Clinical trial NCT03042299
Conditions: Japanese Healthy Adult Male Participants
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2017-02-10; Completion date: 2017-03-11
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the bio-equivalence of a single oral administration of TAK-536 pediatric formulation (granules) in comparison with a TAK-536 commercial formulation (tablet) in Japanese healthy adult male participants in an open label, 2-period, 2-treatment, cross-over design.

Detailed description:
The purpose of this study is to evaluate the bio-equivalence of a single oral administration of TAK-536 pediatric formulation (granules) in comparison with a TAK-536 commercial formulation (tablet) in healthy adult male participants in an open label, 2-period, 2-treatment, cross-over design.

Arms: arm 1: TAK-536 10 milligram (mg), granules (pediatric formulation), under fasted condition, orally, once on Day 1 of Intervention Period 1, followed by a Washout Period of at least 6 days, further followed by TAK-536 10 mg, tablet (commercial formulation), under fasted condition, orally, once on Day 1 of Intervention Period 2. arm 2: TAK-536 10 mg, tablet (commercial formulation), under fasted condition, orally, once on Day 1 of Intervention Period 1, followed by a Washout Period of at least 6 days, further followed by TAK-536 10 mg, granules (pediatric formulation), under fasted condition, orally, once on Day 1 of Intervention Period 2.
Interventions: intervention 1: TAK-536 intervention 2: TAK-536
Intervention descriptions: intervention 1: TAK-536 granules. intervention 2: TAK-536 tablet.

Protocol documents:
Prot_000.pdf: 
Certain information within this clinical study report has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or company 
confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable information or 
company confidential information may be removed in their entirety if it is considered that they do not add 
substantially to the interpretation of the data (eg, appendix of investigator’s curriculum vitae). 


PROTOCOL
A Randomized, Open Label, 2-Period, 2-Treatment, Cross-over Phase 1 Study to Evaluate 
the Bio-equivalence of Single Oral Dose of TAK-536 Pediatric Formulation and TAK-536 
Commercial Formulation in Healthy Adult Male Subjects
A Phase 1, Bio-equivalence Study of TAK-536 Pediatric Formulation
Sponsor:
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka, Japan
Study Number:
Azilsartan-1004
IND Number:
Not Applicable
EudraCT Number:
Not Applicable
Compound:
TAK-536
Date:
22 Dec 2016
Version/Amendment 
Number:
First 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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1.0
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES
1.1
Contacts and Responsibilities of Study-Related Activities
See the annex.


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1.2
Principles of Clinical Studies
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation E6 Good Clinical Practice Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES........................................................................................................................2
1.1
Contacts and Responsibilities of Study-Related Activities..........................................2
1.2
Principles of Clinical Studies .....................................................................................3
2.0
STUDY SUMMARY ......................................................................................................8
3.0
LIST OF ABBREVIATIONS........................................................................................11
4.0
INTRODUCTION.........................................................................................................12
4.1
Background .............................................................................................................12
4.2
Rationale for the Proposed Study.............................................................................13
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................14
5.1
Objectives................................................................................................................14
5.1.1
Primary Objective .......................................................................................14
5.1.2
Secondary Objective ...................................................................................14
5.2
Endpoints.................................................................................................................14
5.2.1
Primary Endpoints.......................................................................................14
5.2.2
Secondary Endpoints...................................................................................14
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................15
6.1
Study Design ...........................................................................................................15
6.2
Justification for Study Design, Dose, and Endpoints ................................................17
6.3
Premature Termination or Suspension of Study or Study Site...................................18
6.3.1
Criteria for Premature Termination or Suspension of the Study...................18
6.3.2
Criteria for Premature Termination or Suspension of Study Sites ................18
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site...........................................................................18
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............19
7.1
Inclusion Criteria .....................................................................................................19
7.1.1
Justification of Inclusion Criteria.................................................................19
7.2
Exclusion Criteria ....................................................................................................19
7.2.1
Justification of Exclusion Criteria ...............................................................20
7.3
Excluded Medications, Supplements, Dietary Products............................................21
7.4
Diet, Fluid, Activity Control ....................................................................................22
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................23
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................24
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................25


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8.1
Study Drug ..............................................................................................................25
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................25
8.1.2
Storage........................................................................................................26
8.1.3
Dose and Regimen ......................................................................................26
8.1.4
Overdose.....................................................................................................26
8.2
Study Drug Assignment and Dispensing Procedures ................................................26
8.3
Randomization Code Creation and Storage..............................................................27
8.4
Accountability and Destruction of Sponsor-Supplied Drugs.....................................27
9.0
STUDY PLAN ..............................................................................................................28
9.1
Study Procedures.....................................................................................................28
9.1.1
Informed Consent Procedure.......................................................................28
9.1.2
Demographics, Medical History, and Medication History Procedure...........28
9.1.3
Physical Examination Procedure .................................................................28
9.1.4
Weight, Height and BMI.............................................................................29
9.1.5
Vital Sign Procedure ...................................................................................29
9.1.6
Documentation of Concomitant Medications...............................................29
9.1.7
Documentation of Concurrent Medical Conditions......................................29
9.1.8
Procedures for Clinical Laboratory Samples................................................29
9.1.9
ECG Procedure ...........................................................................................31
9.1.10
Pharmacokinetic Sample Collection ............................................................31
9.1.11
Pharmacokinetic Parameters........................................................................31
9.1.12
Documentation of Subjects Failure..............................................................32
9.1.13
Documentation of Randomization ...............................................................33
9.2
Monitoring Subject Treatment Compliance..............................................................33
9.3
Schedule of Observations and Procedures................................................................33
9.3.1
Screening ....................................................................................................33
9.3.2
Randomization (Day 1) ...............................................................................34
9.3.3
Treatment Phase (Days 1 to 3).....................................................................34
9.3.4
Day of Discharge (Day 3)............................................................................34
9.3.5
Early Termination .......................................................................................34
9.3.6
Follow-up Examination (Day 6)..................................................................34
9.4
Blood Sampling Volume and Frequency..................................................................35
10.0
ADVERSE EVENTS ....................................................................................................36
10.1
Definitions...............................................................................................................36
10.1.1
AEs.............................................................................................................36


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10.1.2
Additional Points to Consider for AEs.........................................................36
10.1.3
SAEs...........................................................................................................38
10.1.4
Severity of AEs...........................................................................................39
10.1.5
Causality of AEs to Study Drugs.................................................................39
10.1.6
Relationship of AEs to Study Procedures ....................................................39
10.1.7
Start Date....................................................................................................40
10.1.8
End Date.....................................................................................................40
10.1.9
Pattern of Adverse Event.............................................................................40
10.1.10
Action Taken with Study Drug....................................................................40
10.1.11
Outcome .....................................................................................................41
10.2
Procedures...............................................................................................................41
10.2.1
Collection and Reporting of AEs.................................................................41
10.2.2
Collection and Reporting of SAEs...............................................................42
10.2.3
Reporting of Abnormal Liver Function Tests ..............................................43
10.3
Follow-up of SAEs ..................................................................................................43
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities...........43
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................44
12.0
DATA HANDLING AND RECORDKEEPING............................................................45
12.1
Case Report Forms (Electronic) ...............................................................................45
12.2
Record Retention .....................................................................................................45
13.0
STATISTICAL METHODS..........................................................................................47
13.1
Statistical and Analytical Plans ................................................................................47
13.1.1
Analysis Sets...............................................................................................47
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................47
13.1.3
Pharmacokinetic Analysis ...........................................................................47
13.1.4
Safety Analysis ...........................................................................................48
13.2
Interim Analysis and Criteria for Early Termination ................................................49
13.2.1
Timing of Interim Analysis .........................................................................49
13.2.2
Statistical Analysis Plan for Interim Analysis..............................................49
13.3
Determination of Sample Size..................................................................................49
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................50
14.1
Study-Site Monitoring Visits ...................................................................................50
14.2
Protocol Deviations..................................................................................................50
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................50
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................51


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15.1
IRB Approval ..........................................................................................................51
15.2
Subject Information, Informed Consent, and Subject Authorization .........................51
15.3
Subject Confidentiality ............................................................................................52
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................53
15.4.1
Publication and Disclosure..........................................................................53
15.4.2
Clinical Trial Registration...........................................................................53
15.4.3
Clinical Trial Results Disclosure .................................................................53
15.5
Insurance and Compensation for Injury....................................................................53
16.0
REFERENCES..............................................................................................................54
LIST OF IN-TEXT TABLES
Table 6.a
Dosage and Number of Subjects.........................................................................16
Table 7.a
Prohibited Medications, Supplements, Dietary Products or Food Products .........21
Table 9.a
Clinical Laboratory Tests...................................................................................30
Table 9.b
Collection of Blood Samples for Pharmacokinetic Analysis ...............................31
Table 9.c
Approximate Blood Volume ..............................................................................35
Table 10.a
Takeda Medically Significant AE List................................................................39
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design (Period 1 and Period 2)............................................17
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures (Period 1 and Period 2) .......................................55
Appendix B
Responsibilities of the Investigator.....................................................................58


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2.0
STUDY SUMMARY
Clinical Study Sponsor:
Takeda Pharmaceutical Company Limited
Compound:
TAK-536
Study Title: 
A Randomized, Open Label, 2-Period, 2-Treatment,
Cross-over Phase 1 Study to Evaluate the Bio-equivalence 
of Single Oral Dose of TAK-536 Pediatric Formulation and 
TAK-536 Commercial Formulation in Healthy Adult Male 
Subjects
IND No.:
Not applicable
EudraCT No.:
Not applicable
Study Identifier: Azilsartan-1004
Phase: 1
Study Design:
This study is conducted to evaluate the bio-equivalence of a single oral administration of TAK-536 pediatric 
formulation (granules) in comparison with a TAK-536 commercial formulation in healthy adult male subjects in an 
open label, 2-period, 2-treatment, cross-over design.
In case bio-equivalence is not demonstrated because the planned number of subjects is too small, an add-on subject 
study will be conducted.
Primary Objective:
To evaluate the bio-equivalence of a single oral administration of TAK-536 pediatric formulation in comparison with 
a TAK-536 commercial formulation in Japanese healthy adult male subjects
Secondary Objective:
To evaluate the safety of a single oral administration of TAK-536 pediatric formulation in Japanese healthy adult male 
subjects
Subject Population: Japanese healthy adult male subjects
Planned Number of Subjects:
14 subjects (7 for each sequence)
In case an add-on subject study is conducted, the maximum 
number of subjects will be 120 in total (60 per sequence).
Planned Number of Sites:
1 site
Dose Levels:
Each subject will receive either TAK-536 commercial 
formulation or TAK-536 pediatric formulation in each 
period under the conditions described below.
1.
TAK-536 commercial formulation (tablet)
The subject will orally receive one TAK-536 10 mg tablet 
with 200 mL water under fasted conditions in the morning 
(fasted for more than 10 hours after the last meal on the day 
before the study drug administration [Day 1]).
2.
TAK-536 pediatric formulation (granules)
The subject will orally receive one sachet of TAK-536 
granules containing 10 mg TAK-536 with 200 mL water 
under fasted conditions in the morning (fasted for more than 
10 hours after the last meal on the day before the study drug 
administration [Day 1]).
Route of Administration:
Oral


