Clinical trial NCT03808493
Conditions: Japanese Healthy Adult Male
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2019-01-30; Completion date: 2019-03-12
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the BE of single oral dose of TAK-438 OD 20 milligram (mg) tablet without water and TAK-438 20 mg tablet with water (Study 1), and TAK-438 OD 20 mg tablet with water and TAK-438 20 mg tablet with water (Study 2) in Japanese healthy adult male participants.

Detailed description:
The drug being tested in this study is called TAK-438 OD tablet. TAK-438 OD tablet is being tested in Japanese healthy adult men. This study will evaluate bioequivalence of single oral dose of TAK-438 OD 20 mg tablet without water and TAK-438 20 mg tablet with water (Study 1), and TAK-438 OD 20 mg tablet with water and TAK-438 20 mg tablet with water (Study 2).

The study will enroll up to 144 participants in total (Study 1 + 2). In Study 1 and 2, participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups;

Study 1:

* TAK-438 OD 20 mg tablet without water (Period 1) + TAK-438 20 mg tablet with water (Period 2)
* TAK-438 20 mg tablet with water (Period 1) + TAK-438 OD 20 mg tablet without water (Period 2)

Study 2:

* TAK-438 OD 20 mg tablet with water (Period 1) + TAK-438 20 mg tablet with water (Period 2)
* TAK-438 20 mg tablet with water (Period 1) + TAK-438 OD 20 mg tablet with water (Period 2)

This single-center trial will be conducted in Japan. The overall time to participate in this study is approximately 11 days. Participants will make two visits to the clinic and be hospitalized for four days each in Periods 1 and 2.

Arms: arm 1: One TAK-438 OD 20 mg tablet, orally without water under fasted condition, on Period 1 Day 1 in Study 1 (Day 1), followed by a wash-out period (Days 2 to 8), followed by one TAK-438 20 mg tablet, orally with water under fasted condition, on Period 2 Day 1 in Study 1 (Day 9). arm 2: One TAK-438 20 mg tablet, orally with water under fasted condition, on Period 1 Day 1 in Study 1 (Day 1), followed by a wash-out period (Days 2 to 8), followed by one TAK-438 OD 20 mg tablet, orally without water under fasted condition, on Period 2 Day 1 in Study 1 (Day 9). arm 3: One TAK-438 OD 20 mg tablet, orally with water under fasted condition, on Period 1 Day 1 in Study 2 (Day 1), followed by a wash-out period (Days 2 to 8), followed by one TAK-438 20 mg tablet, orally with water under fasted condition, on Period 2 Day 1 in Study 2 (Day 9). arm 4: One TAK-438 20 mg tablet, orally with water under fasted condition, on Period 1 Day 1 in Study 2 (Day 1), followed by a wash-out period (Days 2 to 8), followed by one TAK-438 OD 20 mg tablet, orally with water under fasted condition, on Period 2 Day 1 in Study 2 (Day 9).
Interventions: intervention 1: TAK-438 OD intervention 2: TAK-438
Intervention descriptions: intervention 1: TAK-438 OD tablet intervention 2: TAK-438 tablet

Protocol documents:
Prot_000.pdf: 
 
 
Title: A Randomized, Open-Label, Single-Dose, 2×2 Crossover Phase 1 Study to Evaluate 
the Bioequivalence of TAK-438 OD (Orally Disintegrating) 20 mg Tablet When 
Administered without Water (Study 1) or with Water (Study 2) and TAK-438 20 mg 
Tablet When Administered with Water in Japanese Healthy Volunteer Male Subjects 
 
NCT Number: NCT03808493 
Protocol Approve Date: 12-DEC-2018 
 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 


CONFIDENTIAL
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Open-Label, Single-Dose, 2×2 Crossover Phase 1 Study to Evaluate the
Bioequivalence of TAK-438 OD (Orally Disintegrating) 20 mg Tablet When Administered
without Water (Study 1) or with Water (Study 2) and TAK-438 20 mg Tablet When
Administered with Water in Japanese Healthy Volunteer Male Subjects
A Phase 1 Bioequivalence Study of TAK-438 OD tablet
Study Identifier:
TAK-438ODT-1001
Compound:
TAK-438ODT
Date:
12 December 2018
Version/Amendment 
Number:
Initial Version
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................6
2.0
STUDY SCHEMATIC..................................................................................................10
3.0
SCHEDULE OF STUDY PROCEDURES (STUDIES 1 AND 2)..................................11
4.0
INTRODUCTION.........................................................................................................13
4.1
Background .............................................................................................................13
4.2
Rationale for the Proposed Study.............................................................................13
4.3
Benefit/Risk Profile .................................................................................................13
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................14
5.1
Hypothesis...............................................................................................................14
5.2
Trial Objectives .......................................................................................................14
5.2.1
Trial Primary Objective......................................................................................14
5.2.2
Trial Secondary Objective..................................................................................14
5.2.3
Safety Objective.................................................................................................14
5.3
Endpoints.................................................................................................................14
5.3.1
Primary Endpoint...............................................................................................14
5.3.2
Secondary Endpoints..........................................................................................14
5.3.3
Safety Endpoints................................................................................................14
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................15
6.1
Trial Design.............................................................................................................15
6.2
Procedures for Proceeding to the Pivotal Study........................................................16
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................17
6.3.1
Rationale of Trial Design ...................................................................................17
6.3.2
Rationale for Dose .............................................................................................18
6.3.3
Rationale for Washout Period.............................................................................18
6.3.4
Rationale for Endpoints......................................................................................18
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures ................18
6.4
Trial Beginning and End/Completion.......................................................................19
6.4.1
Definition of Beginning of the Trial ...................................................................19
6.4.2
Definition of End of the Trial.............................................................................19
6.4.3
Definition of Trial Discontinuation ....................................................................19
6.4.4
Criteria for Premature Termination or Suspension of the Trial............................19
6.4.5
Criteria for Premature Termination or Suspension of the Trial Sites...................20
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............21
7.1
Inclusion Criteria .....................................................................................................21


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7.2
Exclusion Criteria ....................................................................................................21
7.3
Excluded Concomitant Medications, Supplements, Dietary Products .......................23
7.4
Diet, Fluid, Activity.................................................................................................24
7.4.1
Diet and Fluid ....................................................................................................24
7.4.2
Activity..............................................................................................................25
7.5
Documentation of Subjects Failure ..........................................................................25
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................26
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................27
7.8
Subject Replacement................................................................................................27
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................28
8.1
Clinical Study Drug .................................................................................................28
8.1.1
Clinical Study Drug Labeling.............................................................................28
8.1.2
Clinical Study Drug Inventory and Storage ........................................................28
8.1.3
Randomization Code Creation and Storage ........................................................29
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs...............................29
9.0
STUDY PROCEDURES...............................................................................................30
9.1
Administrative Procedures.......................................................................................30
9.1.1
Informed Consent...............................................................................................30
9.1.2
Inclusion and Exclusion Criteria.........................................................................30
9.1.3
Medical History/Demographics..........................................................................30
9.1.4
Concomitant Medications...................................................................................31
9.2
Clinical Procedures and Assessments.......................................................................31
9.2.1
Full Physical Exam ............................................................................................31
9.2.2
Height and Weight .............................................................................................31
9.2.3
BMI ...................................................................................................................31
9.2.4
Vital Signs .........................................................................................................31
9.2.5
12-Lead ECG.....................................................................................................32
9.2.6
Study Drug Administration ................................................................................32
9.2.7
Adverse Event Monitoring .................................................................................32
9.2.8
Laboratory Procedures and Assessments ............................................................32
9.3
PK Samples .............................................................................................................34
9.3.1
PK Measurements..............................................................................................35
9.3.2
Confinement ......................................................................................................36
10.0
ADVERSE EVENTS ....................................................................................................37
10.1
Definitions and Elements of AEs .............................................................................37


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10.1.1 SAEs..................................................................................................................39
10.1.2 Special Interest AEs...........................................................................................40
10.2
AE Procedures.........................................................................................................41
10.2.1 Assigning Severity/Intensity of AEs...................................................................41
10.2.2 Assigning Causality of AEs................................................................................41
10.2.3 Assigning Causality of AEs to Study Procedures................................................42
10.2.4 Start Date...........................................................................................................42
10.2.5 End Date............................................................................................................42
10.2.6 Pattern of Adverse Event (Frequency)................................................................42
10.2.7 Action Taken with Study Treatment...................................................................42
10.2.8 Outcome ............................................................................................................43
10.2.9 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................43
10.2.10
Safety Reporting to Investigators, IRBs, and Regulatory Authorities ............45
11.0
STATISTICAL METHODS..........................................................................................46
11.1
Statistical and Analytical Plans ................................................................................46
11.1.1 Analysis Sets......................................................................................................46
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................46
11.1.3 PK Analysis .......................................................................................................46
11.1.4 Safety Analysis ..................................................................................................47
11.2
Interim Analysis and Criteria for Early Termination ................................................48
11.3
Determination of Sample Size..................................................................................48
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................50
12.1
Study-Site Monitoring Visits ...................................................................................50
12.2
Protocol Deviations..................................................................................................50
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................50
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................51
13.1
IRB Approval ..........................................................................................................51
13.2
Subject Information, Informed Consent, and Subject Authorization .........................51
13.3
Subject Confidentiality ............................................................................................52
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................53
13.4.1 Publication and Disclosure.................................................................................53
13.4.2 Clinical Trial Registration..................................................................................53
13.4.3 Clinical Trial Results Disclosure ........................................................................53
13.5
Insurance and Compensation for Injury....................................................................53
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................54


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14.1
Administrative Information......................................................................................54
14.1.1 Study Contact Information .................................................................................54
14.1.2 Investigator Agreement......................................................................................54
14.1.3 Study-Related Responsibilities...........................................................................54
14.1.4 List of Abbreviations .........................................................................................54
15.0
DATA HANDLING AND RECORDKEEPING............................................................55
15.1
eCRFs......................................................................................................................55
15.2
Record Retention .....................................................................................................55
16.0
REFERENCES..............................................................................................................57
17.0
APPENDICES...............................................................................................................58
LIST OF IN-TEXT TABLES
Table 6.a
Dose Levels and Dosing Schedules ....................................................................16
Table 7.a
Excluded Concomitant Medications, Supplements, and Dietary Products...........24
Table 9.a
Primary Specimen Collections ...........................................................................34
Table 9.b
Collection of Blood Samples for PK Analysis ....................................................35
Table 10.a
Takeda Medically Significant AE List................................................................40
LIST OF IN-TEXT FIGURES
Figure 2.a
Schematic of the Study Design (Studies 1 and 2, with 7-day Washout Period)....10
CCI


