastrointestinal diseases that would be expected to influence the 
absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic ulcer disease, 
erosive esophagitis, frequent [more than once per week] occurrence of heartburn, or any 
surgical intervention).
10. The subject has a history of cancer, except the basal cell carcinoma which has been in 
remission for at least 5 years prior to Day 1 of Period 1.
11. The subject has a positive test result for hepatitis B virus surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen, or serological 
reactions for syphilis at Screening.
12. The subject has poor peripheral venous access.
13. The subject has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) 
or at least 400 mL within 12 weeks (84 days) prior to the start of the study drug administration 
in Period 1.
14. The subject has undergone whole blood collection of at least 800 mL in total within 52 weeks 
(364 days) prior to the start of the study drug administration in Period 1.
15. The subject has undergone blood component collection within 2 weeks (14 days) prior to the 
start of the study drug administration in Period 1.
16. The subject has an abnormal (clinically significant) ECG at Screening or prior to the study 
drug administration in Period 1.
17. The subject has abnormal laboratory values that suggest a clinically significant underlying 
disease, or subject with the following laboratory abnormalities at Screening or prior to the 
study drug administration in Period 1: ALT and/or AST >1.5× the upper limits of normal 
(ULN).
18. The subject who, in the opinion of the investigator or sub-investigator, is unlikely to comply 
with the protocol or is unsuitable for any other reason.
[Justification of Exclusion Criteria]
1.
This was set in consideration of the subject’s safety.


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2.
This minimum time interval from the previous clinical study has been 
established to exclude the possible influence of the previous clinical study in 
order to ensure the safety of subjects, with reference to “General Considerations 
for Clinical Trials,” Pharmaceutical Safety Bureau Notification No.380 (April 
21, 1998) [15], and “Standard Intervals to be Observed between Participation in 
Clinical Studies” [16].
3.
This criterion has been established since bias may be generated in the safety 
evaluation. TAK-491 has been included in this criterion since TAK-491 is a 
prodrug of TAK-536 and its previous use may lead to bias in the safety 
evaluation, as with the previous use of TAK-536.
4. to 7., 12., 18. These criteria have been established as the standard exclusion criteria for 
conducting a clinical pharmacology study.
8.
This criterion has been established to exclude any influence on the laboratory test 
values at Screening and the safety and PK evaluations after study treatment.
9. to 11., 16., 17 To enroll healthy adult male subjects in accordance with “Partial Revision of the 
Guideline for Bioequivalence Studies of Generic Products,” Pharmaceutical and 
Food Safety Bureau Notification No. 0229-10 (February 29, 2012) [12].
13. to 15.
These criteria have been established in accordance with “Law Enforcement 
Regulation on Securing a Stable Supply of Safe Blood Products,” the Ministry of 
Health and Welfare Ordinance No.22 (June 25, 1956) [13].
7.3
Excluded Medications, Supplements, Dietary Products
Use of excluded agents (prescribed or over-the-counter [OTC] drugs) and dietary products is listed
in Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
From 4 weeks (28 days) before the study drug 
administration in Period 1 to the day of discharge 
(Day 3) in Period 2
From 72 hours before the study drug administration 
to the day of discharge (Day 3) in each period
Concomitant drugs (prescribed or OTC drugs)
Foods and beverages containing grapefruit (juice, pulp), 
Seville-type (sour) oranges, pineapple (juice, pulp), 
caffeine or alcohol
Vitamins, Chinese herbal medicines, dietary products 
containing St. John’s wort, Korean ginseng, kava kava, 
ginkgo, or melatonin
OTC: over-the-counter
Subjects must be instructed not to take any medications including OTC products, without first
consulting with the investigator or sub-investigator. Use of prohibited concomitant drugs will be
allowed when the investigator or sub-investigator deems it necessary to use any of the concomitant
drugs for reasons including treatment of an AE.


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7.4
Diet, Fluid, Activity
7.4.1
Diet and Fluid
On the day of blood collection for laboratory tests (screening examination and follow-up
examinations), the subjects must finish the last meal at least 8 hours before visiting the study site.
During hospitalization, the subjects take given meals and are not allowed to take any other food.
Meal menus will be the same for each period.
On the day of the study drug administration (Day 1) under fasted condition in each period, the 
subjects must fast from at least 10 hours before the study drug administration to 4 hours after the 
study drug administration. The subjects will be instructed to have lunch at 13:00 and dinner at 
19:00 (approximate time). Under fed condition, the subjects will have breakfast at 8:30 
(approximate time) and will have the study drug at 30 minutes after starting the breakfast. The 
subjects will have lunch at 13:00 and dinner at 19:00 (approximate time).On the days other than 
the above, the subjects will be instructed to have breakfast at 9:00, lunch at 13:00 and dinner at 
19:00 (approximate time). The subject can choose not to have breakfast on Day 3 (the day of 
discharge).
Excessive drinking and eating should be avoided during the entire study period including
follow-up examinations.
On the day of the study drug administration (Day 1) for both periods, the subjects should be
prohibited from drinking any liquid from 1 hour before to 4 hours after the study drug
administration, with the exception of drink provided as a part of breakfast (under fed condition) 
and water (200 mL) taken with the study drug.
7.4.2
Activity
Smoking is not allowed during the study period.
Supine position is not allowed for 4 hours after the study drug administration, unless it is required
for examinations. The subjects will engage in 15 minutes of light exercise a day during
hospitalization.
The subjects should abstain from excessive exercise after signing of the informed consent until
completion of follow-up examination in Period 2. The subjects will be instructed to lead the same
kind of daily life in Period 2 as that in Period 1, and lead a regular life throughout the washout
period between the study drug administrations.
Blood donation is not allowed for at least 12 weeks after the final examination of this study. The
investigator or sub-investigator will instruct the subjects on the prohibition of blood donation.
If a subject visits another medical institution during the study period, the investigator or
sub-investigator should be informed of the circumstances and therapy in advance whenever
possible, and should communicate to the medical institution about the subject’s participation in the
study.


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7.5
Documentation of Subject Failure
The investigator or sub-investigator must account for all subjects who sign informed consent. If a
subject discontinues the study before the study drug administration in Period 1, the investigator or
sub-investigator should complete the electronic case report form (eCRF).
The primary reason for subject failure is to be recorded in the eCRF using the following categories:

Death.

AE.

Screen failure (failed inclusion criteria or did meet exclusion criteria) <specify reason>.

Protocol deviation.

Lost to follow-up

Withdrawal by subject <specify reason>.

Study terminated by sponsor.

Sample size sufficient.

Other <specify reason>.
7.6
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 screen failure subjects who 
discontinue or withdraw prior to the start of the study drug administration in Period 1, refer to 
Section 7.5.
1. Death.
The subject died on study.
Note: If the subject dies on study, the event will be considered as serious adverse event (SAE). 
See Section 10.2.9.3 for the reporting procedures.
2. AE.
The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE.

Liver Function Test (LFT) Abnormalities
-
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


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-
ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
3. Protocol deviation.

The discovery after the first dose of study drug in Period 1 that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health.
4. Lost to follow-up.
The subject did not return to the study site and attempts to contact the subject were 
unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documentation.
5. Withdrawal by subject.
The subject wishes to withdraw from the study. The reason for withdrawal, if provided, should 
be recorded in the eCRF.
6. Study terminated by Sponsor.
The Sponsor terminates the study.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.7
Procedures for Discontinuation or Withdrawal of a Subject
The investigator or sub-investigator may discontinue a subject’s study participation at any time
during the study when the subject meets the study termination criteria described in Section 7.6. In
addition, a subject may discontinue his 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 sub-investigator. In addition, efforts should be made to perform
all procedures scheduled for Early Termination visit if possible.
7.8
Subject Replacement
A subject who discontinues the study after the study drug administration in Period 1 will not be
replaced with a reserve subject. If a subject has not received the study drug as scheduled during 
Period 1 owing to any reason occurring before the study drug administration, a reserve subject will 
be allowed to participate in the study.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
Code name: TAK-536
Generic name: Azilsartan (JAN)
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
Strength: Contains 10 mg of TAK-536 in 1 g
Formulation: White to nearly white granules
8.1.1
Clinical Study Drug Labeling
Each aluminum strip sachet contains 1 g of TAK-536 granules containing 10 mg TAK-536. 
Twelve sachets are packaged in a box.
Each outer box indicates the following information: the drug is for study use only, study drug 
name, study number, the sponsor name and address, batch number, storage condition, and 
expiration date.
8.1.2
Clinical Study Drug Inventory and Storage
Study drug is 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 its designee. Study drug must be stored under the conditions specified on the 
label, and remain in the original container until dispensed. A daily temperature log of the drug 
storage area must be maintained every working day.
8.1.3
Randomization Code Creation and Storage
The designee of the Sponsor will generate the randomization code. All randomization information 
will be stored in a secured area, accessible only by authorized personnel.
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs
The site designee will receive the procedure for handling, storage, and management of study drug 
created by the Sponsor, and follow the procedure to manage the Sponsor-supplied drug supplies. 
The investigator will also receive the procedure from the Sponsor. The procedure will provide 
instructions on ensuring appropriate receipt, handling, storage, management, and dispensation of 
the sponsor-supplied drug. The procedure will also stipulate the methods for collection of unused 
study drugs from the subject and their return to the sponsor, or other disposal of unused supplies.
The 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 PROCEDURES
The following sections describe the study procedures and data to be collected by the investigator or
sub-investigator. For each procedure, subjects are to be assessed by the same investigator,
sub-investigator or site personnel whenever possible. The Schedule of Study Procedures is located
in Section 3.0.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 13.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
9.1.1.1
Assignment of Subject Identification Numbers
A unique subject identification number will be assigned to each subject at the time that informed
consent is explained; this subject number will be used throughout the study.
9.1.1.2
Study Drug Assignment
The study is conducted in an open label manner.
Subjects will be assigned to each sequence, in the order in which they are randomized into the 
study, to receive their treatment according to the randomization code.
Subjects will be assigned to receive a 4-digit enrollment number. This 4-digit number will be used 
by the study site to facilitate the prelabeling of PK samples and will be a subject identifier used on 
all PK sample collections. It should also be contained on the PK transport tubes shipped to the 
bioanalytical laboratory, and will be used by the laboratory to report the subject data results. This 
4-digit number does not replace the 3-digit subject identification number. In case it becomes 
necessary to replace a subject before the study drug administration in Period 1 after randomization, 
the reserve subject will replace the initial subject and receive the study drug scheduled for the 
initial subject.
9.1.2
Inclusion and Exclusion
For the eligibility, each subject will be assessed in accordance with the inclusion and exclusion 
criteria described in Section 7.0.
9.1.3
Medical History/Demography
Demographic information to be obtained will include date of birth, sex, caffeine consumption, 
alcohol use and smoking classification of the subject.
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under this study that resolved within 1 year prior to 