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Duration of Treatment:
Single dose×2 period (with a washout period of at least 6 
days)
Study Length:
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 is aged 20 to 35 years, inclusive, at the time of informed consent.
5. The subject weighs at least 50.0 kg, and has a body mass index (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 on the 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 known hypersensitivity to any component of the formulation of TAK-536 or any angiotensin II 
receptor blocker (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 medication, 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) 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 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) electrocardiogram (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 


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the following laboratory abnormalities at Screening or prior to the study drug administration in Period 1: alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (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
Pharmacokinetics: AUC48 and Cmax of TAK-536.
Secondary endpoints
Pharmacokinetics: AUC∞, tmax, MRT, and λz.
Safety: adverse events (AEs), vital signs (sitting blood pressure, sitting pulse [beats per minute], and body 
temperature), weight, resting 12-lead ECGs, and laboratory test results (hematology, serum chemistry, and urinalysis).
Statistical Considerations:
(1)
Plasma drug concentration
For plasma concentration of TAK-536, descriptive statistics will be provided by visit for each formulation (TAK-536 
commercial formulation, TAK-536 pediatric formulation). In addition, the plasma concentration-time profiles will be
also provided.
For pharmacokinetic parameters except AUMClast and AUMC∞, descriptive statistics will be provided. For the ratio 
between each formulation (TAK-536 pediatric formulation/TAK-536 commercial formulation) for pharmacokinetic 
parameters AUC48 and Cmax, descriptive statistics will be provided.
(2)
Assessment of bio-equivalence on pharmacokinetic parameters
The difference in the least square means between formulations (TAK-536 pediatric formulation - TAK-536 
commercial formulation) and the two-sided 90% confidence interval will be provided using a crossover analysis of 
variance (ANOVA) model. The ANOVA model will include log-transformed (natural log) pharmacokinetic 
parameters AUC48 and Cmax as dependent variable, and formulation, group, and period as independent variables. For 
log-transformed (natural log) pharmacokinetic parameters AUClast, AUC∞, MRT∞,ev, λz, and non-natural log 
tansformed tmax, same analyses will be performed.
Sample Size Justification:
Based on the currently available results of the studies conducted to date, the residual sum of squares of 
pharmacokinetic parameters Cmax and AUC48 in the present study was assumed to be 0.13 and 0.08, respectively. For 6 
subjects per sequence (total of 12 subjects per formulation), in two one-sided t-tests [H0: ln(μ)≤ln(θ1), ln(μ)≥ln(θ2); H1: 
ln(θ1)<ln(μ)<ln(θ2); where μ=μt/μs, μt was the population mean for the pediatric formulation, μs was the population 
mean for the TAK-536 commercial formulation, θ1=0.80, and θ2=1.25] with a one-sided significance level of 5% and
alternative hypothesis μ=0.95, more than 90% power of simultaneous detection of the bio-equivalence for 
pharmacokinetic parameters Cmax and AUC48. Taking into account possible occurence of dropouts during the study 
and feasibility, 7 subjects per sequence (total of 14 subjectsper formulation) were set.
In case bio-equivalence cannot be demonstrated with the number of subjects initially planned on account of 
insufficient subjects, an add-on subject study will be conducted in accordance with the Guideline for Bioequivalence 
Studies of Generic Products. The maximum number of subjects in the add-on subject study is 120 (60 per sequence), 
which is determined based on study feasibility, but is not on statistical consideration. The number of subjects in the 
add-on subject study will be determined based on the result of the interim analysis in this study and the currently 
available results of the studies conducted to date.


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3.0
LIST OF ABBREVIATIONS
ACE
angiotensin converting enzyme
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANOVA
analysis of variance
ARB
angiotensin II receptor blocker
AST
aspartate aminotransferase
BMI
body mass index
CI
confidence interval
CKD
chronic kidney disease
ECG
electrocardiogram
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
IRB
institutional review board
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
OTC
over-the-counter
PMDA
Pharmaceuticals and Medical Devices Agency
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment emergent adverse event
TPC
Takeda Pharmaceutical Company Limited
ULN
upper limits of normal


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4.0
INTRODUCTION
4.1
Background
Hypertension develops in not only in adults, but also in children and adolescents. While there are 
few epidemiological reports about the number of pediatric patients with hypertension in Japan, it is 
reported that hypertension is detected in 0.1% to 1% among elementary-school and 
junior-high-school students and in about 3% among high-school students in health checkups for 
Japanese children [1][2]. According to the 2013 Population Projection, 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 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[8] recommend angiotensin II receptor blockers 
(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 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
Upon beginning the development of TAK-536 for infants and children (from 1 year old to less than 
6 years old), TPC decided that pediatric patients, who have difficulty swallowing tablets, require 
pediatric formulations to ensure individually targeted dose adjustment and treatment adherence.
TPC then decided to evaluate the bio-equivalence of TAK-536 pediatric formulation in 
comparison with a TAK-536 10 mg commercial formulation in healthy adult male subjects in 
accordance with the partial revision of the Guideline for Bioequivalence Studies of Generic 
Products (hereafter referred to as the Guideline for Bioequivalence Studies of Generic Products) 
[9].
This protocol is designed in accordance with Good Clinical Practice (GCP).


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
To evaluate the bio-equivalence of a single oral administration of TAK-536 pediatric formulation 
in comparison with a TAK-536 commercial formulation in Japanese healthy adult male subjects.
5.1.2
Secondary Objective
To evaluate the safety of a single oral administration of TAK-536 pediatric formulation in 
Japanese healthy adult male subjects.
5.2
Endpoints
5.2.1
Primary Endpoints
Pharmacokinetics: AUC48 and Cmax of TAK-536.
5.2.2
Secondary Endpoints
Pharmacokinetics: AUC∞, tmax, MRT, and λz.
Safety: adverse events (AEs), vital signs (sitting blood pressure, sitting pulse, and body 
temperature), weight, resting 12-lead electrocardiograms (ECGs), and laboratory test 
results (hematology, serum chemistry, and urinalysis).


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
1. Study Design
This study is conducted to evaluate the bio-equivalence of a single oral administration of TAK-536 
pediatric formulation (granules) in comparison with a TAK-536 commercial formulation in 
healthy adult male subjects in an open label, 2-period, 2-treatment, cross-over design.
In case bio-equivalence is not demonstrated because the planned number of subjects is too small, 
an add-on subject study will be performed.
2. Sample size
A total of 14 subjects (7 for each sequence) will be enrolled in this study.
In case an add-on subject study is conducted, the maximum number of subjects will be 120 (60 per 
sequence).
3. Dose and mode of administration
The dosage and number of subjects are presented in Table 6.a. Each subject will receive either 
TAK-536 commercial formulation (tablet) or TAK-536 pediatric formulation (granules) in each 
period under the conditions described below.
1)
TAK-536 commercial formulation (TAK-536 10 mg tablet)
The subject will orally receive one TAK-536 10 mg tablet with 200 mL water under fasted 
conditions in the morning (fasted for more than 10 hours after the last meal on the day before the 
study drug administration [Day 1]).
2)
TAK-536 pediatric formulation (TAK-536 granules)
The subject will orally receive one sachet of TAK-536 granules containing 10 mg TAK-536 with 
200 mL water under fasted conditions in the morning (fasted for more than 10 hours after the last 
meal on the day before the study drug administration [Day 1]).


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Table 6.a
Dosage and Number of Subjects
Sequence
Dose
Number of 
Subjects
Administration 
Condition
Period 1
Period 2
a
One sachet of 
TAK-536 granules 
(10 mg/sachet)
One tablet of 
TAK-536 10 mg
7
Fasted
b
One tablet of 
TAK-536 10 mg
One sachet of 
TAK-536 granules 
(10 mg/sachet)
7
Add-on Subject Study (if conducted)
Sequence
Dose
Maximum 
Number of 
Subjects
Administration 
Condition
Period 1
Period 2
a
One sachet of 
TAK-536 granules
(10 mg/sachet)
One tablet of 
TAK-536 10 mg
60
Fasted
b
One tablet of 
TAK-536 10 mg
One sachet of 
TAK-536 granules 
(10 mg/sachet)
60
4. Planned number of study sites
One study site
5. Planned duration of subject participation and number of visits of each subject in the study
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 from the day before the study 
drug administration (Day -1) and observations during their hospitalization according to the study 
schedule specified in Appendix A, 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. A washout period of at least 6 days 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.
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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A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Figure 6.a
Schematic of Study Design (Period 1 and Period 2)
Element
Screening
Treatment (TAK-536 10 mg)*
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
*: A washout period of at least 6 days will be placed between the study drug administrations in Period 1 and Period 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. If this is the case, 
the subject will visit the study site 4 times in this study.
6.2
Justification for Study Design, Dose, and Endpoints
1. Justification for the Study Design
In accordance with the Guideline for Bioequivalence Studies of Generic Products [9], a 2-period, 
2-treatment, cross-over design, which allows bio-equivalence evaluation with minimal effect on 
inter-subject variation, was selected for this study.
2. Justification for the 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 [10] and the Guideline for 
Bioequivalence Studies of Generic Products [9].
3. Justification for Dose
Three formulations of TAK-536 tablets (10 mg, 20 mg, and 40 mg) are marketed for adult 
patients, and TAK-536 pediatric formulations are being developed for infants and children (from 1 
year old to less than 6 years old) who have difficulty swallowing these tablets. Weight-based 
dosing is planned in this age category. The clinically recommended general dose is considered to
be lower than the lowest daily dose of 20 mg for adult patients. Considering the above, 10 mg is
selected as the dose of the study drug, since a TAK-536 10 mg tablet with the lowest strength is 
considered to be the most suitable as a standard among the commercial formulations.
4. Justification for the Washout Period
The elimination half-life of TAK-536 after a single administration of TAK-536 10 mg tablet is 
13.1 hours. When TAK-536 10 mg was administered once under fasted conditions in a phase 1, 
single dose study conducted in Japan, plasma TAK-536 concentration was 9 ng/mL at 72 hours 
after the administration in the subject with detectable plasma TAK-536 levels for the longest 
duration. It was assumed in accordance with the Guideline for Bioequivalence Studies of Generic 
Products [9] that the plasma TAK-536 level would be below the lower limit of quantification 


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(<1 ng/mL) at 65.5 hours, which is equivalent to 5 times the elimination half-life (13.1 hours), 
after this time point (72 hours). The duration of washout period in this study will therefore be at 
least 6 days, in which drug is considered to be eliminated in living body.
5. Justification for the Endpoints
1)
Justification for the Pharmacokinetic Endpoints
In accordance with the Guideline for Bioequivalence Studies of Generic Products [9], AUC48 and
Cmax of TAK-536 will be eavaluated. The plasma concentration will be evaluated until 48 hours 
postdose for TAK-536, the time point when their AUCt is over 80% of their AUC∞.
2)
Justification for the Safety Examinations, Observations, and Endpoints
AEs, vital signs (sitting blood pressure, sitting pulse, and body temperature), weight, resting 
12-lead ECGs, and laboratory test results (hematology, serum chemistry, and urinalysis) were set 
as standard endpoints used for assessing safety in clinical pharmacology studies.
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site
In the event that the sponsor, an institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable study sites during the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to the study drug administration 
in Period 1.
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 is aged 20 to 35 years, inclusive, at the time of informed consent.
5. The subject weighs at least 50.0 kg, and has a body mass index (BMI) between 18.5 and 
25.0 kg/m2, inclusive, at Screening.
7.1.1
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 (1956) [11], 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 [12].
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 on the 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.