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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceuticals Company Limited
Compound:
TAK-438 OD Tablet
TAK-438 tablet
Study Identifier: TAK-438ODT-1001
Phase: 1
Protocol Title: A Randomized, Open-Label, Single-Dose, 2×2 Crossover Phase 1 Study to Evaluate the
Bioequivalence of TAK-438 OD (Orally Disintegrating) 20 mg Tablet When Administered without Water (Study 1) 
or with Water (Study 2) and TAK-438 20 mg Tablet When Administered with Water in Japanese Healthy Volunteer 
Male Subjects
Trial Design:
This study which consists of two studies, Study 1 and Study 2, is a pharmacokinetic (PK) study in healthy Japanese 
subjects to evaluate the bioequivalence (BE) of single oral dose of TAK-438 OD 20 mg tablet without water and 
TAK-438 20 mg tablet with water (Study 1), and TAK-438 OD 20 mg tablet with water and TAK-438 20 mg tablet 
with water (Study 2) in an open-label and crossover (2x2) design. The safety of single oral dose of TAK-438 OD
20 mg tablet, and TAK-438 20 mg tablet under fasted conditions will be also evaluated.
Pilot and Pivotal BE studies are planned for Study 1 and Study 2 in accordance with the “Guideline for Bioequivalence 
Studies of Generic Products” (PFSB/ELD Notification No.0229-10 dated 29 February 2012) as follows;
Pilot and Pivotal BE studies will be conducted in the same design (inclusion/exclusion criteria, dose, regimen and 
schedule). Pilot BE studies will be conducted first for the sample size estimation to demonstrate the bioequivalence in 
Pivotal BE studies. The data from Pilot BE studies can be merged with the data from Pivotal BE study as needed when 
the bioequivalence is evaluated. Pivotal BE studies will not be conducted in the case the bioequivalence is 
demonstrated in Pilot BE study, or the results from Pilot BE study indicate that it is not feasible to demonstrate the 
bioequivalence.
In the Pilot BE study, 24 subjects will be enrolled in each study (12 subjects in each treatment sequence). Subjects will 
be randomly assigned to either Treatment Sequences with 1:1 allocation in each study.
In the Pivotal BE study, 26 to 48 subjects will be enrolled in each study (13 to 24 subjects in each treatment sequence 
depending on outcome of the pilot BE study). Subjects will be randomly assigned to either Treatment Sequences with 
1:1 allocation in each study.
In each treatment sequence of Pilot and Pivotal BE studies, subjects will receive a single dose of either of TAK-438 
OD 20 mg tablet without water or TAK-438 20 mg tablet with water (Study 1), and either of TAK-438 OD 20 mg 
tablet with water or TAK-438 20 mg tablet with water (Study 2) on Day 1 in Periods 1 and 2. If a subject discontinues 
from the study, a replacement subject may be enrolled, if deemed appropriate by the investigator and sponsor. The 
study site should contact the sponsor for the replacement of subject’s treatment assignment and medication 
identification number.
Trial Primary Objective:
To evaluate the bioequivalence of a single oral administration of a TAK-438 OD 20 mg tablet without water in 
comparison with TAK-438 20 mg tablet (Study 1), and TAK-438 OD 20 mg tablet with water in comparison with 
TAK-438 20 mg tablet (Study 2) in Japanese healthy male subjects.
Secondary Objective:
To assess the PK parameters other than AUClast and Cmax of TAK-438F in Japanese healthy male subjects who take 
TAK-438 20 mg.
Trial Subject Population: Healthy Japanese adult male subjects, aged 20 to 60 years, inclusive.


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CONFIDENTIAL
Planned Number of Subjects:
For Study 1 and Study 2:
Pilot study: 12 per sequence, 24 in total
Pivotal study: 13 to 24, 26 to 48 in total
Up to approximately 144
Planned Number of Sites:
1 site
Dose Levels:
Study 1: One TAK-438 OD 20 mg tablet without 
water or one TAK-438 20 mg tablet taken orally with 
150 mL of water under fasted (without breakfast 
[after at least 10 hours of fasting]) condition.
Study 2: One TAK-438 OD 20 mg tablet or one 
TAK-438 20 mg tablet taken orally with 150 mL of 
water under fasted (without breakfast [at least 
10 hours of fasting]) condition
Route of Administration:
Oral
Duration of Treatment:
Study 1: Single oral administration (TAK-438 OD
20 mg tablet or TAK-438 20 mg tablet) in Periods 1 
and 2
Study 2: Single oral administration (TAK-438 OD
20 mg tablet or TAK-438 20 mg tablet) in Periods 1 
and 2
Planned Trial Duration:
From the day before study drug administration through
48 hours after administration in Periods 1 and 2
Main 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 healthy Japanese adult male, aged 20 to 60 years, inclusive, at the time of informed consent.
4.
The subject weighs at least 50 kg and has a body mass index (BMI) from 18.5 to 25.0 kg/m2, inclusive at 
Screening.
5.
The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing products (eg, nicotine 
patch) for at least 6 months prior to the start of study drug administration in Period 1.
6.
The subject must be judged to be in good health by the investigator, based on clinical evaluations including 
laboratory safety tests, medical history, physical examination, 12-lead electrocardiogram (ECG), and vital sign 
measurements performed at the Screening Visit and prior to the start of study drug administration in Period 1.
Main Criteria for Exclusion:
1.
The subject has received any investigational compound within 16 weeks (112 days) prior to the start of study 
drug administration in Period 1.
2.
The subject has received TAK-438 in a previous clinical study or as a therapeutic agent.
3.
The subject is an immediate family member of or a study site employee, or is in a dependent relationship with a 
study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may 
consent under duress.
4.
The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, 
metabolic, gastrointestinal, urologic, or endocrine disease or other abnormality (other than the disease being 
studied), which may impact the ability of the subject to participate in the study or potentially confound its results.
5.
The subject has hypersensitivity to any component of TAK-438 OD tablet or TAK-438 tablet.
6.
The subject has a positive urine drug result for drugs of abuse at Screening.


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CONFIDENTIAL
7.
The subject has a history of drug or 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, or food products during the time periods.
9.
The subject has current or recent (within 6 months) gastrointestinal disease 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.
11.
The subject has a positive test result for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) 
antibody, human immunodeficiency virus (HIV) antibody/antigen, or serological reactions for syphilis at 
Screening.
12.
The subject has poor peripheral venous access.
13.
The subject has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) or at least 400 mL 
within 12 weeks (84 days) prior to the start of 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 study drug administration in Period 1.
15.
The subject has undergone blood component collection within 2 weeks (14 days) prior to the start of study drug 
administration in Period 1.
16.
The subject has a Screening or Check-in (Day -1) ECG that was abnormal (clinically significant).
17.
The subject has abnormal Screening laboratory values that suggest a clinically significant underlying disease or 
subject with the following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) above 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.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the study is:
PK (plasma concentration)
AUClast and Cmax of TAK-438F.
The secondary endpoints of the study are:
PK (plasma concentration)
AUC∞, tmax, MRT∞,ev, and λz of TAK-438F.
Safety:
Treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital signs, weight, and 12-lead ECG.
Statistical Considerations:
PK:
The following analyses will be separately conducted for each study (Study 1 and Study 2) based on the PK analysis 
set.
Analytical methods:
1)
Plasma concentrations
At each time point scheduled for blood sampling, descriptive statistics of plasma concentrations of TAK-438F
will be provided for each formulation (ie, TAK-438 OD tablet and TAK-438 tablet). Case plots and mean plots 
with standard deviations (SD) will be provided for each formulation. Descriptive statistics of PK parameters will 
be provided for each formulation. Additionally, descriptive statistics will be provided for AUClast and Cmax ratios 
(TAK-438 OD tablet/TAK-438 tablet).


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CONFIDENTIAL
2)
Bioequivalence assessment
For log-transformed (natural log) AUClast and Cmax of TAK-438F (ie, the primary endpoint of the study), the 
two-sided 90% confidence interval (CI) of the difference in the least square means between the formulations 
(TAK-438 OD tablet − TAK-438 tablet) will be provided using the analysis of variance (ANOVA) model. The 
same analyses will be performed for untransformed AUClast and Cmax.
The same analyses will also be performed for AUC∞, tmax, MRT∞. ev, and λz to provide additional information.
(ie, the secondary endpoints of the study).
Safety:
The following analyses will be separately conducted for each study (Study 1 and Study 2) based on the safety analysis 
set.
Analytical methods:
1)
TEAEs
A TEAE is defined as an AE with a date of onset that occurs on or after the start of study drug administration. 
Frequency distribution of TEAEs will be provided for all TEAEs, drug-related TEAEs, TEAEs by intensity, 
drug-related TEAEs by intensity, and serious TEAEs for each formulation. TEAEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary and tabulated by system organ class (SOC) 
and preferred term (PT) for each formulation.
2)
Clinical laboratory tests, vital signs, weight, and 12-lead ECG
For continuous variables in clinical laboratory tests, vital signs and ECG parameters, descriptive statistics of 
observed values and changes from baseline will be provided for each scheduled time point by formulation.
For categorical variables in clinical laboratory tests and ECG parameters, shift tables showing the number of 
subjects in each category at baseline and each post-baseline scheduled time point will be provided for each 
formulation.
Sample Size Justification:
For each of the studies (Study 1 and Study 2), the planned number of subjects is 12 per sequence (total of 24 subjects) 
in the pilot study, and a maximum of 24 per sequence (total of 48 subjects) in the pivotal study. Statistical basis for the 
sample size is presented below.
Assuming a root mean square error of 0.195 for PK parameters in the pilot study, the power of two one-sided t-tests to 
verify the bioequivalence [H0: ln(μ)≤ln(θ1), ln(μ)≥ln(θ2); H1: ln(θ1)<ln(μ)<ln(θ2); where μ=μt/μs, μt is the mean for
TAK-438 OD tablet, μs is the mean for TAK-438 tablet, θ1=0.80, and θ2=1.25] at a one-sided significance level of 5% 
and μ=0.95 to 1.05 would be ≥90% with a sample size of 12 subjects per sequence (total of 24 subjects).
In the case that the pivotal study will be implemented, the number of subjects will be recalculated based on the results 
from the pilot study. Assuming a maximal root mean square error of 0.195 for PK parameters in preceding studies of 
TAK-438, two one-sided t-tests with a one-sided significance level of 5% and μ=0.90 to 1.11 would need a maximum 
of 24 subjects per sequence (total of 48 subjects) to provide 90% power to verify the bioequivalence.