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signing of informed consent. Ongoing conditions or diseases are considered concurrent medical 
conditions.
Medication history information to be obtained includes any medication relevant to the eligibility 
criteria, stopped within 4 weeks (28 days) prior to signing of informed consent.
9.1.4
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 signing of informed consent through the end of the study, and 
all medications including vitamin supplements, OTC medications, and Chinese herbal medicines, 
must be recorded in the eCRF. Documentation will include generic medication name, route of 
administration, start and end dates, and reason for use.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Exam
Physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; (11) 
other.
9.2.2
Height and Weight
A subject should have weight and height measured with shoes off. Height is recorded in 
centimeters (cm) without decimal places by rounding. Weight is collected in kilograms (kg) with 1 
decimal place.
9.2.3
BMI
BMI is calculated using the formula provided below.
BMI = weight (kg)/height (m)2
BMI should be reported to 1 decimal place by rounding. The inclusion criterion for BMI will be 
assessed based on a rounded value.
9.2.4
Vital Signs
Vital signs will include sitting systolic blood pressure and diastolic blood pressure (resting more 
than 5 minutes) (mmHg), sitting pulse rate (beats per minute), and body temperature (axillary) 
(°C).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within an acceptable time window (see Appendix B).


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9.2.5
12-Lead ECG
A resting 12-lead ECG will be recorded. The investigator or sub-investigator (or a qualified 
physician at the study site) will interpret the ECG findings using one of the following categories: 
within normal or abnormal. In the case that the ECG findings are abnormal, the investigator or 
sub-investigator (or a qualified physician at the study site) will judge if it is clinically significant. 
The following parameters will be recorded on the eCRF from the subject’s ECG trace: heart rate, 
RR interval, PR interval, QT interval, QRS interval, and QTc interval (corrected by the 
Fridericia’s formula).
When 12-lead ECG measurements are scheduled at the same time as blood draws, the blood draw 
will take priority and 12-lead ECGs will be obtained within an acceptable time window (see 
Appendix B).
9.2.6
Study Drug Administration
Each subject will receive TAK-536 pediatric formulation under one of the following treatment
conditions in each period.
1. One sachet of TAK-536 10 mg granules (TAK-536 10 mg) will be administered orally with 
200 mL of water in the morning under fasted condition (fasted overnight for at least 10 hours 
prior to study drug administration).
2. One sachet of TAK-536 10 mg granules (TAK-536 10 mg) will be administered orally with 
200 mL of water in the morning under fed condition (at 30 minutes after starting breakfast).
9.2.7
AE Monitoring
AE monitoring begins after the signing of informed consent. A complete description of AE
collections and procedures is provided in Section 10.2.
9.2.8
Laboratory Procedures and Assessments
All samples will be collected in accordance with the separately defined laboratory procedures. 
Laboratory samples will be taken following a minimum 8 hour overnight fast on the days 
stipulated in the study schedule (see Section 3.0).
9.2.8.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Red blood cells (RBC)
Hemoglobin
White blood cells (WBC) with differential (neutrophils, 
basophils, eosinophils, lymphocytes, monocytes)
Hematocrit
Platelets


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Serum Chemistry
Serum Chemistry evaluations will consist of the following standard chemistry panel:
ALT
Sodium
AST
Chloride
ALP
Calcium
GGT
Inorganic phosphorus
Total bilirubin
Total cholesterol
Total protein
Fasting triglyceride
Albumin
Uric acid
Creatinine
LDH
BUN
Creatine kinase
Potassium
Fasting glucose
Urinalysis
Urinalysis will consist of the following tests:
pH
Qualitative tests for glucose, protein, occult blood, ketone 
body, bilirubin, and urobilinogen
Specific gravity
Other
Only for eligibility assessment:
Serum (immunology tests)
Urine (urine drug tests)
HBsAg, HCV antibody, HIV antibody/antigen, serum 
test for syphilis
phencyclidine, benzodiazepines, cocaine, antihypnotic 
agents, cannabinoids, opioids, barbiturates, and tricyclic 
antidepressants
HBsAg=hepatitis B surface antigen, HCV=hepatitis C virus, HIV=human immunodeficiency virus.
Note: The investigator or sub-investigator will inform the results of immunology and urine drug tests directly to
subjects. The Sponsor will confirm the overall test results (“Positive” or “All negative”), rather than detailed results,
for subjects (including reserve subjects) to be administered the study drug.
The local laboratory will perform laboratory tests for hematology, serum chemistry, and 
urinalysis. The results of laboratory tests will be returned to the investigator or sub-investigator, 
who is responsible for reviewing and filing these results.
If subjects experience ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, ALP, 
ALT, AST, total bilirubin, GGT, and INR) should be performed within a maximum of 7 days and 
preferably within 48 to 72 hours after the abnormality was noted (Refer to Section 7.6 and Section 
10.2.9.4 for the appropriate guidance on reporting abnormal liver function tests).
The investigator will maintain a copy of the reference ranges for the laboratory used.


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All clinically significant laboratory abnormalities must be recorded as an AE in the subject’s 
source documents and on the appropriate eCRF. A clinically significant laboratory abnormality 
that has been verified by retesting will be followed until the abnormality returns to an acceptable 
level or a satisfactory explanation has been obtained.
9.3
PK Samples
Blood samples for PK analysis of TAK-536 will be collected according to the study schedule 
specified in Section 3.0. Instructions for sample processing and shipment are provided in a 
separately defined procedure.
9.3.1
PK Measurements
The following PK parameters of unchanged TAK-536 will be determined from the plasma 
concentration-time profile up to 48 hours after the study drug administration based on 
non-compartmental analysis. Actual sampling times, instead of scheduled sampling times, will be 
used in all PK computations.
The following PK parameters will be calculated from plasma concentrations of TAK-536, unless 
otherwise specified:
Symbol/Term
Definition
Plasma
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration.
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity.
Cmax
Maximum observed plasma concentration (observed value).
tmax
Time of first occurrence of Cmax (observed value).
MRT
Mean residence time.
λz
Terminal disposition phase rate constant.
t1/2z
Terminal disposition phase half-life.
CL/F
Apparent clearance after extravascular administration.
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration.
9.3.1.1
Plasma for PK Measurements
Blood samples (one 3-mL sample per scheduled time) for PK analysis of unchanged TAK-536 will 
be collected into Vacutainers containing ethylenediaminetetraacetic acid dipotassium salt 
dihydrate (EDTA-2K) according to the schedule specified in Table 9.a.


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Table 9.a
Collection of Plasma Samples for PK Analysis
Analyte
Sample Type
Dosing Day
(Periods 1 and 2)
Scheduled Time
Unchanged TAK-536
Plasma
Day 1 of each period
Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 
16, 24, and 48 hours postdose
The actual time of sample collection will be recorded on the source document and eCRF.
If the subject is prematurely terminating from the study within 48 hours after the study drug 
administration, the blood sample for unchanged TAK-536 measurement will be collected at early 
termination.
9.3.2
Confinement
Subjects will be admitted to the study site on the day before the study drug administration (Day -1) 
in both Periods 1 and 2, and will be hospitalized under medical supervision for 4 days (until 48 
hours after the study drug administration). They will undergo daily examinations from the day 
before the study drug administration (Day -1) and observations during their hospitalization 
according to the study schedule specified in Section 3.0, and will be discharged from the study site 
on Day 3 after confirmation of safety by the investigator or sub-investigator.