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5. The subject has a known hypersensitivity to any component of the formulation of TAK-536 or 
any 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 medication, 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) 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 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 with the following laboratory abnormalities at Screening or prior to the 
study drug administration in Period 1: alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (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.
7.2.1
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 the General 
Considerations for Clinical Trials (Pharmaceutical Safety Bureau Notification 
No.380, April 21, 1998) [13], and Standard Intervals to be Observed between 
Participation in Clinical Studies [14].
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 pharmacokinetic evaluations after 
study treatment.
9. to 11., 16., 17 To enroll healthy adult male subjects in accordance with the Guideline for 
Bioequivalence Studies of Generic Products [9].
13. to 15.
These criteria have been established in accordance with the Law Enforcement 
Regulation on Securing a Stable Supply of Safe Blood Products [11].
7.3
Excluded Medications, Supplements, Dietary Products
Use of the concomitant drugs (prescribed or over-the-counter [OTC] drugs) and consumption of 
dietary products listed in Table 7.a is prohibited until the specified period.
Table 7.a
Prohibited Medications, Supplements, Dietary Products or Food 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)
Vitamins, Chinese herbal medicines, dietary products containing St. 
John’s wort, Korean ginseng, kava kava, ginkgo, or melatonin
Foods and beverages containing grapefruit 
(juice, pulp), Seville-type (sour) oranges,
pineapple (juice, pulp), caffeine or alcohol
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 deem 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 Control
The investigator or sub-investigator and study collaborator should instruct subjects to follow the 
following requirements. Subjects will be kept under the supervision of the investigator or 
sub-investigator during hospitalization.
1. Foods
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 same for each period.
On the day of the study drug administration (Day 1) 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.
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.
2. Beverages
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 water (200 mL) taken with the study drug.
3. Smoking
Smoking is not allowed during the study period.
4. Body position and exercises
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.
5. Blood donation after study completion
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.
6. Other
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 


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possible, and should communicate to the medical institution about the subject’s participation in the 
study.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug
should be recorded in the electronic case report form (eCRF) using the following categories. For 
screen failure subjects who will discontinue or withdraw prior to the start of the study drug 
administration in Period 1, refer to Section 9.1.12.
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 10.2.2 for the reporting procedures.
2. AE. The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE.

Liver Function Test Abnormalities
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any time 
during study drug treatment:
–
ALT or AST >8×ULN, or
–
ALT or AST >5×ULN and persists for more than 2 weeks, or
–
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
international normalized ratio (INR) >1.5, or
–
ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (>5%).

The subject used any prohibited concomitant drugs (prescribed or OTC drugs) or foods listed 
in Table 7.a during the specified period when the investigator or sub-investigator deem it 
necessary to use any of the concomitant drugs for reasons including treatment of an AE.
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.

The subject used any prohibited concomitant drugs (prescribed or OTC drugs) or foods and the 
like listed in Table 7.a during the specified period.
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.


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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.
7.6
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 7.5. 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.
A subject who discontinues the study after the study drug administration in Period 1 will not be 
replaced with a reserve subject (see Section 9.3.1). 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
This section contains information regarding all medications and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.
8.1
Study Drug 
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term “study drug” refers to all or any of the drugs defined below.
8.1.1.1
Study drug
1. Code name, chemical name, strength, and formulation
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:

TAK-536 tablet: Contains 10 mg of TAK-536 in 1 tablet

TAK-536 granules: Contains 10 mg of TAK-536 in 1 g
Formulation:

TAK-536 tablet: Pale-yellowish red film-coated tablet

TAK-536 granules: White to nearly white granules
2. Packaging

TAK-536 tablet: Each press through package (PTP) sheet contains 14 tablets of TAK-536. Ten
sheets are packaged in a box.

TAK-536 granules: Each aluminum strip sachet contains 1 g of TAK-536 granules containing 
10 mg TAK-536. Twenty sachets are packaged in a box.
3. Labeling
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.
4. Manufacturing
TAK-536 tablets are manufactured by TPC. TAK-536 granules are manufactured by 
 
.


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8.1.2
Storage
The study drugs are to be stored at room temperature (1°C to 30°C).
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor, or its designee for destruction. Study drug must be stored under the conditions 
specified on the label, and remain in the original container until dispensed. A daily temperature log 
of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
Each subject will receive either TAK-536 commercial formulation (tablet) or TAK-536 pediatric 
formulation (granules) in each Period as described below.
1. TAK-536 commercial formulation (tablet)
The subject will orally receive one TAK-536 10 mg tablet with 200 mL water under fasted 
conditions in the morning (fasted for more than 10 hours after the last meal on the day before the 
study drug administration [Day 1]).
2. TAK-536 pediatric formulation (granules)
The subject will orally receive one sachet of TAK-536 granules containing 10 mg TAK-536 with 
200 mL water under fasted conditions in the morning (fasted for more than 10 hours after the last 
meal on the day before the study drug administration [Day 1]).
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE eCRF(s) according to Section 10.0.
SAEs associated with overdose should be reported according to the procedure outlined in Section 
10.2.2.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Study Drug Assignment and Dispensing Procedures
The study is conducted in an open label manner.
Subjects will be assigned, 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 pharmacokinetic samples and will be a subject identifier used on all PK sample collections.. It 
should also be contained on the pharmacokinetic transport tubes shipped to the bioanalytical 


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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 scheduled subject and receive the study drug for the initial subject will be used.
8.3
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.
8.4
Accountability and Destruction of Sponsor-Supplied Drugs
The site designee will receive the procedures for handling, storage, and management of the study 
drugs created by the sponsor, and follow the procedures for manage the sponsor-supplied drug 
supplies. A copy of these procedures will be provided to the investigator as well. The manual will 
provide instructions on ensuring appropriate receipt, handling, storage, management, and 
dispensation of the sponsor-supplied drug. The manual will also describe procedures for the 
collection of unused study drugs from the subject and their return to the sponsor, or the destruction 
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 PLAN
9.1
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 Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is explained; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, 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 study that resolved within 1 year prior to 
signing of informed consent. Ongoing conditions are considered concurrent medical conditions 
(see Section 9.1.7).
Medication history information to be obtained includes any medication relevant to the eligibility 
criteria, stopped within 4 weeks (28 days) prior to signing of informed consent.
9.1.3
Physical Examination Procedure
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.
Any Clinically Significant findings/changes on a pretreatment physical examination assessed by 
the investigator or sub-investigator will be recorded as an AE or a concurrent medical condition in 
the source document and on the appropriate eCRF described in Section 10.0 or Section 9.1.7.
On a post treatment physical examination, any Clinically Significant findings/changes compared 
with a result of a pretreatment physical examination, as determined by the investigator or 
sub-investigator, will be recorded as an AE in source documentation and on the AE eCRF 
described in Section 10.0.


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9.1.4
Weight, Height and BMI
A subject should have weight and height measured with shoes off. The BMI is calculated using 
metric units with the formula provided below. Height is recorded in centimeters (cm) without 
decimal places. Weight is collected in kilograms (kg) with 1 decimal place. BMI should be derived 
as:
BMI = weight (kg)/height (m)2
Note that although height is reported in centimeters, the formula uses meters for height; meters can 
be determined from centimeters by dividing by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2
Weight and BMI should be reported to 1 decimal place by rounding. Height in centimeters will be 
rounded to the nearest integer. Thus, in the above example BMI would be reported as 25.6 kg/m2.
9.1.5
Vital Sign Procedure
Vital signs will include sitting systolic blood pressure and diastolic blood pressure (resting more 
than 5 minutes) (in mmHg), sitting pulse (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 A).
9.1.6
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by the sponsor. At each study visit, subjects will be asked whether they have taken any medication
other than the study drug used from 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.
9.1.7
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at the first examination after the informed consent, according the 
judgment of the investigator or sub-investigator. The condition (ie, diagnosis) should be described.
9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Laboratory 
samples will be taken following a minimum 8 hour overnight fast on the days stipulated in the 
Schedule of Study Procedures (Appendix A).
Table 9.a lists the tests that will be obtained for each laboratory specimen.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cells (RBC)
White blood cells (WBC)
with differential (neutrophils, basophils, 
eosinophils, lymphocytes, monocytes)
Hemoglobin
Hematocrit
Platelets
ALT
AST
ALP
GGT
Total bilirubin
Total protein
Albumin
Creatinine
BUN
Potassium
Sodium
Chloride
Calcium
Inorganic phosphorus
Total cholesterol
Fasting triglyceride
Uric acid
LDH
Creatine kinase
Fasting glucose
pH
Specific gravity
Qualitative tests for glucose, 
protein, occult blood, ketone body, 
bilirubin, and urobilinogen
Only for eligibility assessment:
Serum (immunology tests)
Urine (urine drug tests)
HBsAg, HCV antibody, HIV antigen/antibody, serum 
test for syphilis
phencyclidine, benzodiazepines, cocaine, antihypnotic 
agents, cannabinoids, opioids, barbiturates, and tricyclic 
antidepressants
Note: The investigator or sub-investigator will report 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 7.5 and Section 
10.2.3 for the appropriate guidance on reporting abnormal liver function tests).
The investigator will maintain a copy of the reference ranges for the laboratory used.
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.