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CONFIDENTIAL
2.0
STUDY SCHEMATIC
Figure 2.a
Schematic of the Study Design (Studies 1 and 2, with 7-day Washout Period)
Element
Screening
Period 1
Period 2
Study Day
-28 to -2
-1
1
2
3
8
9
10
11
Visit/
Confinement
Visit
Confinement
Confinement
Procedure
Informed consent
Screening tests
Check-in/Examinations
Examinations/Randomization 
Administration of study drug
for Period 1
Examinations
Examinations/Discharge
Washout
Check-in/Examinations
Administration of study drug
for Period 2//Examinations
Examinations
Examinations/Discharge


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3.0
SCHEDULE OF STUDY PROCEDURES (STUDIES 1 AND 2)
Screening
Period
ET
Check in
Treatment Period
Study Day
-28 to -2
-1a
1 to 3
Scheduled Time (Hours)
Pre-
dose
0.5
1
1.5
2
3
4
6
8
10
12
16
24
36
48
Administrative Procedures
Informed consent
X
Inclusion/exclusion 
criteriad
X
X
X
Medical history/ 
demographics
X
Prior and concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Physical examination
X
X
X
X
X
Weight, height and BMI
X
Xb
Xb
Xb
Vital signs
X
X
X
X
X
Safety ECG 
X
X
X
X
Study drug administration
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments
Hematology, Chemistry 
and Urinalysis
X
X
X
X
Urine drug screen
X
HIV and Hepatitis screen
X
PK Evaluations
Plasma sample for 
TAK-438
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xc
Other
Confinement
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: AE, adverse event; BMI, body mass index; ECG, electrocardiogram; ET, early termination; PK, pharmacokinetic(s)
a 18 hours prior to dosing
b Only weight
c Plasma samples for TAK-438 PK evaluations should be collected only in the case of early termination within 48 hours after the study drug administration
d At Screening and prior to the administration of study drug on Period 1. It will not be conducted on Day 1 (the day of the administration of the study drug on Period 2).


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4.0
INTRODUCTION
4.1
Background
TAK-438 is a novel class of stomach acid suppressants, referred to as a potassium-competitive 
acid blocker (P CAB). The efficacy and safety of TAK-438 were established in the clinical studies 
in patients with acid-related diseases. TAK-438 10 mg and 20 mg tablets were approved in 
December 2014 in Japan, indicated for erosive esophagitis (including a maintenance treatment of 
erosive esophagitis), gastric ulcer, duodenal ulcer, prevention of recurrent gastric or duodenal 
ulcer during low-dose aspirin therapy, prevention of recurrent gastric or duodenal ulcer during 
non-steroidal anti-inflammatory drug (NSAID) therapy, and adjunct to Helicobacter pylori (H. 
pylori) eradication.
TAK-438 10 mg and 20 mg tablet is widely used in elderly patients. A formulation with easier 
administration is preferable in Japan, super-aging society, because patients with decreased 
deglutition function exist. TAK-438 OD tablet is rapidly disintegrated in the oral cavity so that 
elderly patients can easily take without sticking feeling in their throat. TAK-438 OD tablet, which 
is able to be taken easily without water, may leads to compliance improvement in elderly patients 
and those who with limited water intake due to complication such as chronic kidney disease.
Therefore, Takeda is considering the development of TAK-438 OD 10 mg and 20 mg tablet as a 
new formulation corresponding to the strength of TAK-438 10 mg and 20 mg tablet.
4.2
Rationale for the Proposed Study
To develop TAK-438 OD 10 mg and 20 mg, this study was planned to verify the bioequivalence of 
a single dose of TAK-438 OD 20 mg tablet without water and a single dose of TAK-438 20 mg 
tablet with water (Study 1) as well as the bioequivalence of a single dose of TAK-438 OD 20 mg 
tablet with water and a single dose of TAK-438 20 mg with water (Study 2) in healthy adult male 
subjects (in regard to TAK-438 OD 10 mg, please refer to Section 6.3.2).
4.3
Benefit/Risk Profile
There will be no benefit to subjects in this study other than receiving physical examinations and 
obtaining information about their general health.
Because TAK-438 (10 mg tablet and 20 mg tablet) has been already approved for marketing and 
its safety is established, the risk to subject is considered not to exceed the risk of receiving 
TAK-438.
For further information on TAK-438 OD, please refer to the Investigator’s Brochure.


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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study was designed based on the following hypothesis:
TAK-438 OD 20 mg tablet and TAK-438 20 mg tablet will be shown to be bioequivalent.
5.2
Trial Objectives
5.2.1
Trial Primary Objective
To evaluate the bioequivalence of a single oral administration of a TAK-438 OD 20 mg tablet
without water in comparison with TAK-438 20 mg tablet (Study 1), and TAK-438 OD 20 mg 
tablet with water in comparison with TAK-438 20 mg tablet (Study 2) in Japanese healthy male
volunteer subjects.
5.2.2
Trial Secondary Objective
To assess the Pharmacokinetic (PK) parameters other than AUClast and Cmax of TAK-438F in 
Japanese healthy volunteer male subjects who take a single oral dose of TAK-438 20 mg.
5.2.3
Safety Objective
To assess the safety in Japanese healthy volunteer male subjects who take a single oral dose of 
TAK-438 20 mg.
5.3
Endpoints
5.3.1
Primary Endpoint
PK (plasma concentration): AUClast and Cmax of TAK-438F
5.3.2
Secondary Endpoints
PK (plasma concentration): AUC∞, tmax, MRT∞,ev and λz of TAK-438F.
5.3.3
Safety Endpoints
Treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital signs, weight, and 
electrocardiogram (ECG) parameters


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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design
This study which consists of two studies, Study 1 and Study 2, is a PK study in healthy Japanese 
subjects to evaluate the bioequivalence of single oral dose of TAK-438 OD 20 mg tablet without 
water and TAK-438 20 mg tablet with water (Study 1), and TAK-438 OD 20 mg tablet with water
and TAK-438 20 mg tablet with water (Study 2) in an open-label and crossover (2x2) design. The 
safety of TAK-438 OD 20 mg tablet, and TAK-438 20 mg tablet under fasted conditions without 
breakfast will also be evaluated.
Pilot and Pivotal BE studies are planned for Study 1 and Study 2 in accordance with the “Guideline 
for Bioequivalence Studies of Generic Products” (PFSB/ELD Notification No.0229-10 dated 29 
February 2012) [1] as follows;
Pilot and Pivotal BE studies will be conducted in the same design (inclusion/exclusion criteria, 
dose, regimen and schedule). Pilot BE studies will be conducted first for the sample size estimation 
to demonstrate the bioequivalence in Pivotal BE study. Pivotal BE study with the estimated sample 
size will be conducted to demonstrate the bioequivalence. The data from Pilot BE studies can be 
merged with the data from Pivotal BE study as needed when the bioequivalence is evaluated. 
Pivotal BE studies will not be conducted in the case the bioequivalence is demonstrated in Pilot BE 
study, or the results from Pilot BE study indicate that it is not feasible to demonstrate the 
bioequivalence.
In the Pilot BE study, 24 subjects will be enrolled in each study (12 subjects in each treatment 
sequence). Subjects will be randomly assigned to either Treatment Sequences with 1:1 allocation 
in each study.
In the Pivotal BE study, 26 to 48 subjects will be enrolled in each study (13 to 24 subjects in each 
treatment sequence depending on outcome of the pilot BE study). Subjects will be randomly 
assigned to either Treatment Sequences with 1:1 allocation in each study.
In each treatment sequence of Pilot and Pivotal BE studies, subjects will receive a single dose of 
either of TAK-438 OD 20 mg tablet without water or TAK-438 20 mg tablet with water (Study 1), 
and either of TAK-438 OD 20 mg tablet with water or TAK-438 20 mg tablet with water (Study 2) 
on Day 1 in Period 1 and 2. If a subject discontinues from the study, a replacement subject may be 
enrolled, if deemed appropriate by the investigator and sponsor. The study site should contact the 
sponsor for the replacement of subject’s treatment assignment and medication identification
number.
The planned dose levels and dosing schedules of TAK-438 OD to be evaluated are outlined in 
Table 6.a.


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Table 6.a
Dose Levels and Dosing Schedules
Study 1: BE study when administered without water for TAK-438 OD tablet
Pilot BE Study
Sequence
Period 1
Period 2
Number of subjects
A
One TAK-438 OD 20 mg tablet
without water
One TAK-438 20 mg tablet
with 150 mL water
12
B
One TAK-438 20 mg tablet
with 150 mL water
One TAK-438 OD 20 mg tablet
without water
12
Dosing Condition: Fasted (without breakfast) condition
Pivotal BE Study
Sequence
Period 1
Period 2
Number of subjects
A
One TAK-438 OD 20 mg tablet
without water
One TAK-438 20 mg tablet
with 150 mL water
13- 24
B
One TAK-438 20 mg tablet
with 150 mL water
One TAK-438 OD 20 mg tablet
without water
13-24
Dosing Condition: Fasted (without breakfast) condition
Study 2: BE study when administered with water for TAK-438 OD tablet
Pilot BE Study
Sequence
Period 1
Period 2
Number of subjects
C
One TAK-438 OD 20 mg tablet
with 150 mL water
One TAK-438 20 mg tablet
with 150 mL water
12
D
One TAK-438 20 mg tablet
with 150 mL water
One TAK-438 OD 20 mg tablet
with 150 mL water
12
Dosing Condition: Fasted (without breakfast) condition
Pivotal BE study
Sequence
Period 1
Period 2
Number of subjects
C
One TAK-438 OD 20 mg tablet
with 150 mL water
One TAK-438 20 mg tablet
with 150 mL water
13-24
D
One TAK-438 20 mg tablet
with 150 mL water
One TAK-438 OD 20 mg tablet
with 150 mL water
13-24
Dosing Condition: Fasted (without breakfast) condition
6.2
Procedures for Proceeding to the Pivotal Study
In this study, an interim analysis will be performed after the completion of the pilot study to 
determine whether the results may warrant further analysis in the pivotal study for both Studies 1 


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and 2. On the basis of bioequivalence assessment in the pilot study, the Sponsor will decide, after 
discussion(s) with the medical experts, on whether to proceed to the pivotal study and promptly 
notify the investigator of the decision.
In the case that the results from interim analysis satisfy the criteria of bioequivalence:
The study (Study 1 or 2) will be completed with the pilot study and without implementing the 
pivotal study.
In the case that the results from interim analysis do not meet the criteria of bioequivalence:
The pivotal study will be implemented after the number of subjects required to conclude the 
bioequivalence in the study (Study 1 or 2) is calculated based on the results from the pilot study.
Any evidence from the pilot study suggesting difficulties in bioequivalence testing in the pivotal
study may lead to the pivotal study not being implemented.
Criteria of bioequivalence:
In each of Study 1 and Study 2, the study drugs will be assessed for bioequivalence according to
the Guideline for Bioequivalence Studies of Generic Products, [1]. If any of the following criteria 
is satisfied, TAK-438 OD tablet and TAK-438 tablet will be concluded to be bioequivalent.