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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the 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.
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 sub-investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters may be considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator or 
sub-investigator judges the change to be beyond the range of normal physiologic fluctuation). 
A laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. The first 
examination after the informed consent (eg, laboratory test, ECG, X-ray, etc) should NOT be 
recorded as an AE unless related to a study procedure. However, if the subject experiences a 


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worsening or complication of such a concurrent medical history condition, the worsening or 
complication should be recorded appropriately as an AE (worsening or complication occurs 
after informed consent is signed). The investigator or sub-investigator should ensure that the 
event term recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature. The investigator or sub-investigator should ensure that the AE term recorded 
captures the change from baseline in the condition (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. The investigator or sub-investigator 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 first administration of 
study drug or after any change in study drug, the worsening or complication should be 
recorded as a new AE. Investigators or sub-investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study drug, the event should be captured once with the maximum severity recorded.
Pre-planned surgeries or procedures:

Pre-planned procedures (surgeries or therapies) that were scheduled prior to the signing of 
informed consent are not considered AEs. However, if a pre-planned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures (surgeries or therapies) 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.
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. It is up to the investigator or sub-investigator to decide whether a dose is to 
be considered an overdose, in consultation with the Sponsor.


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
All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the eCRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on an AE page of the eCRF 
according to Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.9.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence in a clinical investigation subject who has
signed the informed consent to participate in a study:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Results in 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
Acute liver failure
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizure
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
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.
10.2
AE Procedures
10.2.1
Assigning Severity of AEs
The different categories of severity are:
Mild:
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.


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10.2.2
Assigning Causality of AEs
The causality of each AE to the study drug 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 is at least a reasonable possibility, ie, the relationship 
cannot be ruled out, although factors other than the drug, such as underlying 
diseases, complications, concomitant drugs and concurrent treatments, may also 
be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3
Assigning Causality of AEs to Study Procedures
The causality of each AE to study procedures will be assessed.
The causality should be assessed as Related if the investigator or sub-investigator considers that 
there is reasonable possibility that an event is due to a study procedure. Otherwise, the causality 
should be assessed as Not Related.
10.2.4
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 sub-investigator.
10.2.5
End Date
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.6
Pattern of Adverse Event (Frequency)
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.7
Action Taken With Study Treatment

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study drug was stopped for a reason other than the particular AE; eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped; or the 
particular AE occurred before starting study drug.


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10.2.8
Outcome

Recovered/resolved – subject returned to the first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages; the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; 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 become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is 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.
10.2.9
Collection and Reporting of AEs, SAEs, and Abnormal LFTs
10.2.9.1 Collection Period
Collection of AEs (ie, AEs, SAEs, and Abnormal LFTs) will commence at the time the subject 
signs the informed consent until the follow-up examination.
10.2.9.2 Reporting AEs
At each study visit, the investigator or sub-investigator will assess whether any subjective AEs 
have occurred. A neutral question, such as “How have you been feeling since your last visit?” may 
be asked. Subjects may report AEs occurring at any other time during the study.
Subjects experiencing an SAE 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. Nonserious AEs that begin prior to 
the first exposure to study drug, related or unrelated to the study procedure, need not be 
followed-up for the purposes of the protocol.
All subjects experiencing AEs after the first exposure to study drug, whether considered associated 
with the use of the study drug or not, must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or until there is a 
satisfactory explanation for the changes observed. All AEs will be documented in the AE page of 
the eCRF, whether or not the investigator or sub-investigator concludes that the event is related to 
the drug treatment. The following information will be documented for each event:


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
Event term.

Start and end date and time.

Pattern of AE (frequency).

Intensity.

Investigator’s or sub-investigator’s opinion of the causality between the event and 
administration of study drug (related or not related).

Investigator’s or sub-investigator’s opinion of the causality to study procedure(s), including 
the details of the suspected procedure.

Action taken with study drug.

Outcome of event.

Seriousness.

Timing of occurrence (after the administration of study drug).
10.2.9.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the
procedure outlined below:
An SAE should be reported by the investigator or sub-investigator to the Sponsor within 1 
business day of the first onset or notification of the SAE, along with any relevant information. The 
investigator should submit the detailed SAE Form to the Sponsor within 10 calendar days. The 
information should be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s or sub-investigator’s name.

Name of the study drug(s).

Causality assessment.
Any SAE spontaneously reported to the investigator or sub-investigator following the AE 
collection period should be reported to the Sponsor if considered related to study participation.
SAE Follow-Up
If the information which is not available at the time of the first report becomes available at a later 
date, the investigator or sub-investigator should complete a follow-up SAE form copy or provide 
the other written documentation and submit it to the Sponsor immediately. Copies of any relevant 
data from the hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) 
should be submit to the Sponsor, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event.


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10.2.9.4 Reporting of Abnormal LFTs
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 after the study drug administration, the event should be 
recorded as an SAE and reported as per Section 10.2.9.3. The investigator or sub-investigator must 
contact the monitor for discussion of the relevant subject details and possible alternative etiologies, 
such as acute viral hepatitis A or B or other acute liver disease or medical history/concurrent 
medical conditions. Follow-up laboratory tests as described in Section 9.2.8 must also be 
performed.
10.2.10 Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs and the
head of the study site. Relative to the first awareness of the event by/or further provision to the 
Sponsor or Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and 
life-threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The Sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of the study drug or that would be 
sufficient to consider changes in the study 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
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
The statistical analysis plan (SAP) will be prepared and finalized prior to the database lock. This
document will provide further details regarding the definitions of analysis variables, and analysis
methodologies to address all study objectives.
11.1.1
Analysis Sets
In this study, two kinds of analysis sets are defined: PK analysis set and safety analysis set.
11.1.1.1 Safety Analysis Set
The safety analysis set is defined as “all subjects who received at least one dose of the study drug”.
11.1.1.2 PK Analysis Set
The PK analysis set is defined as “all subjects who received the study drug, completed the 
minimum protocol-specified procedures without any major protocol deviations, and were
evaluable for PK”.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Main demographics and other baseline characteristics will be summarized overall and by
treatment group using the pharmacokinetic analysis set and the safety analysis set.
11.1.3
PK Analysis
The following statistical analyses will be performed on the PK analysis set.
1. Plasma drug concentrations
For plasma concentration of unchanged TAK-536, descriptive statistics will be provided by 
time point for each treatment condition (fed and fasted condition). In addition, the plasma 
concentration-time profiles will be also provided with both conditions on the same graph.
For PK parameters, descriptive statistics will be provided by each treatment condition.
2. Assessment of food effect on PK parameters
The difference in the least square means between treatment conditions (fed-fasted) and the 
two-sided 90% confidence interval (CI) will be provided using a crossover analysis of variance 
(ANOVA) model. The ANOVA model will include log-transformed (natural log) PK
parameters other than tmax as dependent variable, and treatment condition, group, and period as 
independent variables. For non-natural log transformed tmax, same analyses will be performed.
3. Methods of data transformation and handling of missing data
Details will be described in the SAP.


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4. Significance level, confidence coefficient
Confidence coefficient: 90% (two-sided)
11.1.4
Safety Analysis
The following statistical analyses will be performed on the safety analysis set.
11.1.4.1 AEs
TEAE is defined as an event whose date of onset occurs on or after the start of study drug.
TEAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA)
dictionary. The frequency distribution will be provided using the system organ class and the 
preferred term for each treatment condition as follows:

All TEAEs

Drug-related TEAEs

Intensity of TEAEs

Intensity of drug-related TEAEs

TEAEs leading to study drug discontinuation

Serious TEAEs
11.1.4.2 Clinical Laboratory Evaluation
For continuous variables, the observed values and the changes from baseline will be summarized
by treatment condition for each time point using descriptive statistics. Case plots for the observed 
values will also be provided for each treatment condition.
For categorical variables, shift tables showing the number of subjects in each category at baseline
and each post-baseline time point will be provided for each treatment condition.
11.1.4.3 Vital Signs
The observed values and the changes from baseline will be summarized by treatment condition for 
each time point using descriptive statistics. Case plots for the observed values will also be 
provided for each treatment condition.
11.1.4.4 Other Safety Parameters
For ECG parameters, the observed values and the changes from baseline will be summarized by 
treatment condition for each time point using descriptive statistics. Case plots for the observed 
values will also be provided for each treatment condition.
For 12-lead ECG interpretation, shift tables showing the number of subjects in each category at 
baseline and each post-baseline time point will be provided for each treatment condition.


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11.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
11.3
Determination of Sample Size
A total of 12 subjects (6 per sequence)
[Sample size justification]
A total of 12 subjects, with 6 subjects in each sequence were considered sufficient sample size to 
evaluate the PK and safety of TAK-536. The sample size is not based on statistical consideration.