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9.1.9
ECG Procedure
A resting 12-lead ECG will be recorded. The investigator or sub-investigator (or a qualified 
observer 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 is 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 
Fredericia’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 A).
9.1.10 Pharmacokinetic Sample Collection
9.1.10.1 Collection of Plasma for Pharmacokinetic Sampling
Blood samples (one 3-mL sample per scheduled time) for pharmacokinetic analysis of TAK-536 
will be collected into Vacutainers containing ethylenediaminetetraacetic acid dipotassium salt 
dihydrate (EDTA) according to the schedule in Appendix A. Instructions for sample processing 
and shipment are provided in a separately defined “Procedure for Handling Samples for Drug 
Concentration Measurement”.
Blood samples for determination of TAK-536 will be collected according to Table 9.b
Table 9.b
Collection of Blood Samples for Pharmacokinetic Analysis
Analyte
Matrix
Dosing Day
Scheduled Time
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 TAK-536 will be collected at early termination.
9.1.10.2 Bioanalytical Methods
Plasma concentration of TAK-536 will be measured by high-performance liquid chromatography 
with tandem mass spectrometry (LC/MS/MS method) at 
9.1.11 Pharmacokinetic Parameters
The following pharmacokinetic parameters of TAK-536 will be determined from the 
concentration-time profile up to 48 hours after study drug administration based on 


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non-compartmental analysis. Scheduled sampling times will be used for the estimation of 
pharmacokinetic parameters in principle.
Symbol/Term
Definition
Plasma
AUCt
Area under the concentration-time curve from time 0 to t.
AUClast
Area under the concentration-time curve from time 0 to time of the last quantifiable concentration.
AUMClast
Area under the first moment concentration-time curve from time 0 to time of last quantifiable 
concentration.
MRTlast,ev
Mean residence time after extravascular administration from time 0 to time of last quantifiable 
concentration, calculated as MRTlast=AUMClast/AUClast
Cmax
Maximum observed concentration.
tmax
Time of first occurrence of Cmax.
AUC∞
Area under the concentration-time curve from time 0 to infinity, calculated as 
AUC∞=AUClast+Clast/λz.
λz
Terminal disposition phase rate constant.
t1/2z
Terminal disposition phase half-life, calculated as ln(2)/λz.
CL/F
Apparent clearance after extravascular administration, calculated as Dose/AUC∞after single 
dosing.
AUMC∞
Area under the first moment concentration-time curve from time 0 to infinity, calculated as 
AUMC∞=AUMClast+lqc×tlqc/λz+lqc/λz
2, where tlqc is the time of last quantifiable concentration 
and lqc is the last quantifiable concentration.
MRT∞,ev
Mean residence time after extravascular administration, calculated as AUMC∞/AUC∞.
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration.
9.1.12 Documentation of Subjects Failure
Investigator or sub-investigator must account for all subjects who sign informed consent. If the 
subject discontinues the study before the study drug administration in Period 1, the investigator or 
sub-investigator should complete the eCRF.
The primary reason for subject failure is 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.


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
Sample size sufficient.

Other <specify reason>.
Subject identification numbers assigned to subjects who discontinued the study before the study 
drug administration in Period 1 should not be reused. If the reserve subject participates in the 
study, the same subject identification number of the subject who discontinued the study can be 
used.
9.1.13 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization and are recorded on the eCRF.
9.2
Monitoring Subject Treatment Compliance
Study medication will be administered while subjects are under observation at the study site in 
Period 1 and Period 2. Following each administration of the study drug, appropriate mouth checks
will be performed to ensure that the dose is swallowed and noted in the source document. The date 
and time of each dose will be recorded in the source documents and on the eCRFs. An inventory of 
the study drug supplies dispensed will be performed by the site pharmacist or authorized study 
designee and recorded onto the Drug Accountability Log in the subject’s source document records 
or equivalent.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A.
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening
9.3.1.1
Screening
Subjects will be screened for enrollment between 4 weeks (28 days) and 2 days (the day before 
admission to the study site for Period 1) before the study drug administration in Period 1, after 
obtaining informed consent. Subjects will be screened in accordance with the predefined inclusion 
and exclusion criteria described in Section 7.0.
The investigator or sub-investigator will assess each subject for eligibility for participation in the 
study and inform the subject of the assessment result.
Considering that some of the subjects who are found eligible during screening examinations are 
unable to participate in the study for any reason before the study drug administration (Day 1) in 
Period 1, additional subjects who are found eligible during screening examinations will stand by as 
reserve subjects for Period 1 only. For Period 2, only those subjects who are scheduled to receive 
the study drug will be admitted to the study site on the day before the study drug administration
(Day -1). Subjects who drop out of the study after the study drug administration in Period 1 will 
not be replaced.


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The subjects will undergo the examinations, observations, and assessments specified for screening
(see Appendix A).
9.3.1.2
Admission (Day -1)
The subjects will be admitted to the study site on the day before the study drug administration
(Day -1) in Period 1 and Period 2 and will undergo the specified examinations, observations, and 
assessments (see Appendix A).
9.3.2
Randomization (Day 1)
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized as described in Section 8.2. Subjects will receive 
the study drug of Period 1 at the study site under the supervision of the investigator or designee, as 
described in Section 9.2. The procedure for documenting Subject failure in Period 1 is described in 
Section 9.1.12.
9.3.3
Treatment Phase (Days 1 to 3)
The subjects will undergo the specified examinations, observations, and assessments in Period 1 
and Period 2 (see Appendix A).
9.3.4
Day of Discharge (Day 3)
The subjects will be discharged from the study site after confirming that the subjects are in good 
health by the specified examinations, observations, and assessments in Period 1 and Period 2 (see 
Appendix A).
9.3.5
Early Termination
The reason for discontinuation must be documented in the source document and eCRF.
When a subject prematurely withdraws from the study after the study drug administration in 
Period 1, he will undergo the examinations, observations, and evaluations scheduled for Day 3 
(day of discharge) as far as possible. The blood samples for plasma drug concentration 
measurement should be collected and analyzed only in the case of early termination within 48 
hours after the study drug administration.
For all subjects receiving the study drug, the investigator must complete the Subject Status eCRF 
page.
9.3.6
Follow-up Examination (Day 6)
The subjects will undergo the specified examinations, observations, and assessments scheduled for 
the follow-up examination in Period 1 and Period 2 (see Appendix A).
For all subjects receiving the study drug, the investigator must complete the Subject Status eCRF 
page.


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9.4
Blood Sampling Volume and Frequency
Total blood sampling volume for an individual subject are shown in Table 9.c.
Table 9.c
Approximate Blood Volume
Sample Type
Volume/Sample
Number of
Samples
Total Volume
Screening (clinical laboratory tests, immunology tests)
19 mL
1
19 mL
Clinical laboratory tests (hematology, serum chemistry)
9 mL
8
72 mL
Plasma drug concentration (TAK-536)
3 mL
32
96 mL
Total
187 mL


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


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Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as AEs. The first examination 
after the informed consent (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as 
AEs unless related to study procedures. However, if the subject experiences a worsening or 
complication of such a concurrent medical condition after informed consent is signed, the 
worsening should be recorded appropriately as an AE. 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 concurrent medical condition (eg, asthma, epilepsy) any 
occurrence of an episode should only be captured as an AE if the condition becomes more 
frequent, serious or severe in nature. The investigator or sub-investigator should ensure that the 
AE term recorded captures the change in the condition from Baseline (eg “worsening of…”).

If a subject has a pre-existing degenerative concurrent medical condition (eg, cataracts, 
rheumatoid arthritis), worsening of the condition should only be recorded as an AE if occurring 
to a greater extent to that which would be expected. The investigator or 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 starting administration of 
the study drug, the worsening should be recorded as a new AE. The investigator or 
sub-investigator should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).

If the subject experiences a worsening of an AE after any change in study drug, the worsening 
or complication should be recorded as a new AE. The investigator or sub-investigator should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences changes in severity of an AE that are not related to starting the study 
drug or changing in the dose or regimen, the event should be captured once with the maximum 
severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be recorded as an AE. Complications resulting from any planned surgery 
should be reported as AEs.


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Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition
(surgeries or therapies) 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:

Cases of overdose with any medication without manifested side effects are NOT considered 
AEs, but instead will be documented on an Overdose page of the eCRF. Any manifested side 
effects will be considered AEs and will be recorded on the AE page of the eCRF.
10.1.3 SAEs
An SAE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death if it 
were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life threatening or 
fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List (Table 
10.a).


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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure (including seizure and epilepsy)
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis (including interstitial lung disease)
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by 
a medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements.
10.1.4 Severity of AEs
The different categories of severity are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.5 Causality of AEs to Study Drugs
The causality of each AE to study drugs will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which 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 medications and concurrent 
treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant medications and concurrent treatments.
10.1.6 Relationship 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.


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10.1.7 Start Date
The start date of AEs will be determined in the following criteria;
AEs
Start Date
Any signs/symptoms/diseases 
(diagnosis)
The date that the first signs/symptoms/diseases were noted by the subject 
and/or the investigator or sub-investigator should be recorded.
Asymptomatic diseases
The date when examination was performed for diagnosis and diagnosis was 
confirmed should be recorded.
The date when diagnosis was confirmed should also be recorded even when 
values or findings showed old values or findings or the onset time can be
estimated.
Worsening or complication of 
concurrent medical conditions or any 
signs/symptoms/diseases before 
treatment from signing of informed 
consent
The date that a worsening or complication of the condition was noted first by 
the subject and/or the investigator or sub-investigator should be recorded.
Laboratory values that showed 
normal in the first examination after
signing of informed consent or the 
examination right before the start of 
the study drug showed abnormal in 
the subsequent test.
The date of examination when an abnormal value or findings that was judged 
to be clinically significant was noted should be recorded.
The first examination after signing of 
informed consent or the examination 
right before the start of the study drug 
showed abnormal values/findings 
and the subsequent examinations 
showed worsening of the symptoms.
The date of examination when apparent elevation, reduction, increase or 
decrease was confirmed in judgment according to the trends in those values or 
findings should be recorded.
10.1.8 End Date
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.9 Pattern of Adverse Event
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.1.10 Action Taken with Study Drug
The action taken with the study drug should be defined using the following categories:

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.


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
Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE, the AE that occurred before the study drug administration.
10.1.11 Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE with the condition remaining “recovering/resolving”.

Not recovered/Not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved”.

Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs which are considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 AE Collection Period
Collection of AEs will commence from the time the subject signs the informed consent. Routine 
collection of AEs will continue until the follow-up examination.
10.2.1.2 AE Reporting
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 a serious AE that occurs prior to the first exposure to study drug must be monitored 
until the symptoms subside and any clinically relevant changes in laboratory values have returned 
to baseline or there is a satisfactory explanation for the change. Non-serious AEs that occur prior to 
the first exposure to study drug, related or unrelated to the study procedure, need not to be 
followed-up for the purposes of the protocol.


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All subjects experiencing AEs after the first exposure to study drug, whether considered associated 
with the use of the study drug or not, must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or until there is a 
satisfactory explanation for the changes observed. All AEs will be documented in the AE page of 
the eCRF, whether or not the investigator concludes that the event is related to the drug treatment. 
The following information will be documented for each event:
1. Event term.
2. Start and end date and time.
3. Pattern.
4. Severity.
5. Investigator’s or sub-investigator’s opinion of the causality between the event and 
administration of study drug(s) (related or not related).
6. Investigator’s or sub-investigator’s opinion of the causality to study procedure(s), including 
the details of the suspected procedure.
7. Action taken with study drug (not applicable for the AE that occurred before the study drug 
administration).
8. Outcome of event.
9. Seriousness.
10. Timing of occurrence (after administration of study drug)
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
An SAE should be reported by the investigator or sub-investigator to the sponsor (see Annex) 
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.


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10.2.3 Reporting of Abnormal Liver Function Tests
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified after the study drug administration in Period 1, the 
event (treatment-emergent only) should be recorded as an SAE and reported as per Section 10.2.2. 
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 9.1.8 must also be performed.
10.3
Follow-up of SAEs
If information 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 other 
written documentation and submit it to the sponsor. Copies of any relevant data from the hospital 
notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event.
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, 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 to the regulatory authorities as 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events, unless otherwise required by national regulations. The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of the study drug/sponsor supplied drug or that would be sufficient to consider changes 
in the administration of the study drug/sponsor supplied drug or in the overall conduct of the trial. 
The study site also will forward a copy of all expedited reports to his or her IRB.