For AUClast and Cmax of TAK-438F, the two-sided 90% CI of the difference in the means of 
log-transformed (natural log) parameter between the formulations is between 0.8 and 1.25, 
inclusive.

For AUClast and Cmax of TAK-438F, the difference in the means of log-transformed (natural 
log) parameter between the formulations is between 0.90 and 1.11, inclusive. Furthermore, the 
results of the elution test satisfy the requirements specified in the Guideline for Bioequivalence
Studies of Generic Products [1].
6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale of Trial Design
The study is planned to evaluate the bioequivalence of TAK-438 OD 20 mg tablet when 
administered without water (Study 1) or with water (Study 2) compared to TAK-438 20 mg tablet 
when administered with water in Japanese healthy volunteer male subjects in accordance with the 
Guideline for Bioequivalence Studies of Generic Products [1].
A 2-period, 2-treatment, cross-over design, which allows bioequivalence evaluation with minimal 
effect on inter-subject variation, was selected for this study in accordance with the Guideline for 
Bioequivalence Studies of Generic Products [1].
Open-label design is adopted because the primary objective of the study is to determine the PK
profile of TKA-438F, an objective measure.
To eliminate all biases arising from arbitrary assignment of subjects, subjects will be randomized 
to receive the two treatments in either sequence.


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6.3.2
Rationale for Dose
The marketed formulations of TAK-438 are 10 mg and 20 mg tablets. This study is planned to 
develop both of TAK-438 OD 10 mg and 20 mg tablets for the purpose of making it easier for 
patients to take their medication. 
In this study TAK-438 OD 20 mg tablet is selected to evaluate the bioequivalence when 
administered with/without water in comparison with TAK-438 20 mg tablet according to the 
Guideline for Bioequivalence Studies of Generic Products for Different Strengths of Oral Solid 
Dosage Forms (Pharmaceutical and Food Safety Bureau Notification No. 0229-10 issued on 29 
February 2012, Appendix 2) [2], which recommends to conduct a bioequivalence study with the 
higher strength(ie, TAK-438 OD 20 mg tablet). Also it recommends to evaluate a bioequivalence 
with the other strength (ie, TAK-438 OD 10 mg tablet) according to the Guideline for 
Bioequivalence Studies for Different Oral Solid Dosage Forms (Pharmaceutical and Food Safety 
Bureau Notification No. 0229-10 issued on 29 February 2012, Appendix 4) [3]. The 
bioequivalence of TAK-438 OD 10 mg and 20 mg tablets will be evaluated in a dissolution test, 
but not a human bioequivalence study. 
6.3.3
Rationale for Washout Period
According to the preceding studies of single and multiple doses of TAK-438, the half-life of 
TAK-438F was approximately 7 hours (mean) but the half-life of the metabolite (M-I) of 
TAK-438 was maximum 33.6 hours. Therefore, a 5-fold period (ie, 7 or more days) was adopted in 
light of feasibility.
6.3.4
Rationale for Endpoints
6.3.4.1 PK Endpoints
AUClast and Cmax of TAK-438F will be evaluated in accordance with the Guideline for 
Bioequivalence Studies of Generic Products [1]. The plasma concentration of TAK-438F will be 
evaluated until 48 hours postdose, the time point when their AUClast is estimated to be over 80% of 
their AUC∞based on the available PK results.
6.3.4.2 Safety Endpoints
The safety endpoints in this study are the safety variables such as AEs, clinical laboratory tests, 
vital signs, weight and 12-lead ECG at rest to evaluate the safety following a single dose of 
TAK-438. They are standard endpoints in the Phase 1 studies in healthy subjects.
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures
For this study, the collection of blood samples for PK evaluation is the critical procedure.

At any postdose time point, the blood samples for PK evaluation need to be collected as close 
to the exact nominal time point as possible.


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
All other procedures should be completed as close to the scheduled times as possible, either 
before or after them.

When other procedures are scheduled at the same time as PK sampling, the blood draw will 
take priority and other procedures will be performed within an acceptable time window (refer
to Appendix B).

The order of priority can be changed with joint agreement of the investigator and the Sponsor.

Any unscheduled procedures required for urgently addressing a safety concern will take 
precedence over all routine scheduled procedures.
6.4
Trial Beginning and End/Completion
6.4.1
Definition of Beginning of the Trial
The overall study begins when the first subject signs the study informed consent form.
6.4.2
Definition of End of the Trial
The overall study ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), discontinues from the 
study, or is lost to follow-up (ie, the investigator is unable to contact the subject).
6.4.3
Definition of Trial Discontinuation
Study discontinuation because of nonsafety reasons, such as the following:

A finding (eg, PK, pharmacodynamic, efficacy, biologic targets) from another nonclinical or 
clinical study using the study treatment(s) results in the study being stopped for a 
nonsafety-related reason.

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this study 
become available and results in the study being stopped for a nonsafety-related reason.

The study is stopped because of nonscientific and nonsafety reason, such as slow enrollment.
Study discontinuation because of safety reasons:

Early study termination because of unanticipated concerns of safety to the study subjects 
arising from clinical or nonclinical studies with the study treatment(s), comparator(s), drug(s) 
of the same class, or methodology(ies) used in this study.
6.4.4
Criteria for Premature Termination or Suspension of the Trial
6.4.4.1 Criteria for Premature Termination or Suspension of Trial
The study will be completed as planned unless 1 or more of the following criteria are met that 
require temporary suspension or early termination of the study.


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1. 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 TAK-438 OD, such that the risk is no 
longer acceptable for subjects participating in the study.
2. Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
3. Any subject experiences any of the Takeda Medically Significant List events (as outlined in 
Table 10.a).
4. Liver Function Test (LFT) abnormalities:
a. Any subject experiences alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) >5 × upper limit of normal (ULN) in the absence of a concomitant bilirubin increase.
b. Any subject experiences ALT and/or AST >3 × ULN in the presence of a total bilirubin 
>2 × ULN or an international normalized ratio (INR) >1.5 without findings of cholestasis or 
any other alternative etiology to explain the elevations (ie, Hy’s Law cases).
c. Any subject experiences ALT and/or AST >3 × ULN with appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
6.4.4.2 Procedures for Premature Termination or Suspension of the Trial
In the event that the Sponsor, the institutional review board (IRB), or the 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 the study site during the course of termination or study suspension.
6.4.5
Criteria for Premature Termination or Suspension of the Trial Sites
6.4.5.1 Criteria for Premature Termination or Suspension of the Trial Sites
The study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of Good Clinical Practice, protocol, or contractual agreement, or is 
unable to ensure adequate performance of the study, or as otherwise permitted by the contractual 
agreement.
6.4.5.2 Procedures for Premature Termination or Suspension of the Trial or the Participation of 
Trial Sites
In the event that the Sponsor, the IRB, or the 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 the study site
during the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria:
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 healthy Japanese adult male, aged 20 to 60 years, inclusive, at the time of 
informed consent.
4. The subject weighs at least 50 kg and has a body mass index (BMI) from 18.5 to 25.0 kg/m2, 
inclusive at Screening.
5. The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing 
products (eg, nicotine patch) for at least 6 months prior to the start of study drug administration 
in Period 1.
6. The subject must be judged to be in good health by the investigator, based on clinical 
evaluations including laboratory safety tests, medical history, physical examination, 12-lead 
ECG, and vital sign measurements performed at the Screening Visit and prior to the start of 
study drug administration in Period 1.
Justifications of the inclusion criteria
Criteria 1, 2, 3, 5 and 6:
These are selected as the standard criteria for the conduct of clinical pharmacological studies in 
healthy adults.
Criterion 4:
Since whole blood collections of 400 mL from individuals weighing less than 50 kg is harmful to 
their health, according to Enforcement Regulation on the Law for Securing a Stable Supply of Safe 
Blood Products, Ministry of Health and Welfare Ordinance No. 22 issued in 1956 [4], the lower 
weight limit is set to 50 kg. BMI of the subjects are to be within the range of the standard weight 
according to the Diagnostic Criteria for Obesity proposed by the Japan Society for the Study of 
Obesity [5].
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has received any investigational compound within 16 weeks (112 days) prior to 
the start of study drug administration in Period 1.
2. The subject has received TAK-438 in a previous clinical study or as a therapeutic agent.


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3. The subject is an immediate family member of or a study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study (eg, 
spouse, parent, child, sibling) or may consent under duress.
4. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, urologic, or endocrine disease or other abnormality 
(other than the disease being studied), which may impact the ability of the subject to participate 
in the study or potentially confound its results.
5. The subject has hypersensitivity to any component of TAK-438 OD tablet or TAK-438 tablet.
6. The subject has a positive urine drug result for drugs of abuse at Screening.
7. The subject has a history of drug or 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, or food products during the time 
periods listed in Section 7.3.
9. The subject has current or recent (within 6 months) gastrointestinal disease 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.
11. The subject has a positive test result for hepatitis B virus surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen, or serological 
reactions for syphilis at Screening.
12. The subject has poor peripheral venous access.
13. The subject has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) 
or at least 400 mL within 12 weeks (84 days) prior to the start of 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 study drug administration in Period 1.
15. The subject has undergone blood component collection within 2 weeks (14 days) prior to the 
start of study drug administration in Period 1.
16. The subject has a Screening or Check-in (Day -1) ECG that was abnormal (clinically 
significant).
17. The subject has abnormal Screening laboratory values that suggest a clinically significant 
underlying disease or subject with the following laboratory abnormalities: ALT or AST above 
the ULN.


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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.
Justifications of the exclusion criteria
Criterion 1:
This criterion is meant to ensure the safety of subjects by specifying a minimum interval that they 
are not affected by any previous clinical study, which is based on the General Considerations for 
Clinical Trials, Pharmaceutical Safety Bureau Notification No. 380, issued on 21 April 1998 [6].
Criteria 2, 3, 4, 6, 7, 10, 11, 12, and 18:
These are the standard criteria for clinical pharmacological studies in healthy adults and included 
in consideration of subjects’ safety.
Criteria 5, 16, and 17:
These criteria are selected in consideration of subjects’ safety.
Criterion 8:
This is a standard criterion for clinical pharmacological studies in healthy adults and included in 
considerations of subjects’ safety and possible effects on PK evaluations.
Criterion 9:
This criterion is selected in considerations of subjects’ safety and possible effects on PK 
evaluations.
Criteria 13 to 15:
These criteria are in accordance with Enforcement Regulation on the Law for Securing a Stable 
Supply of Safe Blood Products, Ministry of Health and Welfare Ordinance No. 22, issued in 1956
[4].
7.3
Excluded Concomitant Medications, Supplements, Dietary Products 
Use of excluded concomitant agents (prescription or nonprescription) or dietary products is 
outlined in Table 7.a.
Use of prohibited concomitant medications will be allowed when the investigator or 
sub-investigator deem it necessary to do so for reasons including treatment of an AE.