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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
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 the head of 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 its
designee, including but not limited to the Investigator’s Binder, trial drug, subject medical records, 
informed consent documentation, and review of eCRFs and associated source documents. It is 
important that the investigator, sub-investigator, and other study personnel are available during the 
monitoring visits and that sufficient time is devoted to the process.
12.2
Protocol Deviations
The investigator or sub-investigator can deviate and change from the protocol for any medically
unavoidable reason, for example, to eliminate an immediate hazard to study subjects, without a 
prior written agreement with the Sponsor or a prior approval from IRB. In the event of a deviation
or change, the investigator should notify the Sponsor and the head of the study site of the deviation 
or changes as well as its reason in a written form, and then retain a copy of the written form. When 
necessary, the 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 sub-investigator should document all protocol deviations.
12.3
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 study 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], the Pharmaceuticals and 
Medical Devices Agency of Japan [PMDA]). If the study site is contacted for an inspection by a 
regulatory body, the Sponsor should be notified immediately. The investigator and the head of 
study site guarantee access for quality assurance auditors to all study documents as described in 
Section 12.1.


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13.0
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 International Council for Harmonisation (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 A.
13.1
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. 
The IRB approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, the informed consent form) reviewed; and state the approval 
date. The Sponsor will notify study site once the Sponsor has confirmed the adequacy of site 
regulatory documentation and, when applicable, the Sponsor has confirmed the adequacy of study 
site regulatory documentation. Until the study 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 incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and Sponsor.
13.2
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 
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 the informed consent is 


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given. The informed consent form will detail the requirements of the participant and the fact that 
he is free to withdraw at any time without giving a reason and without prejudice to his 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 the IRB and the Sponsor prior 
to use.
The informed consent form must be written in a language fully comprehensible to the prospective
subject. It is the responsibility of the investigator or sub-investigator to explain the detailed
elements of the informed consent form to the subject. Information should be given in both oral and
written form whenever possible and in the manner deemed appropriate by the IRB.
The subject 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 determines he will participate in the 
study, then the informed consent form must be signed and dated by the subject at the time of 
consent and prior to the subject entering into the study. The subject should be instructed to sign 
using their legal names, not nicknames, using blue or black ballpoint ink. The investigator or 
sub-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 sub-investigator must document the date the subject signs the informed consent in 
the subject’s medical record. Copies of the signed informed consent form shall be given to the 
subject.
All revised informed consent forms must be reviewed and signed by relevant subjects in the same 
manner as the original informed consent. The date the revised consent was obtained should be 
recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, MHRA, PMDA), the Sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 


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reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 13.2).
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).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1
Publication and Disclosure
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results is the 
sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. The investigator or
sub-investigator needs to obtain a prior written approval from the Sponsor to publish any
information from the study externally such as to a professional association.
13.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
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 investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing.
13.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
study 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 subjects. 
Refer to the study site agreement regarding the Sponsor’s policy on subject compensation and 
treatment for injury. If the investigator or sub-investigator has questions regarding this policy, he 
or she should contact the Sponsor or Sponsor’s designee.


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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information
A separate contact information list (Protocol Annex 1) will be provided to the study site.
14.1.2
Investigator Agreement
A separate agreement will be provided to the study site.
14.1.3
Study-Related Responsibilities
A separate contact information list (Protocol Annex 1) will be provided to the study site.
14.1.4
List of Abbreviations
Term
Definition
ACE
angiotensin converting enzyme
AE
adverse event
ALT
alanine aminotransferase
ARB
angiotensin II receptor blocker
AST
aspartate aminotransferase
BMI
body mass index
CKD
chronic kidney disease
eCRF
electronic case report form
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
INR
international normalized ratio
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
PMDA
Pharmaceuticals and Medical Devices Agency
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment emergent AE


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15.0
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 MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The Sponsor or its designee will supply investigational 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 study site.
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included.
The 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 following data will not be recorded into the eCRFs:

Laboratory results

Measurement results of drug concentrations
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator or sub-investigator with use of change and 
modification records of the eCRFs. The investigator must review the data change for completeness 
and accuracy, and must e-sign.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the Sponsor.
15.2
Record Retention
The investigator or the head of the study site agrees to keep the records stipulated in Section 15.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, all original signed and dated 


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informed consent forms, electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the Sponsor or its 
designees. The investigator and the head of the study site are required to retain relevant essential 
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 for 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 for the study.
In addition, the investigator and the head of the study site should retain the relevant essential 
documents until the receipt of a Sponsor-issued notification that states the retention is no longer 
required.


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16.0
REFERENCES
1. Uchiyama M, Sakai K. Studies of blood pressures in school children in northern Japan. Public 
Health. 1985;99:18-22.
2. Tochikubo O, Sasaki O, Umemura S, Kaneko Y. Management of hypertension in high school 
students by using new salt titrator tape. Hypertension. 1986;8:1164-71.
3. Current Population Estimates as of October 1, 2013 [Internet]. Statistics Bureau, Ministry of
Internal Affairs and Communications. [issued on 2016 April 15]. Available from:
http://www.stat.go.jp/data/jinsui/2013np/
4. Stabouli S, Kotsis V, Zakopoulos N. Ambulatory blood pressure monitoring and target organ 
damage in pediatrics. Hypertens. 2007;25(10):1979-86.
5. Lurbe E, Cifkova R, Cruickshank JK, Dillon MJ, Ferreira I, Invitti C, et al. Management of 
high blood pressure in children and adolescents: recommendations of the European Society of 
Hypertension. J Hypertens. 2009;27:1719-42.
6. Bao W, Threefoot SA, Srinivasan SR, Berenson GS. Essential hypertension predicted by 
tracking of elevated blood pressure from childhood to adulthood: the Bogalusa Heart Study. 
Am J Hypertens. 1995;8:657-65.
7. The Japanese Society of Hypertension Committee for Guidelines for the Management of 
Hypertension. The Japanese Society of Hypertension Guidelines for the Management of 
Hypertension (JSH2014). Tokyo: The Japanese Society of Hypertension; 2014.
8. The Japanese Circulation Society. The Guidelines for Drug Therapy in Pediatric Patients with 
Cardiovascular Diseases: V. Antihypertensive Drugs. In: The Guidelines for Diagnosis and 
Therapy of Cardiovascular Diseases (JCS 2012: The 2010-2011 Report of the Joint Working 
Group). [Internet]. 2013 [cited 2014 Dec]. Available from: 
http://www.j-circ.or.jp/guideline/index.htm.
9. Clinical Pharmacokinetic Studies of Pharmaceuticals, Pharmaceutical Affairs Bureau 
Notification No. 796 (June 1, 2001).
10. U.S. Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER). Guidance for Industry Food-Effect Bioavailability 
and Fed Bioequivalence Studies [Internet]. 2002 Dec [cited 2014 Oct 24]. Available from: 
http://www.fda.gov/RegulatoryInformation/Guidances/ucm122046.htm.
11. The Guidance on Clinical Investigation of Medicinal Products in the Pediatric Population, 
Pharmaceutical Affairs Bureau Notification No. 1334 (December 15, 2000).
12. Partial Revision of the Guideline for Bioequivalence Studies of Generic Products, 
Pharmaceutical and Food Safety Bureau Notification No. 0229-10 (February 29, 2012).
13. Law Enforcement Regulation on Securing a Stable Supply of Safe Blood Products, Ministry of 
Health and Welfare Ordinance No. 22 (June 25, 1956).


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14. Japan Society for the Study of Obesity. Diagnostic Criteria for Obesity 2011. Journal of Japan 
Society for the Study of Obesity 2011 (Special Edition).
15. General Considerations for Clinical Trials, Pharmaceutical Affairs Bureau Notification No. 
380 (April 21, 1998).
16. Japan Association of Contract Institutes for Clinical Pharmacology. Standard Intervals to be 
Observed between Participation in Clinical Studies, revised April 22, 2013.


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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
1. Conduct the appropriate study in accordance with the protocol and GCP considering the rights,
safety and wellbeing of human subjects.
2. When a part of the important activities related to the study are delegated to a sub-investigator
or the study collaborator, prepare the lists of activities to be delegated and responsible
personnel, submit the lists to the head of the study site in advance to get them accepted.
3. Prepare a written informed consent form and other written information, and update as
appropriate.
4. Confirm the contents of the clinical study agreement.
5. Provide necessary information on the protocol, medications and responsibilities of individual
personnel to the sub-investigator and study collaborator, and provide guidance and
supervision.
6. Screen subjects who meet the requirements of the protocol, provide the explanation of the
study in writing and obtain the written consent.
7. Assume responsibility for all the medical judgement related to the study.
8. Ensure in collaboration with the head of the study site that sufficient medical care for all 
clinically significant AEs related to the study are provided to subjects throughout and beyond 
the period when subjects participate in the study, upon obtaining consent from the subject.
9. If a subject consults other medical institution or other department, notify the physician of the
medical institution or department of the subject’s participation in the study, as well as the end
and termination of the study in writing, and document such records.
10. In case of urgent report of a SAE, immediately notify the head of the study site and the Sponsor 
in writing.
11. Determine the need of emergency key code blinding of a subject in case of emergency. [For 
double-blined studies only.]
12. Prepare correct and complete eCRFs, and submit them to the Sponsor with electronic
signature.
13. Check and confirm the contents of eCRFs prepared by the sub-investigator or transcribed from
the source data by the study collaborator, and submit them to the Sponsor with electronic
signature.
14. Discuss any proposal from the Sponsor including update of the protocol.
15. Notify the head of the study site of the end of the study in writing.