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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history including concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary.
12.1
Case Report Forms (Electronic)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor and regulatory authorities. 
eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
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.
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 directly into the eCRFs.

Laboratory results

Measurement results of drug concentrations
After the lock of the study database, any change of, modification of or addition to the data on 
eCRFs should be made by the investigator or sub-investigator with use of change and modification 
records of eCRFs (Data Clarification Form) provided by the sponsor.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator and the head of the study site agree to keep the records stipulated in Section 12.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, source worksheets, all original 
signed and dated informed consent forms, electronic copy of eCRFs, including the audit trail, 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 


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essential relevant documents until the day specified as 1) or 2) below, whichever comes later. 
However, if the sponsor requests a longer time period for retention, the head of the study site 
should discuss how long and how to retain those documents with the sponsor.
1. The day on which marketing approval of the study drug is obtained (or the day 3 years after the 
date of notification in the case that the investigation is discontinued).
2. The day 3 years after the date of early termination or completion of the study.
In addition, the investigator and the head of the study site should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
The statistical analysis plan (SAP) will be prepared and finalized prior to the database lock for 
interim analysis. This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address study objectives.
13.1.1 Analysis Sets
In this study, two kinds of analysis sets are defined: pharmacokinetic analysis set and safety 
analysis set. The pharmacokinetic 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 pharmacokinetics.” The safety analysis set is defined as “all 
subjects who received the study drug.”
13.1.2 Analysis of Demographics 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.
13.1.3 Pharmacokinetic Analysis
The following statistical analyses will be performed on the pharmacokinetic analysis set.
1. Plasma drug concentrations
For plasma concentration of TAK-536, descriptive statistics will be provided by visit for each 
formulation (TAK-536 commercial formulation, TAK-536 pediatric formulation). In addition, the 
plasma concentration-time profiles will be also provided.
For pharmacokinetic parameters except AUMClast and AUMC∞, descriptive statistics will be 
provided. For the ratio between each formulation (TAK-536 pediatric formulation/TAK-536 
commercial formulation) for pharmacokinetic parameters AUC48 and Cmax, descriptive statistics 
will be provided.
2. Assessment of bio-equivalence on pharmacokinetic parameters
The difference in the least square means between formulations (TAK-536 pediatric formulation -
TAK-536 commercial formulation) 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) pharmacokinetic parameters AUC48 and Cmax as dependent 
variable, and formulation, group, and period as independent variables. For log-transformed 
(natural log) pharmacokinetic parameters AUClast, AUC∞, MRT∞,ev,λz, and non-natural log 
tansformed tmax, same analyses will be performed.
3. Methods of data transformation and handling of missing data
Details will be described in the Statistical Analysis Plan.


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4. Significance level, confidence coefficient

Significance level: 5% (one-sided test, assessment of bio-equivalence)
5% (two-sided test, other than assessment of bio-equivalence)

Confidence coefficient: 90% (two-sided, assessment of bio-equivalence)
95% (two-sided, other than assessment of bio-equivalence)
5. Interpretation of bio-equivalence assessment
The bio-equivalence of the formulations (TAK-536 commercial formulation and TAK- 536 
pediatric formulation) will be evaluated according to the criteria set forth in the Guideline for 
Bioequivalence Studies of Generic Products [9]. The formulations will be considered 
bioequivalent if the 90% CIs (two-sided) of the differences in the means of the natural 
log-transformed AUC48 and Cmax of TAK-536 between the TAK-536 commercial formulation and 
the TAK-536 pediatric formulation fall within the range of ln(0.80) – ln(1.25).
When the 90% CIs will not fall within the range of ln(0.80) – ln(1.25) with an add-on subject study, 
the formulations will be considered bioequivalent if the differences in the means of the natural 
log-transformed parameters AUC48 and Cmax of TAK-536 between the TAK-536 commercial 
formulation and the TAK-536 pediatric formulation fall within the range of ln(0.90) – ln(1.11), 
and the results of the dissolution test meet the conditions specified in the Guideline for 
Bioequivalence Studies of Generic Products. However, above provision will be applicable only if 
a combined number of subjects in this study and an add-on subject study is 30 subjects or greater.
13.1.4 Safety Analysis
The following statistical analyses will be performed on the safety analysis set.
1. Adverse events (treatment emergent adverse events)
A treatment emergent adverse event (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 MedDRA dictionary. The frequency distribution will be provided 
using the system organ class and the preferred term for each treatment as follows:

All TEAEs

Drug-related TEAEs

Intensity of TEAEs

Intensity of drug-related TEAEs

TEAEs leading to study drug discontinuation 

Serious TEAEs
2. Laboratory test results, resting 12-lead ECGs, and vital signs (sitting blood pressure, sitting 
pulse [beats per minute], and body temperature), weight


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For continuous variables, the observed values and the changes from baseline will be summarized 
by treatment for each visit using descriptive statistics. Case plots for the observed values will also 
be provided for each treatment.
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.
13.2
Interim Analysis and Criteria for Early Termination
Interim analysis will be conducted due to judgment of necessity of an add-on subject study for the 
bioequivalence for TAK-536 commercial formulation and TAK-536 pediatric formulation.
13.2.1 Timing of Interim Analysis
An interim analysis will be performed after the database lock for the total of 14 subjects (7 per 
sequence).
13.2.2 Statistical Analysis Plan for Interim Analysis
The interim analysis will be the same analysis in 13.1.3 2. The further details are described in the 
SAP finalized prior to the database lock for interim analysis.
13.3
Determination of Sample Size
A total of 14 subjects (7 per sequence)
In case an add-on subject study is conducted, the maximum number of subjects will be 120 (60 per 
sequence).
[Rationale for the sample size]
Based on the currently available results of the studies conducted to date, the residual sum of 
squares of pharmacokinetic parameters Cmax and AUC48 in the present study was assumed to be
0.13 and 0.08, respectively. For 6 subjects per sequence (total of 12 subjects per formulation), in
two one-sided t-tests [H0: ln(μ)≤ln(θ1), ln(μ)≥ln(θ2); H1: ln(θ1)<ln(μ)<ln(θ2); where μ=μt/μs, μt was
the population mean for the pediatric formulation, μs was the population mean for the TAK-536 
commercial formulation, θ1=0.80, and θ2=1.25] with a one-sided significance level of 5% and
alternative hypothesis μ=0.95, more than 90% power of simultaneous detection of the 
bio-equivalence for pharmacokinetic parameters Cmax and AUC48. Taking into account possible 
occurence of dropouts during the study and feasibility, 7 subjects per sequence (total of 14 subjects 
per formulation) were set.
In case bio-equivalence cannot be demonstrated with the number of subjects initially planned on 
account of insufficient subjects, an add-on subject study will be conducted in accordance with the 
Guideline for Bioequivalence Studies of Generic Products [9]. The maximum number of subjects 
in the add-on subject study is 120 (60 per sequence), which is determined based on study 
feasibility, but is not on statistical consideration. The number of subjects in the add-on subject 
study will be determined based on the result of the interim analysis in this study and the currently 
available results of the studies conducted to date.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the head of the study site guarantee access to source documents by the 
sponsor or its designee (CRO [contract research organization]) and by the IRB.
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee, including but not limited to the Investigator’s Binder, study drug, subject 
medical records, informed consent documentation, and review of eCRFs and associated source 
documents. It is important that the investigator, sub-investigator and other study personnel are 
available during the monitoring visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator 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 change 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 the IRB should be obtained.
The investigator or sub-investigator should document all protocol deviations.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency [MHRA], 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 the study site 
will guarantee access for quality assurance auditors to all study documents as described in Section 
14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guideline for GCP. Each 
investigator will conduct the study according to applicable local or regional regulatory 
requirements and align his or her conduct in accordance with the “Responsibilities of the 
Investigator” that are listed in Appendix B. The principles of Helsinki are addressed through the 
protocol and through appendices containing requirements for informed consent and investigator 
responsibilities.
15.1
IRB Approval
IRBs must be constituted according to the applicable local requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of members 
who make up the respective IRB. If any member of the IRB has direct participation in this study, 
written notification regarding his or her absence 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
form must be obtained and submitted to the sponsor or designee before commencement of the 
study (ie, before shipment of the sponsor-supplied drug or study specific screening activity). The 
IRB approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, informed consent form) reviewed; and state the approval date. 
The sponsor will notify the site once the sponsor has confirmed the adequacy of site regulatory 
documentation. Until the site receives the 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.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form describe the planned and permitted 


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uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
The informed consent form will detail the requirements of the participant and the fact that he 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.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit the monitor or the sponsor’s designee, representatives 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), 


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including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results, is the sole 
responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator.
The investigator 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.
15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 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.
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to 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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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. J 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]; [184 p.]. Available from:
http://www.j-circ.or.jp/guideline/index.htm.
9. Partial Revision of the Guideline for Bioequivalence Studies of Generic Products, 
Pharmaceutical and Food Safety Bureau Notification No. 0229-10 (February 29, 2012).
10. The Guidance on Clinical Investigation of Medicinal Products in the Pediatric Population, 
Pharmaceutical Safety Bureau Notification No. 1334 (December 15, 2000).
11. Law Enforcement Regulation on Securing a Stable Supply of Safe Blood Products, Ministry of 
Health and Welfare Ordinance No. 22 (June 25, 1956).
12. Japan Society for the Study of Obesity. Diagnostic Criteria for Obesity 2011. Journal of Japan 
Society for the Study of Obesity 2011 (Special Edition).
13. General Considerations for Clinical Trials, Pharmaceutical Safety Bureau Notification No. 380 
(April 21, 1998).
14. 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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Appendix A
Schedule of Study Procedures (Period 1 and Period 2)
Element
Screening
Treatment (a)
Study Day
Day -28 to 
Day -2
(Screening Visit)
Day -1
(Admission)
Day 1
Day 2
Day 3
(Discharge)
Early 
Termination
Day 6 (b)
(Follow-up 
Examination)
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/height (f)
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
Resting 12-lead ECGs (g)
X
X
X
X
X
Laboratory tests (h)
X
X
X
X
X
X
Immunology and urine drug
tests
X
Study drug administration
X
Plasma concentrations(i)
X
X
X
X (j)
AE assessment (k)
X
X
X
X
X
X
X
AE: Adverse event, ECG: Electrocardiogram
(a) A washout period of at least 6 days will be placed between the study drug administrations in Period 1 and Period 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) Inclusion/exclusion criteria will be confirmed at Screening and before the study drug administration in Period 1, 
but will not be confirmed on Day 1 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, and body temperature (axillary) will be 
measured at Screening, predose, 4, 24 and 48 hours postdose, and Day 6.
(f) The subjects are weighed at Screening, predose, 48 hours postdose, and Day 6. Height is measured only at 
screening for calculation of BMI.
(g) The resting 12-lead ECG will be measured at Screening, predose, 48 hours postdose and Day 6.
(h) Laboratory tests include hematology, serum chemistry, and urinalysis. Samples will be collected at Screening, 
predose, 24, 48 hours postdose and Day 6.
(i) Blood samples for PK assessments will be collected at predose (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, 12, 16, 24, and 48 hours postdose.
(j) The blood samples for plasma drug concentration measurement should be collected and analyzed only in the case of 
early termination within 48 hours after the study drug administration.
(k) Collection of AEs will commence from the time the subject signs the informed consent. Routine collection of AEs 
will continue until the follow-up examination in Period 2.