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Table 7.a
Excluded Concomitant Medications, Supplements, and Dietary Products
Throughout the study period, 
beginning from 28 days prior to 
study drug administration (Day 1)
in Period 1
From 7 days prior to study drug 
administration (Day 1) to discharge 
in Periods 1 and 2
From 24 hours prior to study drug 
administration (Day 1) to Discharge 
in Periods 1 and 2
• Prescription medications
• OTC medications
• Neutraceuticals 
(St. John’s wort, ginseng, kava 
kava, ginkgo biloba, and melatonin)
• Chinese herbals
• Immunization/Vaccines
• Nicotine-containing products
• Vitamin supplements
• Alcohol-containing products
• Grapefruit/grapefruit juice
• Caffeine-containing products
OTC=over-the-counter.
Subjects must be instructed not to take any medications including over-the-counter (OTC) 
products, without consulting with the investigator or sub-investigator.
7.4
Diet, Fluid, Activity
7.4.1
Diet and Fluid

Diet
On the day before the visit for blood collection of laboratory tests (Screening visit), the subject 
must finish the dinner by 21:00, and must fast until blood collection in the next morning. For 
laboratory tests scheduled in the afternoon on a study visit, blood samples should be collected 
at least 10 hours after the last meal.
During confinement, the subjects are to take only served meals and are not allowed to take any 
other food. Meal menus will be the same for Periods 1 and 2.
Excessive eating or drinking should be avoided during the study period.
Dinner will be at approximately 19:00 on the day before study drug administration. The 
subjects must fast for at least 10 hours prior to and for 4 hours after dosing.
On the day of the study drug administration, the subjects must not have breakfast. On the day 
of the study drug administration, the approximate time is 13:00 for lunch and 19:00 for dinner. 
If the lunch or dinner time conflicts with the laboratory test schedule, the subject must take 
lunch or dinner promptly after completion of the laboratory tests. On the next day of study drug 
administration, the approximate time is 9:30 for breakfast, 13:00 for lunch, and 19:00 for 
dinner. If the breakfast time conflicts with the laboratory test schedule, the subject must take 
breakfast promptly after completion of the laboratory tests.
Taking breakfast on Day 3 (the day of discharge) is optional.


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
Beverages
On the day of study drug administration, subjects must not drink any liquid from 1 hour prior to 
and 4 hours after dosing, with the exception of the water (150 mL) to take the study drug.

Smoking
Smoking is not allowed during the study period, beginning from 28 days prior to the start of 
study drug administration (Day 1).
7.4.2
Activity
Supine position is not allowed for 4 hours after dosing, unless required for examinations, or for 
other reasons.
Excessive exercise is not allowed during the study period. Subjects should do 15 minutes of light 
exercise a day during the confinement.
Blood donations are not allowed for at least 12 weeks (84 days) after the final examination in this 
study. The investigator or sub-investigator will instruct the subjects on the prohibition of blood 
donations.
If a subject visits another medical institution during the study period, the investigator or 
sub-investigator should be informed of the visit in advance whenever possible, and should be 
reported the circumstances and therapy after visit. The investigator or sub-investigator should 
communicate that medical institution about the subject’s participation in the study.
7.5
Documentation of Subjects Failure
The investigator or sub-investigator must account for all subjects who sign informed consent. If a 
subject is withdrawn from the study before the first study drug administration in Period 1, the 
investigator or sub-investigator should complete the electronic case report form (eCRF).
The primary reason for subject failure is to be recorded in the eCRF using the following categories:

Death.

AE.

Screen failure (failed inclusion criteria or did meet exclusion criteria) <specify reason>.

Protocol deviation.

Lost to follow-up.

Withdrawal by subject <specify reason>.

Study terminated by Sponsor.

Sample size sufficient.

Other <specify reason>.


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Any subject identification number, once assigned to a subject, should not be reused if the assigned 
subject discontinues the study prior to study drug administration in Period 1. Nevertheless, if a 
reserve subject is enrolled in the other sequence, the same subject identification number may be 
used.
7.6
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the eCRF using the following categories. For the subject who is withdrawn 
from the study before the first study drug administration in Period 1, refer to Section 7.5.
1. Death.
The subject died on study.
Note: If the subject dies on study, the event will be considered as serious adverse event (SAE). 
Refer to Section 10.2.9.3 for the reporting procedures.
2. AE.
The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE.
Study drug should be discontinued immediately with appropriate clinical follow-up (including 
repeat laboratory tests, until the subject’s laboratory profile has returned to normal/baseline 
status, refer to Section 9.2.8), if the following circumstances occur at any time during study 
drug treatment:

LFT abnormalities.
-
ALT or AST >8 × ULN, or
-
ALT or AST >5 × ULN and persists for more than 2 weeks, or
-
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or INR 
>1.5, or
-
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
3. Protocol deviation.
The discovery after the first dose of study drug in Period 1 that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health.
4. Lost to follow-up.
The subject did not return to the clinic 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.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category).
6. Study terminated by Sponsor.
The Sponsor terminates the study.
7. Other
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.7
Procedures for Discontinuation or Withdrawal of a Subject
The investigator or sub-investigator may discontinue a subject’s study participation at any time 
during the study if the subject meets the study termination criteria described in Section 7.6. In 
addition, a subject may discontinue his participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination must 
be recorded by the investigator or sub-investigator. In addition, efforts should be made to perform 
all procedures scheduled for the Early Termination Visit.
7.8
Subject Replacement
In consideration of possible subject withdrawals for some reasons prior to the study drug 
administration in Period 1 after Screening, a certain number of individuals judged eligible at 
Screening are to be retained as standbys only for Period 1. Subject replacement is not allowed for 
dropouts after the start of study drug administration.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
Dosage form:
1. TAK-438 OD 20 mg tablet
Appearance: white to almost white uncoated tablet
Content: vonoprazan 20 mg (26.72 mg as vonoprazan fumarate) per tablet
Chemical name: 1-[5-(2-Fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-
methylmethanamine monofumarate
Generic name: vonoprazan fumarate (JAN)
2. TAK-438 20 mg tablet (Takecab® Tablet 20 mg)
Appearance: a pale reddish film-coated tablet with a score line on the both sides
Content: vonoprazan 20 mg (26.72 mg as vonoprazan fumarate) per tablet
Chemical name: 1-[5-(2-Fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-
methylmethanamine monofumarate
Generic name: vonoprazan fumarate (JAN)
Packaging:
TAK-438 OD 20 mg tablets are to be supplied in a bottle which contains 12 tablets and is to be 
further packed in a box. TAK-438 20 mg tablets (Takecab® Tablet 20 mg) are to be supplied in 
commercially available cartons, each of which contains 10 sheets of press through package (PTP), 
each sheet containing 10 tablets. Each carton is to be labeled “study drug”.
Manufacturing:
TAK-438 OD 20 mg tablets are manufactured by Nipro Pharma Corporation. TAK-438 20 mg 
tablets (Takecab® Tablet 20 mg) are to be supplied as commercially available Takecab® Tablet 
20 mg which will be packed by Spera Pharma Inc.
8.1.1
Clinical Study Drug Labeling
A clinical label will be affixed to study drug containers to indicate that the product is for clinical 
study, and the study drug name, the Sponsor and its address, the manufacturing number, the 
method for storage, and the expiration date.
8.1.2
Clinical Study Drug Inventory and Storage
All the study drugs are to be stored at room temperature (1°C to 30°C).
The study drugs must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the Sponsor or designee for destruction. The study drugs must be stored under the 
conditions specified on the label until dispensed. A daily temperature log of the drug storage area 
must be maintained every working day.


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8.1.3
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule
prior to the start of the study. All randomization information will be stored in a secured area, 
accessible only by authorized personnel.
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs
The on-site pharmacist (the site designee) will receive a pharmacy manual created by the Sponsor, 
and follow the manual for storage and accountability of the Sponsor-supplied drug supplies. The
investigator will receive the manual from the Sponsor as well. The manual will provide 
instructions on ensuring appropriate receipt, handling, storage, accountability, and dispensation of 
the Sponsor-supplied drug. The manual will also describe procedures for the collection of unused 
medications from the subject and their return to the Sponsor, or the destruction of any unused 
supplies.
The on-site pharmacist (the site designee) will immediately return any unused study drugs in a 
sealed package to the Sponsor after the study is closed at the study site.


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9.0
STUDY PROCEDURES
The investigator or sub-investigator should collect data according to the procedures described in
the following sections. For each procedure, subjects are to be assessed by the same investigator,
sub-investigator or site designee whenever possible. The Schedule of Study Procedures is located
in Section 3.0.
9.1
Administrative Procedures
9.1.1
Informed Consent
Informed consent must be obtained before the subject enters into the study and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in in Section 13.2.
9.1.1.1 Assignment of Subject Identification Numbers
A unique subject identification number will be assigned to each subject at the time that informed 
consent is explained; this subject identification number will be used throughout the study.
9.1.1.2 Study Drug Assignment
The investigator or sub-investigator will assign the study drugs to subjects who are judged eligible 
based on the examinations prior to study drug administration (eg, screening and laboratory tests). 
For each study and sequence, the subjects will be assigned to the study drug in ascending order of 
their subject identification number according to the randomization schedule.
Subjects will be assigned to receive a 5-digit medication identification number in which 
ten-thousands digit represents the study type, thousands digit represents the sequence of the 
crossover study, and the remaining digits represents the sequential number within each sequence. 
The 5-digit number will be used by the study site to identify the PK samples, and will be the only 
subject identifier used on all PK sample collections. It should also be indicated on the PK sample
vials shipped to the bioanalytical laboratory, and will be used by the laboratory to report the 
subject data results instead of the subject identification number. It does not replace the last 3 digit 
numbers of the subject identification number. In case of subject replacement, the study drug with a 
medication identification number for the withdrawn subject will be used by the replacing subject.
The investigator or its designee will record the medication identification number in the eCRF.
9.1.2
Inclusion and Exclusion Criteria
Each subject will be assessed according to the eligibility criteria provided in Section 7.0.
9.1.3
Medical History/Demographics
Demographic information to be obtained will include date of birth, sex, race as described by the 
subject, height, weight, caffeine use, alcohol use, and smoking classification of the subject.