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Appendix B
Acceptable Time Window for Study Procedure
Acceptable time window for safety examination/test/observations (Periods 1 and 2)
As per the Protocol
Acceptable Time Window
Tests/Observation Item
Designated Time Point
Physical examination
Screening
From 28 days to 2 days before the 
study drug administration
Day -1
same as on the left
Before the study drug administration
From waking-up to immediately 
before the study drug administration
4 hours postdose
±30 minutes
24 and 48 hours postdose
±120 minutes
Follow-up examination (Day 6)
±1 day
Height
Screening
From 28 days to 2 days before the 
study drug administration
Weight
Screening
From 28 days to 2 days before the 
study drug administration
Before the study drug administration
From waking-up to immediately 
before the study drug administration
48 hours postdose
±120 minutes
Follow-up examination (Day 6)
±1 day
Vital signs
(Sitting blood pressure, sitting 
pulse, and body temperature)
Screening
From 28 days to 2 days before the 
study drug administration
Before the study drug administration
From waking-up to immediately 
before the study drug administration
4 hours postdose
±30 minutes
24 and 48 hours postdose
±120 minutes
Follow-up examination (Day 6)
±1 day
Resting 12-lead ECG
Screening
From 28 days to 2 days before the 
study drug administration
Before the study drug administration
From waking-up to immediately 
before the study drug administration
48 hours postdose
±120 minutes
Follow-up examination (Day 6)
±1 day
Laboratory tests
(Blood)
Screening
From 28 days to 2 days before the 
study drug administration
Before the study drug administration
From waking-up to immediately 
before the study drug administration
24 and 48 hours postdose
±120 minutes
Follow-up examination (Day 6)
±1 day


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As per the Protocol
Acceptable Time Window
Tests/Observation Item
Designated Time Point
Laboratory tests
(Urine)
Screening
From 28 days to 2 days before the 
study drug administration
Before the study drug administration
From waking-up to immediately 
before the study drug administration
24 and 48 hours postdose
From waking-up to +120 minutes
Follow-up examination (Day 6)
±1 day
Acceptable time window for PK blood sampling (Periods 1 and 2)
As per the Protocol
Acceptable Time Window
Tests/Observation Item
Designated Time Point
Plasma drug 
concentration
Before the study drug administration
From waking-up to immediately 
before the study drug administration
0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, and 12 hours
postdose
±5 minutes
16, 24, and 48 hours postdose
±15 minutes
Total blood sampling volume for an individual subject is shown below.
Sample Type
Volume
Number of Samples
Total Volume
(mL)
Screening
Period 1
Period 2
Clinical laboratory tests samples
16 mL at Screening/
10 mL at other time points
1
4
4
96
PK samples for TAK-536
3 mL
0
16
16
96
Total blood sampling volume
192


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680800d22
A Randomized, Open-Label, Cross-over Phase 1 Study to Evaluate the Food Effect of Single Oral Dose of
TAK-536 Pediatric Formulation in Healthy Adult Male Subjects
Clinical Approval
06-Mar-2018 00:40 UTC
PPD

SAP_001.pdf: 
 
 
Title: A Randomized, Open-Label, Cross-over Phase 1 Study to Evaluate the Food Effect 
of Single Oral Dose of TAK-536 Pediatric Formulation in Healthy Adult Male Subjects 
 
NCT Number: NCT03434977 
Statistical analysis plan Approve Date: 10-Jan-2018 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


 
 
 
 
STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: Azilsartan-1005 
A Randomized, Open-Label, Cross-over Phase 1 Study to Evaluate the Food Effect of 
Single Oral Dose of TAK-536 Pediatric Formulation in Healthy Adult Male Subjects 
A Phase 1 Food Effect Study of TAK-536 Pediatric Formulation 
PHASE 1 
Version: 1 
Date: 10 January 2018 
 
 
 
 
Prepared by: 
 
 
 
Based on: 
Protocol Version: Original (First Version) 
Protocol Date: 8 December 2017 
 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be 
published or disclosed without written authorization from Takeda. 
PPD


Azilsartan-1005 
Page 2 of 26
Statistical Analysis Plan Version 1 
10 January 2018
 
CONFIDENTIAL 
1.1 
Approval Signatures 
Study Title: 
A Randomized, Open-Label, Cross-over Phase 1 Study to Evaluate the 
Food Effect of Single Oral Dose of TAK-536 Pediatric Formulation in 
Healthy Adult Male Subjects 
A Phase 1 Food Effect Study of TAK-536 Pediatric Formulation 
 
Approvals: 
PPD
PPD
PPD
PPD
PPD


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Statistical Analysis Plan Version 1 
10 January 2018
 
CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
 
1.0 
TITLE PAGE .......................................................................................................................1 
1.1 
Approval Signatures.......................................................................................................2 
2.0 
TABLE OF CONTENTS .....................................................................................................3 
List of In-Text Tables ................................................................................................................4 
List of In-Text Figures ...............................................................................................................4 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................5 
4.0 
OBJECTIVES ......................................................................................................................6 
4.1 
Primary Objectives.........................................................................................................6 
4.2 
Secondary Objectives.....................................................................................................6 
4.3 
Additional Objectives ....................................................................................................6 
4.4 
Study Design ..................................................................................................................6 
5.0 
ANALYSIS ENDPOINTS ..................................................................................................8 
5.1.1 
Primary Endpoints ...................................................................................................8 
5.1.2 
Secondary Endpoints ...............................................................................................8 
6.0 
DETERMINATION OF SAMPLE SIZE ............................................................................9 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .....................................................10 
7.1 
General Principles ........................................................................................................10 
7.1.1 
Study Definitions ...................................................................................................10 
7.1.2 
Definition of Study Days .......................................................................................10 
7.1.3 
Definition of Study Visit Windows .......................................................................10 
7.2 
Analysis Sets ................................................................................................................11 
7.3 
Disposition of Subjects ................................................................................................14 
7.3.1 
Study Information ..................................................................................................14 
7.3.2 
Subject Eligibility ..................................................................................................14 
7.3.3 
Disposition of Subjects ..........................................................................................14 
7.3.4 
Protocol Deviations and Analysis Sets ..................................................................15 
7.4 
Demographic and Other Baseline Characteristics .......................................................15 
7.5 
Medical History and Concurrent Medical Conditions .................................................16 
7.6 
Medication History and Concomitant Medications .....................................................16 
7.7 
Study Drug Exposure and Compliance ........................................................................16 
7.8 
Efficacy Analysis .........................................................................................................16 
7.8.1 
Primary Efficacy Endpoint ....................................................................................16 
7.8.2 
Secondary Efficacy Endpoint ................................................................................16 
7.8.3 
Additional Efficacy Endpoint ................................................................................16 
7.8.4 
Statistical/Analytical Issues ...................................................................................17 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................18 
7.9.1 
Pharmacokinetic Analysis ......................................................................................18 


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7.9.2 
Pharmacodynamic Analysis ...................................................................................20 
7.10 
Other Outcomes ...........................................................................................................20 
7.11 
Safety Analysis ............................................................................................................21 
7.11.1 Adverse Events ......................................................................................................21 
7.11.2 Clinical Laboratory Evaluations ............................................................................23 
7.11.3 Vital Signs and Weight ..........................................................................................24 
7.11.4 12-Lead ECGs ........................................................................................................25 
7.11.5 Other Observations Related to Safety ....................................................................25 
7.12 
Interim Analysis ...........................................................................................................25 
7.13 
Changes in the Statistical Analysis Plan ......................................................................25 
8.0 
REFERENCES ..................................................................................................................26 
 
LIST OF IN-TEXT TABLES 
Table 7.a  Visit Window ................................................................................................................11 
 
LIST OF IN-TEXT FIGURES 
Table 4.a  Dosage, Treatment Condition, and Number of Subjects ................................................6 
Figure 4.b  Schematic of Study Design ...........................................................................................7 
 


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3.0 
LIST OF ABBREVIATIONS 
Term 
Definition 
ACE 
angiotensin converting enzyme 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARB 
angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CKD 
chronic kidney disease 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
INR 
international normalized ratio 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
PMDA 
Pharmaceuticals and Medical Devices Agency 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent AE 


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4.0 
OBJECTIVES 
4.1 
Primary Objectives 
To assess the food effect on the pharmacokinetics (PK) following single oral administration 
of TAK-536 pediatric formulation in Japanese healthy adult male subjects 
 
4.2 
Secondary Objectives 
To assess the food effect on the safety of a single oral administration of TAK-536 pediatric 
formulation in Japanese healthy adult male subjects 
 