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Acceptable Time Windows for Study Procedures
Safety Tests/Observations (Period 1 and Period 2)
As per the Protocol
Acceptable Time Window
Tests/Observation Item
Designated Time Window
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 sign
(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 ECGs
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
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


TAK-536
Study No. Azilsartan-1004
Page 57 of 58
Protocol First Version
22 Dec 2016
CONFIDENTIAL
Pharmacokinetics Test/Observations (Period 1 and Period 2)
As per the Protocol
Acceptable Time Window
Tests/Observation Item
Designated Time Window
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


TAK-536
Study No. Azilsartan-1004
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CONFIDENTIAL
Appendix B
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 procedures related to the study are delegated to the 
sub-investigator or the study collaborator, prepare the lists of procedures 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 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 treatment on all 
clinically significant adverse events related to the study are provided to subjects throughout 
and beyond the period when subjects participate in the study.
9. If a subject is consulting other medical institution or other department, and the subject agrees, 
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. Prepare correct and complete eCRFs, and submit them to the sponsor with electronic signature.
12. 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.
13. Discuss any proposal from the sponsor including update of the protocol.
14. Notify the head of the study site of the end of the study in writing.


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d68051391c
A Randomized, Open Label, 2-Period, 2-Treatment, Cross-over Phase 1 Study to Evaluate the Bio-equivalence
of Single Oral Dose of TAK-536 Pediatric Formulation and TAK-536 Commercial Formulation in Healthy Adult
Male Subjects
Statistical Approval
27-Dec-2016 05:32 UTC
Clinical Pharmacology Approval
27-Dec-2016 06:06 UTC
Clinical VP Approval
27-Dec-2016 06:36 UTC

SAP_001.pdf: 
Certain information within this clinical study report has been redacted (ie, specific content is masked 
irreversibly from view with a black 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 and the language in original document was Japanese.


1.0 
TITLE PAGE 
 
STATISTICAL ANALYSIS PLAN 
Final Analysis 
STUDY NUMBER: Azilsartan-1004 
A Randomized, Open Label, 2-Period, 2-Treatment, Cross-over Phase 1 Study to 
Evaluate the Bio-equivalence of Single Oral Dose of TAK-536 Pediatric Formulation 
and TAK-536 Commercial Formulation in Healthy Adult Male Subjects 
 
A Phase 1, Bio-equivalence Study of TAK-536 Pediatric Formulation 
 
PHASE 1 
Version: 1 
Date: 18 May 2017 
 
 
 
 
 
 
 
 
 
 
 
Based on: 
Protocol Version: Original (First Version) 
Protocol Date: 22 December 2016 
 
 
CONFIDENTIAL PROPERTY OF TAKEDA 


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


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1.1 
Approval Signatures 
Study Title: 
A Randomized, Open Label, 2-Period, 2-Treatment, Cross-over Phase 1 
Study to Evaluate the Bio-equivalence of Single Oral Dose of TAK-536 
Pediatric Formulation and TAK-536 Commercial Formulation in Healthy 
Adult Male Subjects 
A Phase 1, Bio-equivalence Study of TAK-536 Pediatric Formulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.0 
TABLE OF CONTENTS 
 
1.0 
TITLE PAGE .......................................................................................................................1 
1.1 
Approval Signatures.......................................................................................................3 
2.0 
TABLE OF CONTENTS .....................................................................................................4 
List of In-Text Tables ................................................................................................................5 
List of In-Text Figures ...............................................................................................................5 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................6 
4.0 
OBJECTIVES ......................................................................................................................7 
4.1 
Primary Objectives.........................................................................................................7 
4.2 
Secondary Objectives.....................................................................................................7 
4.3 
Additional Objectives ....................................................................................................7 
4.4 
Study Design ..................................................................................................................7 
5.0 
ANALYSIS ENDPOINTS ................................................................................................10 
5.1.1 
Primary Endpoints .................................................................................................10 
5.1.2 
Secondary Endpoints .............................................................................................10 
6.0 
DETERMINATION OF SAMPLE SIZE ..........................................................................11 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .....................................................12 
7.1 
General Principles ........................................................................................................12 
7.1.1 
Study Definitions ...................................................................................................12 
7.1.2 
Definition of Study Days .......................................................................................12 
7.1.3 
Definition of Study Visit Windows .......................................................................12 
7.2 
Analysis Sets ................................................................................................................13 
7.3 
Disposition of Subjects ................................................................................................16 
7.3.1 
Study Information ..................................................................................................16 
7.3.2 
Subject Eligibility ..................................................................................................16 
7.3.3 
Disposition of Subjects ..........................................................................................16 
7.3.4 
Protocol Deviations and Analysis Sets ..................................................................17 
7.4 
Demographic and Other Baseline Characteristics .......................................................17 
7.5 
Medical History and Concurrent Medical Conditions .................................................18 
7.6 
Medication History and Concomitant Medications .....................................................18 
7.7 
Study Drug Exposure and Compliance ........................................................................18 
7.8 
Efficacy Analysis .........................................................................................................18 
7.8.1 
Primary Efficacy Endpoint ....................................................................................18 
7.8.2 
Secondary Efficacy Endpoint ................................................................................18 
7.8.3 
Additional Efficacy Endpoint ................................................................................19 
7.8.4 
Statistical/Analytical Issues ...................................................................................19 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................21 
7.9.1 
Pharmacokinetic Analysis ......................................................................................21 


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7.9.2 
Pharmacodynamic Analysis ...................................................................................24 
7.10 
Other Outcomes ...........................................................................................................24 
7.11 
Safety Analysis ............................................................................................................25 
7.11.1 Adverse Events ......................................................................................................25 
7.11.2 Clinical Laboratory Evaluations ............................................................................27 
7.11.3 Vital Signs and Weight ..........................................................................................28 
7.11.4 12-Lead ECGs ........................................................................................................29 
7.11.5 Other Observations Related to Safety ....................................................................29 
7.12 
Interim Analysis ...........................................................................................................29 
7.13 
Changes in the Statistical Analysis Plan ......................................................................29 
8.0 
REFERENCES ..................................................................................................................30 
 
LIST OF IN-TEXT TABLES 
Table 7.a  Visit Window ................................................................................................................13 
 
LIST OF IN-TEXT FIGURES 
Table 4.a  Dosage and Number of Subjects .....................................................................................8 
Figure 4.b  Schematic of Study Design (Period 1 and Period 2) .....................................................9 
 


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3.0 
LIST OF ABBREVIATIONS 
ACE 
angiotensin converting enzyme 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
ARB 
angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CI 
confidence interval 
CKD 
chronic kidney disease 
ECG 
electrocardiogram 
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 
IRB 
institutional review board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
OTC 
over-the-counter 
PMDA 
Pharmaceuticals and Medical Devices Agency 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse event 
TPC 
Takeda Pharmaceutical Company Limited 
ULN 
upper limits of normal 


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4.0 
OBJECTIVES 
4.1 
Primary Objectives 
To evaluate the bio-equivalence of a single oral administration of TAK-536 pediatric 
formulation in comparison with a TAK-536 commercial formulation in Japanese healthy 
adult male subjects. 
 
4.2 
Secondary Objectives 
To evaluate 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 
1. Study Design 
This study is conducted to evaluate the bio-equivalence of a single oral administration of 
TAK-536 pediatric formulation (granules) in comparison with a TAK-536 commercial 
formulation in healthy adult male subjects in an open label, 2-period, 2-treatment, cross-over 
design. 
In case bio-equivalence is not demonstrated because the planned number of subjects is too 
small, an add-on subject study will be performed. 
2. Sample size 
A total of 14 subjects (7 for each sequence) will be enrolled in this study. 
In case an add-on subject study is conducted, the maximum number of subjects will be 120 
(60 per sequence). 
3. Dose and mode of administration 
The dosage and number of subjects are presented in Table 4.a. Each subject will receive 
either TAK-536 commercial formulation (tablet) or TAK-536 pediatric formulation 
(granules) in each period under the conditions described below. 
1) TAK-536 commercial formulation (TAK-536 10 mg tablet) 
The subject will orally receive one TAK-536 10 mg tablet with 200 mL water under fasted 
conditions in the morning (fasted for more than 10 hours after the last meal on the day before 
the study drug administration [Day 1]). 
2) TAK-536 pediatric formulation (TAK-536 granules) 


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The subject will orally receive one sachet of TAK-536 granules containing 10 mg TAK-536 
with 200 mL water under fasted conditions in the morning (fasted for more than 10 hours 
after the last meal on the day before the study drug administration [Day 1]). 
Table 4.a  Dosage and Number of Subjects 
 
4. Planned number of study sites 
One study site 
5. Planned duration of subject participation and number of visits of each subject in the study 
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 from the 
day before the study drug administration (Day -1) and observations during their 
hospitalization according to the study schedule specified in Appendix A (protocol), 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. 
A washout period of at least 6 days 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. 
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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A schematic of the study design is included as Figure 4.b. A schedule of assessments is listed 
in Appendix A (protocol).  
 
 
Figure 4.b  Schematic of Study Design (Period 1 and Period 2) 


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5.0 
ANALYSIS ENDPOINTS 
5.1.1 Primary Endpoints 
Pharmacokinetics: AUC48 and Cmax of TAK-536. 
 
5.1.2 Secondary Endpoints 
Pharmacokinetics: AUC∞, tmax, MRT, and λz. 
Safety: adverse events (AEs), vital signs (sitting blood pressure, sitting pulse, and body 
temperature), weight, resting 12-lead electrocardiograms (ECGs), and laboratory test 
results (hematology, serum chemistry, and urinalysis). 
 