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Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases that resolved within 1 year prior to the signing of informed consent. 
Ongoing conditions will be considered concurrent medical conditions, which should include 
clinically significant laboratory, 12-lead ECG, or physical examination abnormalities noted at 
screening/baseline examination. Any concurrent medical conditions (ie, diagnoses) should be 
described. Medication history to be obtained will include any medication relevant to eligibility 
criteria and safety evaluations stopped at or within 4 weeks (28 days) prior to the signing of 
informed consent.
9.1.4
Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by the Sponsor. Subjects will be asked whether they have taken any medication other than the 
study drug (used from the signing of informed consent through the end of the study), and all 
medication including vitamin supplements, OTC medications, and oral herbal preparations, must 
be recorded in the eCRF. Documentation will include generic medication names, route of 
administrations, start and end dates, and reasons for use.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Exam
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and 
(11) other.
9.2.2
Height and Weight
Each subject should have his height and weight measured. Height will be recorded in centimeters 
without decimal places (rounding off the first decimal place). Weight will be collected in 
kilograms (kg) with the first decimal place (rounding off the second decimal place).
9.2.3
BMI
Body mass index equals a subject’s weight in kilograms divided by height in meters squared (body 
mass index=kg/m2).The values should be calculated to the first decimal place (rounding off the 
second decimal place). A subject’s eligibility with respect to the BMI is determined based on the
rounded off value. BMI will not be recorded in the eCRF.
9.2.4
Vital Signs
Vital signs will include body temperature (axilla measurement), respiratory rate, supine blood 
pressure (systolic and diastolic, after resting more than 5 minutes), and pulse (beats per minute).


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The same method (eg, the same and appropriately sized cuff, manual or automated) must be used 
for all measurements for each individual subject and should be the same for all subjects. All 
measurements will be recorded on the source documents and in the eCRF.
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 (refer to Appendix B).
9.2.5
12-Lead ECG
A 12-lead ECG will be recorded. Subjects should be resting in a supine position for at least 
5 minutes before each ECG recording. The investigator or sub-investigator (or a qualified 
cardiologist at the study site) will interpret the ECG using one of the following categories: normal 
or abnormal. If an ECG is abnormal, the investigator or sub-investigator (or a qualified 
cardiologist at the study site) will judge clinical significance of the abnormality. The time that the 
ECG was performed will be recorded. 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 
corrected QT interval using Fridericia’s formula (QTcF).
9.2.6
Study Drug Administration
Each subject will receive the study drug in Periods 1 and 2 as described below. The administration
conditions will be the same for the pilot and pivotal studies in Studies 1 and 2.
Study 1: The subject will orally receive one TAK-438 OD 20 mg tablet without water or one 
TAK-438 20 mg with 150 mL of water under fasted (without breakfast [after at least 
10 hours of fasting]) condition. TAK-438 OD 20 mg tablet should not be swallowed 
whole, but be allowed to dissolve in the mouth without the tablet being chewed and then 
swallowed with the saliva. TAK-438 20 mg tablet should be swallowed whole with 
water.
Study 2: The subject will orally receive one TAK-438 OD 20 mg tablet, or one TAK-438 20 mg 
tablet with 150 mL of water under fasted (without breakfast [after at least 10 hours of 
fasting]) condition. The tablets should be swallowed whole with water.
9.2.7
Adverse Event Monitoring
AE monitoring begins after signing of the informed consent form. A complete description of 
adverse event collections and procedures is provided in in Section 10.2.
9.2.8
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be collected following a minimum 10-hour fast on the days stipulated in the Schedule 
of Study Procedures (Section 3.0).


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9.2.8.1 Clinical Laboratory Tests
Hematology
The hematology assessment will include the following tests:
RBC
WBC count with differential
(neutrophils, eosinophils, basophils, monocytes, lymphocytes)
Hemoglobin
Hematocrit
Platelets
Chemistry
The chemistry assessment will include the following tests:
ALT
Albumin
ALP
AST
Total bilirubin
Total protein
Creatinine
BUN
Creatine kinase
GGT
Potassium
Sodium
Fasting glucose
Chloride
Urinalysis
The urinalysis assessment will include the following tests:
pH
Specific gravity
Qualitative tests for protein
Qualitative tests for glucose


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Other
Tests performed at eligibility assessment:
Serum
Immunology tests:
HBsAg, HCV antibody, HIV antigen/antibody, serum test for 
syphilis
Urine
Urine drug tests:
phencyclidine, benzodiazepines, cocaine, antihypnotic agents, 
cannabinoids, opioids, barbiturates, and tricyclic antidepressants
HBsAg= hepatitis B virus surface antigen, HCV= hepatitis C virus, HIV= human immunodeficiency virus, RBC=red 
blood cells, WBC=white blood cells.
Note: The investigator or sub-investigator will report the results of immunology and urine drug screen directly to 
subjects. The Sponsor will confirm the overall test results (as “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, 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 an ALT or AST of >2 ×ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase [ALP], ALT, AST, total bilirubin, gamma-glutamyl transferase 
[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 Sections 10.2.9.3 and 10.2.9.4 for the appropriate guidance on reporting abnormal LFTs
as SAEs or AESIs.
The investigator will maintain a copy of the reference ranges for the laboratory used.
9.3
PK Samples
Samples for PK analyses will be collected as specified in the Schedule of Study Procedures 
(Section 3.0). Please refer to the separately created procedure for information on the collection, 
processing, and shipment of samples to the central laboratory. The actual time of sample collection 
for PK analyses will be recorded on source documents and the eCRF.
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Description of Intended Use
Sample 
Collection
Plasma sample for TAK-438 PK
Plasma
PK analysis
Mandatory


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9.3.1
PK Measurements
The PK parameters of TAK-438F will be determined from the concentration-time profiles for all 
evaluable subjects. Actual sampling times, rather than scheduled sampling times, will be used in 
all computations.
The following PK parameters will be calculated from plasma concentrations of TAK-438F, unless 
otherwise specified:
Symbol/Term
Definition
Plasma
AUClast
Area under the concentration-time curve from time 0 to time of the last quantifiable concentration.
AUC∞
Area under the concentration-time curve from time 0 to infinity.
Cmax
Maximum observed concentration.
tmax
Time of first occurrence of Cmax.
t1/2z
Terminal disposition phase half-life.
λz
Terminal disposition phase rate constant.
MRT∞,ev
Mean residence time after extravascular administration from time 0 to infinity.
9.3.1.1 Plasma for PK Measurements
Blood samples for PK analyses of TAK-438F (one 4-mL sample per scheduled time) will be 
collected in Vacutainers.
Blood samples for PK analyses of TAK-438F will be collected according to the schedule described 
in Table 9.b.
Table 9.b
Collection of Blood Samples for PK Analysis
Analyte
Matrix
Study Day
Scheduled Time
TAK-438F
Plasma
Days 1 to 3
Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours 
postdose
If a subject is prematurely withdrawn from the study after the start of study drug administration, a 
blood sample at the time of early termination will be collected as follows.
In Studies 1 and 2, blood sample for PK analysis of TAK-438F will be collected only if the subject 
is withdrawn from the study within 48 hours after the start of study drug administration.
9.3.1.2 Analytical Methods Used for PK Samples
Plasma concentrations of TAK-438F will be measured using liquid chromatography-tandem mass 
spectrometry (LC/MS/MS).


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9.3.2
Confinement
In both Studies 1 and 2, each subject will be checked-in to the study site on Day -1 and hospitalized
until 48 hours postdose on Day 3. Subjects will undergo daily examinations, observations, and 
assessments as specified in the Schedule of Study Procedures in Section 3.0. Subjects will be 
discharged after being confirmed by physical examination and tests on Day 3 to have no 
significant abnormality in his health.


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


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study procedure. However, if the subject experiences a worsening or complication of such a 
concurrent medical condition, the worsening or complication should be recorded appropriately 
as an AE (worsening or complication occurs after informed consent is signed). Investigators or 
sub-investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators or sub-investigators should ensure that the AE term 
recorded captures the change from baseline in the condition (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators or sub-investigators should ensure that the 
AE term recorded captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study drug or after any change in study drug, the worsening or complication should be 
recorded as a new AE. Investigators or sub-investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study drug, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator, sub-investigator, or the reporting 
physician to decide whether a dose is to be considered an overdose, in consultation with the 
Sponsor.


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
All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the eCRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on AE page of the eCRF 
according to Section 10.0.

SAEs of overdose should be reported according to the procedure outlined in Section 10.2.9.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory 
distress syndrome (ARDS)
Hepatic necrosis
Acute liver failure
Torsade de pointes/ventricular fibrillation/ 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures (including convulsion and 
epilepsy)
Pulmonary fibrosis (including interstitial lung disease)
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis / oculomucocutaneous 
syndrome (Stevens-Johnson syndrome)
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements.
10.1.2 Special Interest AEs
A special interest AE (serious or non-serious) is an event of concern specific to the study drug. The 
special interest AEs in this study will be defined as liver dysfunction, gastrointestinal Clostridium 
difficile infection, and hypersensitivity.
The investigator and sub-investigator will monitor the subject for the occurrence of special interest 
AEs. An occurrence of any special interest AE should be reported according to the procedure 
described in Section 10.2.9.4. Such events may require further investigation to establish their
evaluation.
10.1.2.1 Liver Dysfunction
Liver dysfunction is defined as follows:

ALT or AST >2 × ULN, or

Total bilirubin >2 × ULN
A Liver Dysfunction Form must be completed with relevant detailed information on the subject, 
possible alternative etiologies (eg, acute viral hepatitis A or B or other acute liver disease or 
medical history/concurrent medical conditions), clinical course, and action taken for the event. 
Refer to Section 9.2.8.1 for the follow-up laboratory testing.
10.1.2.2 Gastrointestinal Clostridium difficile Infection
Gastrointestinal Clostridium difficile infection is defined as follows:

An AE with any of the following preferred terms (PT) of the Medical Dictionary for 
Regulatory Activities (MedDRA) Ver. 21.0: Clostridial infection, Clostridium bacteraemia, 


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Clostridium colitis, Clostridium difficile colitis, Clostridium difficile infection, Clostridial 
sepsis, Clostridium test positive, Gastroenteritis clostridial, or pseudomembranous colitis.
A Gastrointestinal Clostridium difficile Infection Form must be completed with relevant detailed
information on the subject, possible alternative etiologies (eg, concomitant use of antibacterial 
agents or immunosuppressive agents, or medical history/concurrent medical conditions), the 
clinical course, and action taken for the event.
10.1.2.3 Hypersensitivity
A hypersensitivity-related AE is defined as follows.