4.3 
Additional Objectives 
Not applicable in this study. 
 
4.4 
Study Design 
This is an open-label, 2×2 crossover study to assess the food effect on the PK and safety of a 
single oral dose of TAK-536 pediatric formulation in Japanese healthy adult male subjects 
under fasted or fed conditions in the morning. 
The dosage, treatment condition, and number of subjects are shown in Table 4.a. Each subject 
will receive the study drug under one of the following treatment conditions in each period. 
1. One sachet of TAK-536 10 mg granules (TAK-536 10 mg) will be administered orally 
with 200 mL of water in the morning under fasted condition (fasted overnight for at least 
10 hours prior to the study drug administration). 
2. One sachet of TAK-536 10 mg granules (TAK-536 10 mg) will be administered orally 
with 200 mL of water in the morning under fed condition (at 30 minutes after starting 
breakfast). 
Table 4.a  Dosage, Treatment Condition, and Number of Subjects 
Sequence 
Number 
of subjects 
Dose of TAK-536 
Regimen 
Period 1 
Period 2 
A 
6 
TAK-536 10 mg Granules 
(TAK-536 10 mg) 
Single oral dose 
under fasted condition 
Single oral dose 
under fed condition 
B 
6 
TAK-536 10 mg Granules 
(TAK-536 10 mg) 
Single oral dose 
under fed condition 
Single oral dose 
under fasted condition 
 
Subjects will be screened for enrollment from 4 weeks (28 days) to 2 days (the day before 
admission) before the study drug administration (Day -28 to Day -2) in Period 1. Subjects 
will be admitted to the study site on the day before the study drug administration (Day -1) in 
both Periods 1 and 2, and will be hospitalized under medical supervision for 4 days (until 48 
hours after the study drug administration). They will undergo daily examinations and 
observations from the day before the study drug administration (Day -1) during their 


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hospitalization according to the study schedule specified in the protocol section 3.0, and will 
be discharged from the study site on Day 3 after confirmation of safety by the investigator or 
sub-investigator. Subjects will return to the study site for follow-up examinations on Day 6. 
At least 6-day washout interval will be placed between the study drug administrations in 
Periods 1 and 2. 
Subjects will visit the study site 5 times, including the visit for screening examinations, in 
this study. They will be hospitalized for a total of 8 days in Periods 1 and 2 (A schematic of 
the study design is shown in Figure 4.b). 
The examinations scheduled on the day before the study drug administration (Day -1) in 
Period 2 can be replaced with the follow-up examinations (Day 6) in Period 1 if they are 
scheduled on the same day. If this is the case, the subject will visit the study site 4 times in 
this study. 
Figure 4.b  Schematic of Study Design 
Element 
Screening 
Treatment (TAK-536 10 mg pediatric formulation) 
Period 1 and Period 2* 
Day 
Day -28 
to Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
 
Day 6 
 
Visit 
Hospitalization 
 
Visit 
Content 
Informed 
consent 
Screening 
Admission 
Study drug 
administration 
 
Discharge 
… 
Follow-up 
examination 
*: There will be at least 6-day washout interval between the study drug administrations in Periods 1 and 2. The examinations 
scheduled on the day before the study drug administration (Day -1) in Period 2 can be replaced with the follow-up 
examinations (Day 6) in Period 1, provided that they are scheduled on the same day. 
 


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5.0 
ANALYSIS ENDPOINTS 
5.1.1 Primary Endpoints 
PK: 
Plasma concentrations and PK parameters of unchanged TAK-536 (Cmax, tmax, 
AUClast, AUC∞, t1/2z, MRT, λz, CL/F, and Vz/F) 
 
5.1.2 Secondary Endpoints 
Safety: 
Adverse events (AEs), vital signs (sitting blood pressure, sitting pulse rate, and 
body temperature), weight, laboratory test results (hematology, serum 
chemistry, and urinalysis), and resting 12-lead ECGs 


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6.0 
DETERMINATION OF SAMPLE SIZE 
A total of 12 subjects (6 per sequence) 
[Sample size justification] 
A total of 12 subjects, with 6 subjects in each sequence, were considered sufficient sample 
size to evaluate the PK and safety of TAK-536. The sample size is not based on statistical 
considerations. 


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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
7.1.1 Study Definitions 
• 
Treatment-emergent adverse event (TEAE): Adverse events that occurred after the start 
of the study drug administration 
* 
Among the TEAEs, those that occurred from the start of the study drug 
administration in Period 1 to before the start of the study drug administration in 
Period 2 are deemed as “TEAEs that occurred in Period 1” and those that 
occurred after the start of the study drug administration in Period 2 as “TEAEs 
that occurred in Period 2.” 
• 
Pretreatment event(PTE):Adverse events that occurred after obtaining the consent but 
before the start of the study drug administration 
• 
Descriptive statistics: Number of subjects, mean, standard deviation, maximum, 
minimum, and quartiles 
• 
Coefficient of variation (CV)(%): Standard deviation / Mean x 100 
• 
QTcF interval: QT interval corrected with Fridericia’s correction 
• 
Treatment conditions: 
- 
Single oral dose under fasted condition 
- 
Single oral dose under fed condition 
• 
Treatment group: 
- 
A (Single oral dose under fasted condition → Single oral dose under fed condition) 
- 
B (Single oral dose under fed condition → Single oral dose under fasted condition) 
 
7.1.2 Definition of Study Days 
• 
Total Study Time in each time interval (hour): Time and date of 
test/observation/assessment - Time and date of start of study drug administration in each 
time interval (rounded to the fourth decimal place) 
 
7.1.3 Definition of Study Visit Windows 
For items of examinations, observations, and assessments described below, evaluable data 
(i.e., non-missing data) will be handled according to the following rules.  
Evaluable data within the visit window will be used.  If more than one evaluable data exist 
within the same visit window, the examinations, observations, and assessments with the 
closest Study Time to the scheduled Study Time will be used. If there are two evaluable 
equidistant to the scheduled Study Time, the later data will be used. The size of difference 
from the Study Time will be determined based on the total Study Time in each time interval 
(hour).  


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For items from examinations, observations, and assessments other than those described below, 
evaluable data will be handled as data at the corresponding visit based on the visits specified 
in the case report form.  However, among the visits specified in the case report form, if the 
follow-up examination in Period 1 (Day 6) and the examination on the day before the study 
drug administration (Day -1) in Period 2 were conducted on the same day and only the 
evaluable data exists from either the follow-up examination (Day 6) for Period 1 or the day 
before the study drug administration (Day -1) for Period 2, that data will be handled though it 
were obtained at both visits.  
 
Table 7.a  Visit Window 
Plasma drug concentration 
Visit 
Scheduled Study Time 
Total Study Time in each time 
interval (hour) 
Predose 
Study Time (hour): 0 
-5.000 - 0.000 
0.5 Hour Postdose 
Study Time (hour): 0.5 
0.417 - 0.583 
1 Hour Postdose 
Study Time (hour): 1 
0.917 - 1.083 
1.5 Hours Postdose 
Study Time (hour): 1.5 
1.417 - 1.583 
2 Hours Postdose 
Study Time (hour): 2 
1.917 - 2.083 
2.5 Hours Postdose 
Study Time (hour): 2.5 
2.417 - 2.583 
3 Hours Postdose 
Study Time (hour): 3 
2.917 - 3.083 
3.5 Hours Postdose 
Study Time (hour): 3.5 
3.417 - 3.583 
4 Hours Postdose 
Study Time (hour): 4 
3.917 - 4.083 
5 Hours Postdose 
Study Time (hour): 5 
4.917 - 5.083 
6 Hours Postdose 
Study Time (hour): 6 
5.917 - 6.083 
8 Hours Postdose 
Study Time (hour): 8 
7.917 - 8.083 
12 Hours Postdose 
Study Time (hour): 12 
11.917 - 12.083 
16 Hours Postdose 
Study Time (hour): 16 
15.750 - 16.250 
24 Hours Postdose 
Study Time (hour): 24 
23.750 - 24.250 
48 Hours Postdose 
Study Time (hour): 48 
47.750 - 48.250 
 
7.2 
Analysis Sets 
• 
Pharmacokinetic (PK) Analysis Set: 
All subjects who received the study drug, 
completed the minimum protocol-specified procedures without any major protocol 
deviations, and were evaluable for pharmacokinetics 
 Any subject who meets the following criteria will be excluded from this analysis set: 
1) Deviations of protocol entry criteria 
- 
Deviations of inclusion criteria 
Inclusion criteria 3, 4, and 5 
- 
Deviations of exclusion criteria 
Exclusion criteria 2, 4, 6, 7, 8, 9, 10, 11, and 17 


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2) Deviations related to treatment procedure or dose 
- 
Deviations related to dose 
Deviations of dosage 
Subjects who received a dose of the study drug other than the 
doses specified in the protocol 
- 
Deviations of regimen 
Deviations of dosing interval (number of days for washout) 
Subjects who received the study drug in Period 2 without 
undergoing a washout period of more than 6 days after the study 
drug administration in Period 1 
Deviations of dosing conditions 
Subjects who did not orally receive a single dose of any study 
drug under treatment conditions specified in that treatment period 
3) Deviations concerning excluded medication or therapy 
- 
Deviations concerning concomitant medications 
Administration of excluded medication 
Subjects who consumed drugs (prescribed or over-the-counter 
drugs) described in Table 7.a “Excluded Medications, 
Supplements, and Dietary Products” listed in the protocol section 
7.3 within the given time 
4) Deviations concerning pharmacokinetic measurements 
- 
Plasma drug concentration 
No conduct/missing of examinations and assessments concerning 
pharmacokinetic variables 
Subjects whose plasma drug concentration data of TAK-536 was 
missing or not used at more than 1 visit 
5) Others 
- 
Matters of subject management 
Matters concerning foods and beverages 
Subjects who consumed meals other than the provided meals 
during hospitalization 
Subjects who consumed meals within 10 hours before the study 
drug administration 
Subjects who consumed meals within 4 hours after the study drug 
administration 
Subjects who consumed beverages other than the drink provided 
as a part of breakfast (under fed condition) and water (200 mL) 


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taken with the study drug from 1 hour before to 4 hours after the 
study drug administration 
Subjects who consumed foods described in Table 7.a “Excluded 
Medications, Supplements, and Dietary Products” listed in the 
protocol section 7.3 within the given time 
Matters concerning smoking 
Subjects who smoked during hospitalization 
Matters concerning body position 
Subjects who took a supine position for 4 hours after the study 
drug administration, unless it was required for examination.  
• 
Safety Analysis Set: All subjects who received the study drug 
 
 


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7.3 
Disposition of Subjects 
7.3.1 Study Information 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variable(s): 
Date First Subject Signed Informed Consent Form 
 
Date Last Subject Completed Study Drug Administration 
 
MedDRA Version 
 
SAS Version Used for Creating the Datasets 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. 
 