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6.0 
DETERMINATION OF SAMPLE SIZE 
A total of 14 subjects (7 per sequence) 
In case an add-on subject study is conducted, the maximum number of subjects will be 120 
(60 per sequence). 
[Rationale for the sample size] 
Based on the currently available results of the studies conducted to date, the residual sum of 
squares of pharmacokinetic parameters Cmax and AUC48 in the present study was assumed to 
be 0.13 and 0.08, respectively. For 6 subjects per sequence (total of 12 subjects per 
formulation), in two one-sided t-tests [H0: ln(μ)≤ln(θ1), ln(μ)≥ln(θ2); H1: ln(θ1)<ln(μ)<ln(θ2); 
where μ=μt/μs, μt was the population mean for the pediatric formulationμs was the population 
mean for the TAK-536 commercial formulation, θ1=0.80, and θ2=1.25] with a one-sided 
significance level of 5% and alternative hypothesis μ=0.95, more than 90% power of 
simultaneous detection of the bio-equivalence for pharmacokinetic parameters Cmax and 
AUC48. Taking into account possible occurence of dropouts during the study and feasibility, 
7 subjects per sequence (total of 14 subjects per formulation) were set. 
In case bio-equivalence cannot be demonstrated with the number of subjects initially planned 
on account of insufficient subjects, an add-on subject study will be conducted in accordance 
with the Guideline for Bioequivalence Studies of Generic Products [1]. The maximum 
number of subjects in the add-on subject study is 120 (60 per sequence), which is determined 
based on study feasibility, but is not on statistical consideration. The number of subjects in 
the add-on subject study will be determined based on the result of the interim analysis in this 
study and the currently available results of the studies conducted to date. 


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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 
 
Formulations: 
- 
TAK-536 commercial formulation 
- 
TAK-536 pediatric formulation 
 
Treatment group: 
- 
a (TAK-536 pediatric formulation→TAK-536 commercial formulation) 
- 
b (TAK-536 commercial formulation→TAK-536 pediatric formulation) 
 
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 fasted conditions in the morning (fasted for more than 
10 hours before the study drug administration) 
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 “Prohibited Medications, 
Supplements, Dietary Products or Food Products” of the 
protocol’s 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 


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Subjects who consumed beverages other than water (200 mL) 
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 “Prohibited 
Medications, Supplements, Dietary Products or Food Products” of 
the protocol’s 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.  In case an add-on subject study 
was conducted, the analysis will be performed for the study which 
was conducted with the originally planned number of subjects and 
for each add-on study.  
(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. 
 


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7.8.3 Additional Efficacy Endpoint 
Not applicable in this study. 
 
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 
The bioequivalence of the formulations (TAK-536 commercial formulation and TAK- 536 
pediatric formulation) will be evaluated according to the criteria set forth in the Guideline for 
Bioequivalence Studies of Generic Products [1]. The formulations will be considered 
bioequivalent if the 90% CIs (two-sided) of the differences in the means of the natural log-
transformed AUC48 and Cmax of TAK-536 between the TAK-536 commercial formulation 
and the TAK-536 pediatric formulation fall within the range of ln(0.80) – ln(1.25). 
When the 90% CIs do not fall within the range of ln(0.80) – ln(1.25) with an add-on subject 
study, the formulations will be considered bioequivalent if the differences in the means of the 
natural log-transformed parameters AUC48 and Cmax of TAK-536 between the TAK-536 
commercial formulation and the TAK-536 pediatric formulation fall within the range of 


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ln(0.90) – ln(1.11), and the results of the dissolution test meet the conditions specified in the 
Guideline for Bioequivalence Studies of Generic Products. However, the above provision 
will be applicable only if the combined number of subjects in this study and an add-on 
subject study is 30 subjects or greater. 
 
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 formulation by 
visit.  
 
(2) 
Mean and standard deviation will be plotted simultaneously for 
both formulations (vertical axis: normal scale). 
 
(3) 
Mean will be plotted simultaneously for both formulations 
(vertical axis: common logarithmic scale). 
 
7.9.1.2 Pharmacokinetic Parameters 
Analysis Set: 
PK Analysis Set 
Analysis Variable(s): 
Pharmacokinetic Parameters of TAK-536 
 
AUC48 
AUClast 
Cmax 
 
AUCinf 
MRTlast,ev 
tmax 
 
Lambda z 
t1/2z 
CL/F 
 
Vz/F 
MRTinf,ev 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables by formulation. 
 
(1) 
Summary of Pharmacokinetic Parameters 
 
For AUC48, AUClast, Cmax, 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 Treatment Ratio in Pharmacokinetic Parameters 
Analysis Set: 
PK Analysis Set 
Analysis Variable(s): 
Treatment Ratio of (TAK-536 commercial formulation/TAK-536 
pediatric formulation) in AUC48 and Cmax of TAK-536 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. 
 
(1) 
Descriptive statistics will be provided for treatment ratio of 
pharmacokinetic parameters.  
 


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7.9.1.4 Assessment of Bioequivalence 
Primary Endpoints 
Analysis Set: 
PK Analysis Set 
Analysis Variable(s): 
Pharmacokinetic Parameters of TAK-536 
 
AUC48 
Cmax 
 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. In case an add-on subject study was conducted, the 
analysis will be performed for the study which was conducted with 
the originally planned number of subjects and for each add-on study.  
 
(1) 
The difference in the least square means between formulations 
(TAK-536 pediatric formulation – TAK-536 commercial 
formulation) 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 as dependent variable, and formulation, treatment 
group, and period as independent variables. 
 
Secondary Endpoints 
Analysis Set: 
PK Analysis Set 
Analysis Variable(s): 
Pharmacokinetic Parameters of TAK-536 
 
AUClast 
AUCinf 
MRTinf,ev 
 
Lambda z 
tmax 
 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. 
 
(1) 
The difference in the least square means between formulations 
(TAK-536 pediatric formulation - TAK-536 commercial 
formulation) 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 dependent variable, and 
formulation, treatment group, and period as independent 
variables. 
 
(2) 
The difference in the least square means between formulations 
(TAK-536 pediatric formulation – TAK-536 commercial 
formulation) 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 
dependent variable, and formulation, treatment group, and 
period as independent variables. 
 
7.9.1.5 Individual Plasma Concentrations 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variable(s): 
Plasma Concentrations of TAK-536 


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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 formulations (vertical axis: normal 
scale). 
 
7.9.1.6 Subject Data Listings for Pharmacokinetic Parameters 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variable(s): 
Pharmacokinetic Parameters of TAK-536 
 
AUC48 
AUClast 
MRTlast,ev 
 
Cmax 
tmax 
AUCinf  
 
Lambda z 
 
 
 
Measuring points of estimating Lambda z (start point, end point, 
and number of points) and adjusted R-squared contribution rate 
 
t1/2z 
CL/F 
Vz/F 
 
MRTinf,ev 
 
 
Analysis Method(s): 
Subject data listings including the following variables will be 
displayed.  
 
(1) 
Subject ID, subject number, treatment group, dose, and timing 
 
7.9.1.7 Subject Data Listings for Treatment Ratio in Pharmacokinetic Parameters 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variable(s): 
Treatment Ratio of (TAK-536 commercial formulation/TAK-536 
pediatric formulation) in AUC48 and Cmax of TAK-536 
Analysis Method(s): 
Subject data listings including the following variables will be 
displayed.  
 
(1) 
Subject ID, subject number, and treatment group 
 
 
 


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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 formulation. 
 
(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 that formulation 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 formulation. 
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 that formulation 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 that formulation 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. 
PTEs will be coded using the MedDRA and will be summarized 


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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 formulation. 
 
(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 


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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 
formulation.  
For each variable other than specific gravity, summaries (3) will be 
provided. 
 
(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(armpit) 
 
 
Sitting Systolic Blood Pressure 
 
 
Sitting Diastolic Blood Pressure 
 
 
Sitting Pulse Rate 
 
 
Weight 
 
Visit: 
Body Temperature (armpit), 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 
variables by formulation. 


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(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 formulation.  
For 12-lead ECG, summaries (3) will be provided by formulation.  
 
(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 
An interim analysis will be conducted due an add-on subject study for the bioequivalence for 
TAK-536 commercial formulation and TAK-536 pediatric formulation. 
 
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 
1. Partial Revision of the Guideline for Bioequivalence Studies of Generic Products, 
Pharmaceutical and Food Safety Bureau Notification No. 0229-10 (February 29, 2012). 
 


1.0 
TITLE PAGE 
 
STATISTICAL ANALYSIS PLAN 
Interim Analysis 
STUDY NUMBER: Azilsartan-1004 
A Randomized, Open Label, 2-Period, 2-Treatment, Cross-over Phase 1 Study to 
Evaluate the Bio-equivalence of Single Oral Dose of TAK-536 Pediatric Formulation 
and TAK-536 Commercial Formulation in Healthy Adult Male Subjects 
 
A Phase 1, Bio-equivalence Study of TAK-536 Pediatric Formulation 
 
PHASE 1 
Version: 1 
Date: 18 May 2017 
 
 
 
 
 
 
 
 
 
 
 
Based on: 
Protocol Version: Original (First Version) 
Protocol Date: 22 December 2016 
 
 
CONFIDENTIAL PROPERTY OF TAKEDA 


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


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1.1 
Approval Signatures 
Study Title: 
A Randomized, Open Label, 2-Period, 2-Treatment, Cross-over Phase 1 
Study to Evaluate the Bio-equivalence of Single Oral Dose of TAK-536 
Pediatric Formulation and TAK-536 Commercial Formulation in Healthy 
Adult Male Subjects 
A Phase 1, Bio-equivalence Study of TAK-536 Pediatric Formulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.0 
TABLE OF CONTENTS 
 
1.0 
TITLE PAGE .......................................................................................................................1 
1.1 
Approval Signatures.......................................................................................................3 
2.0 
TABLE OF CONTENTS .....................................................................................................4 
List of In-Text Tables ................................................................................................................5 
List of In-Text Figures ...............................................................................................................5 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................6 
4.0 
OBJECTIVES ......................................................................................................................7 
4.1 
Primary Objectives.........................................................................................................7 
4.2 
Secondary Objectives.....................................................................................................7 
4.3 
Additional Objectives ....................................................................................................7 
4.4 
Study Design ..................................................................................................................7 
5.0 
ANALYSIS ENDPOINTS ................................................................................................10 
5.1.1 
Primary Endpoints .................................................................................................10 
5.1.2 
Secondary Endpoints .............................................................................................10 
6.0 
DETERMINATION OF SAMPLE SIZE ..........................................................................11 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .....................................................12 
7.1 
General Principles ........................................................................................................12 
7.1.1 
Study Definitions ...................................................................................................12 
7.1.2 
Definition of Study Days .......................................................................................12 
7.1.3 
Definition of Study Visit Windows .......................................................................12 
7.2 
Analysis Sets ................................................................................................................13 
7.3 
Disposition of Subjects ................................................................................................16 
7.3.1 
Study Information ..................................................................................................16 
7.3.2 
Subject Eligibility ..................................................................................................16 
7.3.3 
Disposition of Subjects ..........................................................................................16 
7.3.4 
Protocol Deviations and Analysis Sets ..................................................................17 
7.4 
Demographic and Other Baseline Characteristics .......................................................17 
7.5 
Medical History and Concurrent Medical Conditions .................................................18 
7.6 
Medication History and Concomitant Medications .....................................................18 
7.7 
Study Drug Exposure and Compliance ........................................................................18 
7.8 
Efficacy Analysis .........................................................................................................18 
7.8.1 
Primary Efficacy Endpoint ....................................................................................18 
7.8.2 
Secondary Efficacy Endpoint ................................................................................18 
7.8.3 
Additional Efficacy Endpoint ................................................................................18 
7.8.4 
Statistical/Analytical Issues ...................................................................................19 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................21 
7.9.1 
Pharmacokinetic Analysis ......................................................................................21 


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7.9.2 
Pharmacodynamic Analysis ...................................................................................24 
7.10 
Other Outcomes ...........................................................................................................24 
7.11 
Safety Analysis ............................................................................................................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 ................................................................................................................13 
 
LIST OF IN-TEXT FIGURES 
Table 4.a  Dosage and Number of Subjects .....................................................................................8 
Figure 4.b  Schematic of Study Design (Period 1 and Period 2) .....................................................9 
 
 


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3.0 
LIST OF ABBREVIATIONS 
ACE 
angiotensin converting enzyme 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
ARB 
angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CI 
confidence interval 
CKD 
chronic kidney disease 
ECG 
electrocardiogram 
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 
IRB 
institutional review board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
OTC 
over-the-counter 
PMDA 
Pharmaceuticals and Medical Devices Agency 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse event 
TPC 
Takeda Pharmaceutical Company Limited 
ULN 
upper limits of normal 


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4.0 
OBJECTIVES 
4.1 
Primary Objectives 
To evaluate the bio-equivalence of a single oral administration of TAK-536 pediatric 
formulation in comparison with a TAK-536 commercial formulation in Japanese healthy 
adult male subjects. 
 