An AE related to hypersensitivity (eg, anaphylactic reaction, angioedema, erythema 
multiforme, urticaria, or rash) that led to discontinuation of the study drug.
A Hypersensitivity Form must be completed with relevant detailed information on the subject, 
possible alternative etiologies, the clinical course, and action taken for the event.
The special interest AEs should be record as AEs in the eCRF. The completed eCRF along with all 
other required documentation should be submitted to the Sponsor.
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
10.2.2 Assigning Causality of AEs
The causal relationship of each AE to study drug(s) will be assessed using the following 
categories:


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


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10.2.8 Outcome

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.9 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.9.1 Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at 
the time the subject signs the informed consent and continue until the end of examination at 
48 hours postdose in Period 2.
10.2.9.2 Reporting AEs
At each study visit, the investigator or sub-investigator will assess whether any subjective AEs 
have occurred. A neutral question, such as “How have you been feeling since your last visit?” may 
be asked. Subjects may report AEs occurring at any other time during the study.
Subjects experiencing an SAE prior to the first exposure to study drug must be monitored until the 
symptoms subside and any clinically relevant changes in laboratory values have returned to 
baseline or there is a satisfactory explanation for the change. Nonserious AEs that begin prior to 
the first exposure to study drug, related or unrelated to the study procedure, need not be 
followed-up for the purposes of the protocol.
All subjects experiencing AEs, 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 


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investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Investigator’s or sub-investigator’s opinion of the causal relationship between the event and 
administration of study drug(s).

Investigator’s or sub-investigator’s opinion of the causal relationship to study procedure(s), 
with a description of the suspected procedure.

Action taken with the study drug(s).

Outcome of event.

Seriousness.

Special Interest AEs.

Timing of occurrence (after administration of study drug[s]).
10.2.9.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
An SAE should be reported by the investigator or sub-investigator to the Sponsor within 
1 business day of the first onset or notification of the SAE, along with any relevant information. 
The investigator should submit a detailed SAE Form to the Sponsor within 10 calendar days. The 
information should be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s or sub-investigator’s name.

Name of the study drug(s).

Causality assessment.
Any SAE spontaneously reported to the investigator or sub-investigator following the AE 
collection period should be reported to the Sponsor if considered related to study participation.
SAE Follow-Up
If 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 


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written documentation and promptly submit 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.
10.2.9.4 Reporting Special Interest AEs
When a special interest AE (refer to Section 10.1.2) occurs through the AE collection period, it 
should be reported by the investigator or sub-investigator to the Sponsor within 1 business day of 
the first onset or notification of the event, along with any relevant information. The investigator 
should also submit a Special Interest AE Form to the Sponsor within 10 business days. 
Additionally, the investigator should submit the original copy of the Special Interest AE Form to 
the Sponsor.
The special interest AEs should be record as AEs in the eCRF.
10.2.9.5 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST >3 × ULN and total bilirubin >2 × ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.9.3. The investigator or sub-investigator must report to the study monitor and 
evaluate relevant subject details and possible alternative etiologies, such as acute viral hepatitis A 
or B or other acute liver disease, or medical history/concurrent medical conditions. Follow-up 
laboratory tests as described in Section 9.2.8 must also be performed.
10.2.10 Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs, and 
the head of the study site. Relative to the first awareness of the event by/or further provision to the 
Sponsor or Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and 
life-threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The Sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial. The study site also will forward a copy of all 
expedited reports to his or her IRB.


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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definitions of analysis variables, and analysis 
methodologies to address all study objectives.
After the database of the pilot study is locked for all the subjects’ data, statistical analysis will be 
performed on available data. In the case that the pivotal study is implemented, statistical analysis 
will also be performed on data from the pivotal study after the database of the pivotal study is 
locked for all of the subjects’ data.
11.1.1 Analysis Sets
In this study, 2 analysis sets are defined: the safety analysis set and PK analysis set. The definition 
of each analysis set will be described in the SAP.
The Sponsor will verify the validity of the definitions of the analysis sets and the rules for handling 
data in consultation with a medical expert, as needed. The Sponsor will address all remaining 
uncertainties not specified at planning, and will finalize the SAP prior to the database lock.
11.1.1.1 Safety Analysis Set
The safety analysis set will be defined as all subjects who received at least one dose of study drug.
11.1.1.2 PK Analysis Set
The PK analysis set will be defined as all subjects who received at least one dose of study drug, and 
whose PK data are evaluable.
11.1.2 Analysis of Demography and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized using the safety analysis set 
and PK analysis set.
11.1.3 PK Analysis
11.1.3.1 PK Endpoints and Its Analytical Methods
The primary endpoint of the study is:
PK (plasma concentration)

AUClast and Cmax of TAK-438F.
The secondary endpoints of the study are:
PK (plasma concentration)

AUC∞, tmax, MRT∞,ev, and λz of TAK-438F.


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Analytical methods:
The following analyses will be separately conducted using the PK analysis set for each study
(Study 1 and Study 2).
1) Plasma concentrations
At each time point scheduled for blood sampling, descriptive statistics of plasma 
concentrations of TAK-438F will be provided for each formulation (ie, TAK-438 OD tablet
and TAK-438 tablet). Case plots and mean plots with standard deviations (SD) will be 
provided for each formulation. Descriptive statistics of PK parameters will be provided for
each formulation. Additionally, descriptive statistics will be provided for AUClast and Cmax
ratios (TAK-438 OD tablet/TAK-438 tablet).
2) Testing for bioequivalence:
For log-transformed (natural log) AUClast and Cmax of TAK-438F (ie, the primary endpoint of 
the study), the two-sided 90% CI of the difference in the least square means between the 
formulations (TAK-438 OD tablet – TAK-438 tablet) will be provided using the analysis of 
variance (ANOVA) model. The same analyses will be performed for untransformed AUClast
and Cmax.
The same analyses will also be performed for AUC∞, tmax, MRT∞,ev, and λz (ie, the secondary 
endpoint of the study) to provide additional information.
11.1.3.2 Methods of Data Conversion and Handling of Missing Data
For plasma concentrations and laboratory test results, values below the lower limit of 
quantification will be treated as zero. The details will be provided in the SAP.
11.1.4 Safety Analysis
11.1.4.1 Safety Endpoints and Analytical Methods
Safety endpoints will be the following: 
TEAEs, clinical laboratory tests, vital signs, weight, and 12-lead ECG.
Analytical methods:
The following analyses will be separately conducted using the safety analysis set for each study
(Study 1 and Study 2).
1) TEAEs
A TEAE is defined as an AE with a date of onset that occurs on or after the start of study drug
administration. The analyses of TEAEs will be conducted for the following. TEAEs will be 
coded using the MedDRA dictionary and tabulated by system organ class (SOC) and PT for 
each formulation:

The frequency of all TEAEs


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
The frequency of drug-related TEAEs

The frequency of TEAEs by intensity

The frequency of drug-related TEAEs by intensity

The frequency of serious TEAEs
2) Clinical laboratory tests
For continuous variables, descriptive statistics of observed values and changes from baseline 
will be provided for each scheduled time point by formulation. Case plots of observed values 
will be provided for each formulation.
For categorical variables, shift tables showing the number of subjects in each category at 
baseline and each post-baseline scheduled time point will be provided for each formulation.
3) Vital signs and weight
For continuous variables, descriptive statistics of observed values and changes from baseline 
will be provided for each scheduled time point by formulation. Case plots of observed values 
will be provided for each formulation.
4) Other safety parameters
12-lead ECG parameters will be summarized as follows:
For continuous variables, descriptive statistics of observed values and changes from baseline 
will be provided for each scheduled time point by formulation. Case plots of observed values
will be provided for each formulation.
For categorical variables, shift tables showing the number of subjects in each category at 
baseline and each post-baseline scheduled time point will be provided for each formulation.
11.2
Interim Analysis and Criteria for Early Termination
After the completion of the pilot study, an analysis will be separately conducted for each study
(Study 1 and Study 2) on data obtained from the pilot study to determine whether the results may 
warrant further analysis in the pivotal study. On the basis of bioequivalence assessment in the pilot
study, the Sponsor will determine entry into the pivotal study after discussion(s) with the medical 
experts, and will promptly notify the investigator. Refer to Section 6.2 for the procedures for 
proceeding to the pivotal study.
11.3
Determination of Sample Size
In Studies 1 and 2, the planned number of subjects is 12 per sequence (total of 24 subjects) in the 
pilot study, and 24 per sequence (total of 48 subjects) in the pivotal study. Statistical basis for the 
sample size is presented below.
Assuming a root mean square error of 0.195 for PK parameters in the pilot study, the power of two 
one-sided t-tests to verify the bioequivalence [H0: ln(μ)≤ln(θ1), ln(μ)≥ln(θ2); H1: 
ln(θ1)<ln(μ)<ln(θ2); where μ=μt/μs, μt is the mean for TAK-438 OD tablet, μs is the mean for the 
concomitant administration of TAK-438 tablet, θ1=0.80, and θ2=1.25] at a one-sided significance 


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level of 5% and μ=0.95 to 1.05 would be ≥90% with a sample size of 12 subjects per sequence
(total of 24 subjects).
In the case that the pivotal study will be implemented, the number of subjects will be recalculated 
based on the results from the pilot study. Assuming a maximal root mean square error of 0.195 for 
PK parameters in the pivotal study, two one-sided t-tests with a one-sided significance level of 5% 
and μ=0.90 to 1.11 would need a maximum of 24 subjects per sequence (total of 48 subjects) to 
provide 90% power to verify the bioequivalence.


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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the Sponsor or its 
designee (contract research organization [CRO]) 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, trial drug, subject 
medical records, informed consent documentation, and review of eCRFs and associated source 
documents. It is important that the investigator and other study personnel are available during the 
monitoring visits and that sufficient time is devoted to the process.
12.2
Protocol Deviations
The investigator or sub-investigator can deviate and change from the protocol for any medically 
unavoidable reason, for example, to eliminate an immediate hazard to study subjects, without a 
prior written agreement with the Sponsor or a prior approval from IRB. In the event of a deviation 
or change, the investigator should notify the Sponsor and the head of the study site of the deviation 
or 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 IRB should be obtained.
The investigator or sub-investigator should document all protocol deviations.
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and 
Medical Devices Agency of Japan [PMDA]). If the study site is contacted for an inspection by a 
regulatory body, the Sponsor should be notified immediately. The investigator and the head of the 
study site guarantees access for quality assurance auditors to all study documents as described in 
Section 12.1.