(1) 
Display of analysis variables 
 
7.3.2 Subject Eligibility 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variable(s): 
Randomization 
[Eligible for Randomization, Not 
Eligible for Randomization] 
 
Primary Reason for 
Subject Not Being Eligible 
[Adverse Event, Death, Lost to 
Follow-up,  
Protocol Deviation, Sufficient 
Subject, Screening Failure, Study 
Termination by Sponsor, Voluntary 
Withdrawal, Other] 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. 
When calculating percentages for the primary reasons for subject not 
eligible for randomization, the total number of subjects who were not 
eligible for randomization will be used as the denominator. 
 
(1) 
Frequency distributions 
 
7.3.3 Disposition of Subjects 
Analysis Set: 
All Subjects Who Were Eligible for Randomization 
Analysis Variable(s): 
Study Completion Status 
[Completed All Planned Study Visits, 
Did Not Complete All Planned Study 
Visits] 
 
Reason for 
Discontinuation of Study 
Visits 
[Adverse Event, Death, Lost to 
Follow-up, Protocol Deviation, Study 
Termination by Sponsor, Voluntary 
Withdrawal, Other] 
Analysis Method(s): 
The following summaries will be provided by treatment group and 
by combining the treatment groups.  When calculating percentages 
for the primary reasons for subject who did not complete all planned 
study visits, the total number of subjects who did not complete all 
planned study visits will be used as the denominator. 
 
(1) 
Frequency distributions 


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7.3.4 Protocol Deviations and Analysis Sets 
7.3.4.1 Protocol Deviations 
Analysis Set: 
All Subjects Who Were Eligible for Randomization 
Analysis Variable(s): 
Protocol Deviations 
[Deviations of Protocol Entry Criteria, 
Deviations Concerning Excluded 
Medication or Therapy, 
Noncompliance with Protocol, 
Deviations Related to Treatment 
Procedure or Dose,  Deviations of 
Discontinuation Criteria, Major GCP 
Violations] 
Analysis Method(s): 
The following summaries will be provided by treatment group and 
by combining the treatment groups.  
The number of subjects with protocol deviations will be calculated 
and the details of deviations will be shown after classifying the 
contents of deviations into the above categories.  A subject who has 
several categories will be counted once in each appropriate category.  
(1) 
Frequency distributions 
 
7.3.4.2 Analysis Sets 
Analysis Set: 
All Subjects Who Were Eligible for Randomization 
Analysis Variable(s): 
Handling of Subjects in 
Analysis Sets 
[Categories are based on the 
specifications in the List of Subject 
Evaluability Assignments] 
 
Inclusion/Exclusion of 
Analysis Set 
 
 
Safety Analysis Set 
[Included] 
 
PK Analysis Set 
[Included] 
Analysis Method(s): 
The following summaries will be provided by treatment group for 
(1), and by treatment group and by combining the treatment groups 
for (2).  
For (1), a subject who has several categories will be counted once in 
each appropriate category. 
 
(1) 
Frequency distributions for handling of cases in each analysis 
set 
(2) 
Frequency distributions for number of cases included in each 
analysis set 
 
7.4 
Demographic and Other Baseline Characteristics 
Analysis Set: 
Safety Analysis Set 
PK Analysis Set 


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Analysis Variable(s): 
Age (years) 
 
 
Height (cm) 
 
 
Weight (kg) (prior to 
administration in Period 1) 
 
 
BMI (kg/m2) (prior to 
administration in Period 1) 
 
 
Smoking Classification 
[The subject has never smoked,  
The subject is a current smoker,  
The subject is an ex-smoker] 
 
Alcohol Classification 
[Everyday, 2 to 3 Days a Week,  
2 to 3 Days a Month, Never] 
 
Caffeine Classification 
[Yes, No] 
Analysis Method(s): 
The following summaries will be provided by treatment group and 
by combining the treatment groups.   
(1) 
Frequency distributions for categorical variables and 
descriptive statistics for continuous variables  
 
7.5 
Medical History and Concurrent Medical Conditions 
Not applicable in this study. 
 
7.6 
Medication History and Concomitant Medications 
Not applicable in this study. 
 
7.7 
Study Drug Exposure and Compliance 
Not applicable in this study. 
 
7.8 
Efficacy Analysis 
7.8.1 Primary Efficacy Endpoint 
Not applicable in this study. 
 
7.8.2 Secondary Efficacy Endpoint 
Not applicable in this study. 
 
7.8.3 Additional Efficacy Endpoint 
Not applicable in this study. 


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7.8.4 Statistical/Analytical Issues 
7.8.4.1 Adjustments for Covariates 
Not applied in this study. 
 
7.8.4.2 Handling of Dropouts or Missing Data 
Missing test results or data determined to be non-evaluable according to this Statistical 
Analysis Plan will not be used for hypothesis testing and estimations.  
Values below the lower limit of quantification in drug concentrations and laboratory test 
values will be treated as zero, and values above the upper limit of quantification in laboratory 
test values will be treated as the upper limit of quantification. 
 
7.8.4.3 Multicenter Studies 
Not applied in this study. 
 
7.8.4.4 Multiple Comparison/Multiplicity 
Not applied in this study. 
 
7.8.4.5 Use of an "Efficacy Subset" of Subjects 
Not applied in this study. 
 
7.8.4.6 Active-Control Studies Intended to Show Equivalence or Non-Inferiority 
Not applied in this study. 
 
7.8.4.7 Examination of Subgroups 
Not applied in this study. 
 
 


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7.9 
Pharmacokinetic/Pharmacodynamic Analysis 
7.9.1 Pharmacokinetic Analysis 
7.9.1.1 Plasma Concentrations 
Analysis Set: 
PK Analysis Set 
Analysis Variable(s): 
Plasma Concentrations of TAK-536 
Visit: 
Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, and 48 Hours 
Postdose 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. 
 
(1) 
Descriptive statistics will be provided for each treatment 
condition by visit.  
 
(2) 
Mean and standard deviation will be plotted simultaneously for 
both treatment conditions (vertical axis: normal scale). 
 
(3) 
Mean will be plotted simultaneously for both treatment 
conditions (vertical axis: common logarithmic scale). 
 
7.9.1.2 Pharmacokinetic Parameters 
Analysis Set: 
PK Analysis Set 
Analysis Variable(s): 
Pharmacokinetic Parameters of TAK-536 
 
Cmax 
tmax 
AUClast 
 
AUCinf 
t1/2z 
MRTlast,ev 
 
MRTinf,ev 
Lambda z 
CL/F 
 
Vz/F 
 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables by treatment condition. 
 
(1) 
Summary of Pharmacokinetic Parameters 
 
For Cmax, AUClast, and AUCinf, descriptive statistics, 
geometric mean, and CV will be provided. 
For Tmax, descriptive statistics will be provided.  
For all other variables, descriptive statistics and CV will be 
provided. 
 
7.9.1.3 Assessment of Food Effect 
Analysis Set: 
PK Analysis Set 
Analysis Variable(s): 
Pharmacokinetic Parameters of TAK-536 
 
Cmax 
tmax 
AUClast 
 
AUCinf 
t1/2z 
MRTlast,ev 
 
MRTinf,ev 
Lambda z 
CL/F 
 
Vz/F 
 
 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. 


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(1) 
The difference in the least square means between treatment 
conditions (single oral dose under fed condition – single oral 
dose under fasted condition) and the two-sided 90% confidence 
interval will be provided using a crossover ANOVA model. 
The ANOVA model will include log-transformed (natural log) 
analysis variables other than tmax as the dependent variable, 
and treatment condition, treatment group, and period as 
independent variables. 
 
(2) 
The difference in the least square means between treatment 
conditions (single oral dose under fed condition – single oral 
dose under fasted condition) and the two-sided 90% confidence 
interval will be provided using a crossover ANOVA model. 
The ANOVA model will include non-natural log-transformed 
tmax as the dependent variable, and treatment condition, 
treatment group, and period as independent variables. 
 
7.9.1.4 Individual Plasma Concentrations 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variable(s): 
Plasma Concentrations of TAK-536 
Visit: 
Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, and 48 Hours 
Postdose 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. 
 