4.2 
Secondary Objectives 
To evaluate 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 
1. Study Design 
This study is conducted to evaluate the bio-equivalence of a single oral administration of 
TAK-536 pediatric formulation (granules) in comparison with a TAK-536 commercial 
formulation in healthy adult male subjects in an open label, 2-period, 2-treatment, cross-over 
design. 
In case bio-equivalence is not demonstrated because the planned number of subjects is too 
small, an add-on subject study will be performed. 
2. Sample size 
A total of 14 subjects (7 for each sequence) will be enrolled in this study. 
In case an add-on subject study is conducted, the maximum number of subjects will be 120 
(60 per sequence). 
3. Dose and mode of administration 
The dosage and number of subjects are presented in Table 4.a. Each subject will receive 
either TAK-536 commercial formulation (tablet) or TAK-536 pediatric formulation 
(granules) in each period under the conditions described below. 
1) TAK-536 commercial formulation (TAK-536 10 mg tablet) 
The subject will orally receive one TAK-536 10 mg tablet with 200 mL water under fasted 
conditions in the morning (fasted for more than 10 hours after the last meal on the day before 
the study drug administration [Day 1]). 
2) TAK-536 pediatric formulation (TAK-536 granules) 


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The subject will orally receive one sachet of TAK-536 granules containing 10 mg TAK-536 
with 200 mL water under fasted conditions in the morning (fasted for more than 10 hours 
after the last meal on the day before the study drug administration [Day 1]). 
Table 4.a  Dosage and Number of Subjects 
 
4. Planned number of study sites 
One study site 
5. Planned duration of subject participation and number of visits of each subject in the study 
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 from the 
day before the study drug administration (Day -1) and observations during their 
hospitalization according to the study schedule specified in Appendix A (protocol), 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. 
A washout period of at least 6 days 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. 
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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A schematic of the study design is included as Figure 4.b. A schedule of assessments is listed 
in Appendix A (protocol).  
 
 
Figure 4.b  Schematic of Study Design (Period 1 and Period 2) 


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5.0 
ANALYSIS ENDPOINTS 
5.1.1 Primary Endpoints 
Pharmacokinetics: AUC48 and Cmax of TAK-536. 
 
5.1.2 Secondary Endpoints 
Pharmacokinetics: AUC∞, tmax, MRT, and λz. 
Safety: adverse events (AEs), vital signs (sitting blood pressure, sitting pulse, and body 
temperature), weight, resting 12-lead electrocardiograms (ECGs), and laboratory test 
results (hematology, serum chemistry, and urinalysis). 
 


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6.0 
DETERMINATION OF SAMPLE SIZE 
A total of 14 subjects (7 per sequence) 
In case an add-on subject study is conducted, the maximum number of subjects will be 120 
(60 per sequence). 
[Rationale for the sample size] 
Based on the currently available results of the studies conducted to date, the residual sum of 
squares of pharmacokinetic parameters Cmax and AUC48 in the present study was assumed to 
be 0.13 and 0.08, respectively. For 6 subjects per sequence (total of 12 subjects per 
formulation), in two one-sided t-tests [H0: ln(μ)≤ln(θ1), ln(μ)≥ln(θ2); H1: ln(θ1)<ln(μ)<ln(θ2); 
where μ=μt/μs, μt was the population mean for the pediatric formulation, μs was the 
population mean for the TAK-536 commercial formulation, θ1=0.80, and θ2=1.25] with a 
one-sided significance level of 5% and alternative hypothesis μ=0.95, more than 90% power 
of simultaneous detection of the bio-equivalence for pharmacokinetic parameters Cmax and 
AUC48. Taking into account possible occurence of dropouts during the study and feasibility, 
7 subjects per sequence (total of 14 subjects per formulation) were set. 
In case bio-equivalence cannot be demonstrated with the number of subjects initially planned 
on account of insufficient subjects, an add-on subject study will be conducted in accordance 
with the Guideline for Bioequivalence Studies of Generic Products [1]. The maximum 
number of subjects in the add-on subject study is 120 (60 per sequence), which is determined 
based on study feasibility, but is not on statistical consideration. The number of subjects in 
the add-on subject study will be determined based on the result of the interim analysis in this 
study and the currently available results of the studies conducted to date. 


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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
7.1.1 Study Definitions 
 
Descriptive statistics: Number of subjects, mean, standard deviation, maximum, 
minimum, and quartiles 
 
Coefficient of variation (CV)(%): Standard deviation / Mean x 100 
 
Formulations: 
- 
TAK-536 commercial formulation 
- 
TAK-536 pediatric formulation 
 
Treatment group: 
- 
a (TAK-536 pediatric formulation→TAK-536 commercial formulation) 
- 
b (TAK-536 commercial formulation→TAK-536 pediatric formulation) 
 
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).  
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.  
 


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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 
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) 


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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 fasted conditions in the morning (fasted for more than 
10 hours before the study drug administration) 
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 “Prohibited Medications, 
Supplements, Dietary Products or Food Products” of the 
protocol’s 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 water (200 mL) 
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 “Prohibited 
Medications, Supplements, Dietary Products or Food Products” of 
the protocol’s section 7.3 within the given time 
Matters concerning smoking 
Subjects who smoked during hospitalization 
Matters concerning body position 


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Subjects who took a supine position for 4 hours after the study 
drug administration, unless it was required for examination.  
 
 


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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 
 
 
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: 
PK Analysis Set 
Analysis Variable(s): 
Age (years) 
 
 
Height (cm) 
 
 
Weight (kg) (prior to 
administration in Period 1) 
 


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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 
The bioequivalence of the formulations (TAK-536 commercial formulation and TAK- 536 
pediatric formulation) will be evaluated according to the criteria set forth in the Guideline for 
Bioequivalence Studies of Generic Products [1]. The formulations will be considered 
bioequivalent if the 90% CIs (two-sided) of the differences in the means of the natural log-
transformed AUC48 and Cmax of TAK-536 between the TAK-536 commercial formulation 
and the TAK-536 pediatric formulation fall within the range of ln(0.80) – ln(1.25). 
When the 90% CIs do not fall within the range of ln(0.80) – ln(1.25) with an add-on subject 
study, the formulations will be considered bioequivalent if the differences in the means of the 
natural log-transformed parameters AUC48 and Cmax of TAK-536 between the TAK-536 
commercial formulation and the TAK-536 pediatric formulation fall within the range of 
ln(0.90) – ln(1.11), and the results of the dissolution test meet the conditions specified in the 
Guideline for Bioequivalence Studies of Generic Products. However, the above provision 
will be applicable only if the combined number of subjects in this study and an add-on 
subject study is 30 subjects or greater. 


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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 formulation by 
visit.  
 
(2) 
Mean and standard deviation will be plotted simultaneously for 
both formulations (vertical axis: normal scale). 
 
(3) 
Mean will be plotted simultaneously for both formulations 
(vertical axis: common logarithmic scale). 
 
7.9.1.2 Pharmacokinetic Parameters 
Analysis Set: 
PK Analysis Set 
Analysis Variable(s): 
Pharmacokinetic Parameters of TAK-536 
 
AUC48 
AUClast 
Cmax 
 
AUCinf 
MRTlast,ev 
tmax 
 
Lambda z 
t1/2z 
CL/F 
 
Vz/F 
MRTinf,ev 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables by regimen. 
 
(1) 
Summary of Pharmacokinetic Parameters 
 
For AUC48, AUClast, Cmax, 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 Treatment Ratio in Pharmacokinetic Parameters 
Analysis Set: 
PK Analysis Set 
Analysis Variable(s): 
Treatment Ratio of (TAK-536 commercial formulation/TAK-536 
pediatric formulation) in AUC48 and Cmax of TAK-536 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. 
 
(1) 
Descriptive statistics will be provided for treatment ratio of 
pharmacokinetic parameters.  
 


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7.9.1.4 Assessment of Bioequivalence 
Primary Endpoints 
Analysis Set: 
PK Analysis Set 
Analysis Variable(s): 
Pharmacokinetic Parameters of TAK-536 
 
AUC48 
Cmax 
 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. 
 
(1) 
The difference in the least square means between formulations 
(TAK-536 pediatric formulation – TAK-536 commercial 
formulation) 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 as dependent variable, and formulation, treatment 
group, and period as independent variables. 
 
Secondary Endpoints 
Analysis Set: 
PK Analysis Set 
Analysis Variable(s): 
Pharmacokinetic Parameters of TAK-536 
 
AUClast 
AUCinf 
MRTinf,ev 
 
Lambda z 
tmax 
 
Analysis Method(s): 
The following analysis will be performed for the above analysis 
variables. 
 
(1) 
The difference in the least square means between formulations 
(TAK-536 pediatric formulation - TAK-536 commercial 
formulation) 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 dependent variable, and 
formulation, treatment group, and period as independent 
variables. 
 
(2) 
The difference in the least square means between formulations 
(TAK-536 pediatric formulation – TAK-536 commercial 
formulation) 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 
dependent variable, and formulation, treatment group, and 
period as independent variables. 
 
7.9.1.5 Individual Plasma Concentrations 
Not applicable at the time of interim analysis.  
 


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7.9.1.6 Subject Data Listings for Pharmacokinetic Parameters 
Not applicable at the time of interim analysis.  
 
7.9.1.7 Subject Data Listings for Treatment Ratio in Pharmacokinetic Parameters 
Not applicable at the time of interim analysis.  
 
 
 


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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 
Not applicable at the time of interim analysis.  
 
7.12 
Interim Analysis 
An interim analysis will be conducted due an add-on subject study for the bioequivalence for 
TAK-536 commercial formulation and TAK-536 pediatric formulation. 
 
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 
1. Partial Revision of the Guideline for Bioequivalence Studies of Generic Products, 
Pharmaceutical and Food Safety Bureau Notification No. 0229-10 (February 29, 2012).