(1) 
Individual plasma concentrations will be plotted 
simultaneously for both treatment conditions (vertical axis: 
normal scale). 
 
7.9.1.5 Subject Data Listings for Pharmacokinetic Parameters 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variable(s): 
Pharmacokinetic Parameters of TAK-536 
 
Cmax 
tmax 
AUClast 
 
AUCinf 
t1/2z 
MRTlast,ev  
 
MRTinf,ev 
Lambda z 
 
 
Measuring points of estimating Lambda z (start point, end point, 
and number of points) and adjusted R-squared contribution rate 
 
CL/F 
Vz/F 
 
Analysis Method(s): 
Subject data listings including the following variables will be 
displayed.  
 
(1) 
Subject ID, subject number, treatment group, treatment 
condition, and timing 
 
 
 
 


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7.9.2 Pharmacodynamic Analysis 
Not applicable in this study. 
 
7.10 
Other Outcomes 
Not applicable in this study. 
 
 
 


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7.11 
Safety Analysis 
7.11.1 Adverse Events 
7.11.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
TEAE 
Categories: 
Relationship to Study Drug [Related, Not Related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables by treatment condition. 
 
(1) 
Overview of TEAE 
 
1) All TEAEs (number of events, number and percentage of 
subjects)  
 
2) Relationship of TEAEs to study drug (number of events, 
number and percentage of subjects) 
 
3) Intensity of TEAEs (number of events, number and 
percentage of subjects) 
 
4) TEAEs leading to study drug discontinuation (number of 
events, number and percentage of subjects) 
 
5) Serious TEAEs (number of events, number and percentage 
of subjects) 
 
6) Relationship of serious TEAEs to study drug (number of 
events, number and percentage of subjects) 
 
7) Serious TEAEs leading to study drug discontinuation 
(number of events, number and percentage of subjects) 
 
8) TEAEs resulting in death (number of events, number and 
percentage of subjects) 
 
TEAEs will be counted according to the rules below. When 
calculating percentages for TEAE, the number of subjects who were 
treated by the study drug under that treatment condition in the safety 
analysis set will be used as the denominator. 
[Number of subjects with TEAEs] 
• In case of “frequency distributions by relationship to study drug” 
A subject with occurrences of TEAE in both categories (i.e., 
Related and Not Related) will be counted once in the Related 
category. 
• In case of “frequency distributions by intensity” 
A subject with multiple occurrences of TEAE will be counted 
once for the TEAE with the maximum intensity. 
• In case of distributions other than the above 
A subject with multiple occurrences of TEAE will be counted only 
once. 
[Number of events] 
For each summary, the total number of events will be calculated. 
 


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7.11.1.2 Displays of Treatment-Emergent Adverse events 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables by treatment condition. 
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 SOC only or PT only. 
 
(1) 
All TEAEs by SOC and PT 
 
(2) 
All TEAEs by SOC 
 
(3) 
All TEAEs by PT 
 
(4) 
Drug-Related TEAEs by SOC and PT 
 
(5) 
Intensity of All TEAEs by SOC and PT 
 
(6) 
Intensity of Drug-Related TEAEs by SOC and PT 
 
(7) 
TEAEs Leading to Study Drug Discontinuation by SOC and 
PT 
 
(8) 
Serious TEAEs by SOC and PT 
 
The method of counting events when conducting each frequency 
distribution will be as follows: 
[Number of subjects with TEAEs] 
• In case of “frequency distributions by SOC and PT, by SOC only, 
or PT only” 
A subject with multiple occurrences of TEAE within a SOC will 
be counted only once in that SOC. A subject with multiple 
occurrences of medical history or concurrent medical condition 
within a PT will be counted only once in that PT. Also, when 
calculating percentages for TEAE, the number of subjects who 
were treated by the study drug under that treatment condition in 
the safety analysis set will be used as the denominator. 
• In case of “frequency distributions by SOC and PT” 
A subject with multiple occurrences of TEAE within a SOC or a 
PT will be counted only once for the TEAE with the maximum 
intensity. Also, when calculating percentages for TEAE, the 
number of subjects who were treated by the study drug under that 
treatment condition in the safety analysis set will be used as the 
denominator. 
 
7.11.1.3 Displays of Pretreatment Events 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variable(s): 
PTE 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. 


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PTEs will be coded using the MedDRA and will be summarized 
using SOC and PT, where SOC will be sorted alphabetically and PT 
will be sorted in decreasing frequency.   
 
(1) 
All PTEs by SOC and PT 
(2) 
Serious PTEs by SOC and PT 
 
The method of counting events when conducting each frequency 
distribution will be as follows: 
[Number of subjects with PTEs] 
• A subject with multiple occurrences of PTE 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. 
 
7.11.2 Clinical Laboratory Evaluations 
7.11.2.1 Hematology and Serum Chemistry 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Hematology 
 
RBC 
WBC 
Hemoglobin 
 
Hematocrit 
Platelets 
 
 
WBC Differentials (Neutrophil, Basophil, Eosinophil, 
Lymphocyte, and Monocyte) 
 
Serum Chemistry 
 
ALT 
AST 
 
 
Alkaline Phosphatase 
 
 
GGT 
Total Bilirubin 
Total Protein 
 
Albumin 
Creatinine 
Urea Nitrogen 
 
Potassium 
Sodium 
Chloride 
 
Calcium 
Iinorganic 
Phosphorus 
Total Cholesterol 
 
Fasting 
Triglycerides 
Urine Acid 
LDH 
 
Creatine Kinase 
Fasting Glucose 
Categories: 
Results of determination based on reference values 
 
 
[Below lower limit of reference value, Within 
the range of reference value, Over upper limit 
of reference value] 
Visit: 
Predose, 24 and 48 Hours Postdose, Follow-up Examination (Day 6) 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables by treatment condition. 
 
(1) 
Descriptive statistics for observed values for each visit and 
changes (each visit after administration-predose) will be 
provided. 
 
(2) 
Case Plots 
 
(3) 
A shift table for each visit before and after administration will 


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be provided for the results of determination based on the 
reference values.  
 
7.11.2.2 Urinalysis 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Specific Gravity 
 
 
pH 
 
 
Glucose 
 
 
Protein 
 
 
Blood 
 
 
Ketone Body 
 
 
Bilirubin 
 
 
Urobilinogen 
 
Categories: 
Results of determination based on reference values 
 
 
[Below lower limit of reference value, 
Within the range of reference value, 
Over upper limit of reference value] 
Visit: 
Predose, 24 and 48 Hours Postdose, Follow-up Examination (Day 6) 
Analysis Method(s): 
For specific gravity, summaries (1) to (3) will be provided by 
treatment condition.  
For each variable other than specific gravity, summary (3) will be 
provided by treatment condition. 
 
(1) 
Descriptive statistics for observed values for each visit and 
changes (each visit after administration-predose) will be 
provided. 
 
(2) 
Case Plots 
 
(3) 
A shift table for each visit before and after administration will 
be provided for the results of determination based on the 
reference values.  
 
7.11.3 Vital Signs and Weight 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Body Temperature (axillary) 
 
 
Sitting Systolic Blood Pressure 
 
 
Sitting Diastolic Blood Pressure 
 
 
Sitting Pulse Rate 
 
 
Weight 
 
Visit: 
Body Temperature (axillary), Sitting Systolic Blood Pressure, Sitting 
Diastolic Blood Pressure, Sitting Pulse Rate: 
Predose, 4, 24, and 48 Hours Postdose, Follow-up Examination 
(Day 6) 
Weight: 
Predose, 48 Hours Postdose, Follow-up Examination (Day 6) 
Analysis Method(s): 
The following analysis will be performed for the above analysis 


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variables by treatment condition. 
 
(1) 
Descriptive statistics for observed values for each visit and 
changes (each visit after administration-predose) will be 
provided. 
 
(2) 
Case Plots 
 
7.11.4 12-Lead ECGs 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Heart Rate 
 
 
RR Interval 
 
 
PR Interval 
 
 
QRS Interval 
 
 
QT Interval 
 
 
QTcF Interval 
 
 
12-Lead ECG Interpretation 
[Within Normal Limits, Abnormal but 
not Clinically Significant, Abnormal 
and Clinically Significant] 
Visit: 
Predose, 48 Hours Postdose, Follow-up Examination (Day 6) 
Analysis Method(s): 
For each variable other than 12-lead ECG interpretations, summaries 
(1) and (2) will be provided by treatment condition.  
For 12-lead ECG, summary (3) will be provided by treatment 
condition.  
 
(1) 
Descriptive statistics for observed values for each visit and 
changes (each visit after administration-predose) will be 
provided. 
 
(2) 
Case Plots 
 
(3) 
A shift table for each visit before and after administration will 
be provided. 
 
7.11.5 Other Observations Related to Safety 
Not applicable in this study. 
 
7.12 
Interim Analysis 
Not applicable in this study. 
7.13 
Changes in the Statistical Analysis Plan  
The analysis plan described in this Statistical Analysis Plan is the same as the analysis plan 
described in the protocol.  
 


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8.0 
REFERENCES 
Not applicable in this study.