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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Council for Harmonisation 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 A.
13.1
IRB Approval
IRBs must be constituted according to the applicable local requirements of each participating 
region. The Sponsor or designee will require documentation noting all names and titles of 
members who make up the respective IRB. If any member of the IRB has direct participation in 
this study, written notification regarding his or her abstinence from voting must also be obtained.
The Sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements and 
other documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB for approval. The IRB’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the Sponsor or designee before commencement of the study. 
The IRB approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, informed consent form) reviewed; and state the approval date. 
The Sponsor will notify study site once the Sponsor has confirmed the adequacy of study site 
regulatory documentation. Until the site receives notification no protocol activities, including 
screening, may occur.
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the Sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and Sponsor.
13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form describes the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 


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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 by the 
investigator or sub-investigator 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 prior to subject entering into the study.
Once signed, the original informed consent form will be stored in the investigator’s site file. The 
investigator or sub-investigator must document the date the subject signs the informed consent in 
the subject’s medical record. Copies of the signed informed consent form shall be given to the 
subject.
All revised informed consent forms must be reviewed and signed by relevant subjects in the same 
manner as the original informed consent. The date the revised consent was obtained should be 
recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, MHRA, PMDA), the Sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 


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reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (refer to Section 13.2).
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1 Publication and Disclosure
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results is the 
sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. The investigator or 
sub-investigator needs to obtain a prior written approval from the Sponsor to publish any 
information from the study externally, such as to a professional association.
13.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum, register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with facility name, investigator’s city, state (for Americas 
investigators), country, and recruiting status will be registered and available for public viewing.
13.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
study site where the subject is participating. If a local underwriter is required, then the Sponsor or 
Sponsor’s designee will obtain clinical study insurance against the risk of injury to study subjects. 
Refer to the study site agreement regarding the Sponsor’s policy on subject compensation and 
treatment for injury. If the investigator or sub-investigator has questions regarding this policy, he 
or she should contact the Sponsor or Sponsor’s designee.


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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information
A separate contact information list (Protocol Annex 1) will be provided to the study site.
14.1.2 Investigator Agreement
A separate agreement will be provided to the study site.
14.1.3 Study-Related Responsibilities
A separate contact information list (Protocol Annex 1) will be provided to the study site.
14.1.4 List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
BUN
blood urea nitrogen
eCRF
electronic case report form
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HBsAg
hepatitis B virus 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
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
PK
pharmacokinetics
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reaction
TAK-438F TAK-438 free base
ULT
upper limit of normal


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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The Sponsor or its designee will supply study sites with access to eCRFs. The Sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the Sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the study site.
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change.
The investigator must review the eCRFs for completeness and accuracy and must sign and date 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 in the eCRFs:

Laboratory results

Measurement results of drug concentrations
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator or sub-investigator with use of change and 
modification records of the eCRFs. The investigator must review the data change for completeness 
and accuracy, and must e-sign.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by 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.
15.2
Record Retention
The investigator and the head of the study site agree to keep the records stipulated in Section 15.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, all original signed and dated 


TAK-438ODT
Study ID TAK-438ODT-1001
Page 56 of 60
Protocol
12 December 2018
CONFIDENTIAL
informed consent forms, electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the Sponsor or its 
designees.
The investigator and the head of the study site are required to retain relevant essential documents 
until the day specified as 1 or 2 below, whichever comes later. However, if the Sponsor requests a 
longer time period for retention, the head of the study site should discuss how long and how to 
retain those documents with the Sponsor.
1. The day on which marketing approval for the study drug is obtained (or the day 3 years after 
the date of notification in the case that the investigation is discontinued.)
2. The day 3 years after the date of early termination or completion for the study.
In addition, the investigator and the head of the study site should retain the relevant essential 
documents until the receipt of a Sponsor-issued notification that states the retention is no longer 
required.


TAK-438ODT
Study ID TAK-438ODT-1001
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Protocol
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CONFIDENTIAL
16.0
REFERENCES
1. Guideline for Bioequivalence Studies of Generic Products, Pharmaceutical and Food Safety 
Bureau Notification No. 0229-10 (February 29, 2012).
2. Guideline for Bioequivalence Studies of Generic Products for Different Strengths of Oral 
Solid Dosage Forms, Pharmaceutical and Food Safety Bureau Notification No. 0229-10 
(February 29, 2012).
3. Guideline for Bioequivalence Studies for Different Oral Solid Dosage Forms, Pharmaceutical 
and Food Safety Bureau Notification No. 0229-10 (February 29, 2012).
4. Enforcement Regulation on the Law for Securing a Stable Supply of Safe Blood Products, 
Ministry of Health and Welfare Ordinance No. 22 (25 June 1956).
5. Japan Society for the Study of Obesity. Diagnostic Criteria for Obesity 2011. Journal of Japan 
Society for the Study of Obesity 2011 (Extra Edition).
6. General Considerations for Clinical Trials, Pharmaceutical Safety Bureau Notification No. 380 
(21 April 1998).


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d6809ec8f2
An Open-Label, Crossover Phase 1 Study to Evaluate the Bioequivalence of TAK-438 OD (Orally Disintegrating)
Tablet When Administered without Water (Study 1) or with Water (Study 2) and TAK-438 tablet in Healthy Adult
Male Subjects
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

SAP_001.pdf: 
 
 
Title: A Randomized, Open-Label, Single-Dose, 2×2 Crossover Phase 1 Study to Evaluate 
the Bioequivalence of TAK-438 OD (Orally Disintegrating) 20 mg Tablet When 
Administered without Water (Study 1) or with Water (Study 2) and TAK-438 20 mg 
Tablet When Administered with Water in Japanese Healthy Volunteer Male Subjects 
 
NCT Number: NCT03808493 
Statistical analysis plan  Approve Date: 27-DEC-2018 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 


1.0 
TITLE PAGE 
 
STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: TAK-438ODT-1001 
A Randomized, Open-Label, Single-Dose, 2×2 Crossover Phase 1 Study to Evaluate the 
Bioequivalence of TAK-438 OD (Orally Disintegrating) 20 mg Tablet When 
Administered without Water (Study 1) or with Water (Study 2) and TAK-438 20 mg 
Tablet When Administered with Water in Japanese Healthy Volunteer Male Subjects 
PHASE 1 
Version: 1st 
Date: 27 December 2018 
 
 
 
 
Prepared by:  
 
 
 
 
 
 
Based on: 
Protocol Version: 1 
Protocol Date: 12 December 2018 
 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be 
published or disclosed without written authorization from Takeda. 
PPD
PPD
PPD


 
TAK-438ODT-1001 
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CONFIDENTIAL 
1.1 
Approval Signatures 
Electronic signatures can be found on the last page of this document. 


 
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CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
 
1.0 
TITLE PAGE .................................................................................................................. 1 
1.1 
Approval Signatures .................................................................................................. 2 
2.0 
TABLE OF CONTENTS ................................................................................................. 3 
List of In-Text Figures........................................................................................................... 4 
3.0 
LIST OF ABBREVIATIONS .......................................................................................... 5 
4.0 
OBJECTIVES ................................................................................................................. 6 
4.1 
Primary Objective ...................................................................................................... 6 
4.2 
Secondary Objective .................................................................................................. 6 
4.3 
Safety Objective ........................................................................................................ 6 
4.4 
Study Design ............................................................................................................. 6 
5.0 
ANALYSIS ENDPOINTS ............................................................................................... 8 
5.1 
Primary Endpoints ..................................................................................................... 8 
5.2 
Secondary Endpoints ................................................................................................. 8 
5.3 
Safety Endpoints ........................................................................................................ 8 
6.0 
DETERMINATION OF SAMPLE SIZE ......................................................................... 9 
7.0 
METHODS OF ANALYSIS AND PRESENTATION ................................................... 10 
7.1 
General Principles .................................................................................................... 10 
7.1.1 Study Definitions ............................................................................................... 10 
7.2 
Analysis Sets ........................................................................................................... 10 
7.3 
Disposition of Subjects ............................................................................................ 10 
7.3.1 Study Information .............................................................................................. 10 
7.3.2 Screen Failures................................................................................................... 11 
7.3.3 Subject Eligibility .............................................................................................. 11 
7.3.4 Disposition of Subjects ...................................................................................... 11 
7.3.5 Protocol Deviations and Analysis Sets ............................................................... 12 
7.4 
Demographic and Other Baseline Characteristics ..................................................... 13 
7.5 
Medical History and Concurrent Medical Conditions ............................................... 13 
7.6 
Medication History and Concomitant Medications ................................................... 13 
7.7 
Study Drug Exposure and Compliance ..................................................................... 13 
7.8 
Efficacy Analysis ..................................................................................................... 14 
7.8.1 Primary Efficacy Endpoint(s) ............................................................................. 14 
7.8.2 Secondary Efficacy Endpoint(s) ......................................................................... 14 
7.8.3 Additional Efficacy Endpoint(s) ......................................................................... 14 
7.8.4 Statistical/Analytical Issues ................................................................................ 14 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis .......................................................... 15 
7.9.1 Pharmacokinetic Analysis .................................................................................. 15 
7.9.2 Pharmacodynamic Analysis ............................................................................... 17 


 
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7.10 
Other Outcomes ....................................................................................................... 17 
7.11 
Safety Analysis ........................................................................................................ 18 
7.11.1 Adverse Events .................................................................................................. 18 
7.11.2 Clinical Laboratory Evaluations ......................................................................... 20 
7.11.3 Vital Signs and Weight ...................................................................................... 22 
7.11.4 12-Lead ECGs ................................................................................................... 22 
7.11.5 Other Observations Related to Safety ................................................................. 23 
7.12 
Interim Analysis ...................................................................................................... 23 
7.13 
Changes in the Statistical Analysis Plan ................................................................... 23 
8.0 
REFERENCES .............................................................................................................. 24 
 
LIST OF IN-TEXT FIGURES 
Figure 4.a 
Schematic of Study Design .................................................................................. 7 
 


 
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3.0 
LIST OF ABBREVIATIONS 
ALP 
alkaline phosphatse 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
asparate aminotransferase 
BMI 
body mass index 
BUN 
blood urea nitrogen 
ECG 
electrocardiogram 
GGT 
gamma-glutamyl transferase 
MedDRA 
Medical Dictionary for Regulatory Activities 
SOC 
System Organ Class 
TAK-438F 
freebase of TAK-438 
TEAE 
treatment-emergent adverse event 
PT 
Preferred Term 
PTE 
pretreatment event 
 


 
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4.0 
OBJECTIVES 
4.1 
Primary Objective 
To evaluate the bioequivalence of a single oral administration of a TAK-438 OD 20 mg tablet 
without water in comparison with TAK-438 20 mg tablet (Study 1), and TAK-438 OD 20 mg 
tablet with water in comparison with TAK-438 20 mg tablet (Study 2) in Japanese healthy 
male volunteer subjects. 
4.2 
Secondary Objective 
To assess the Pharmacokinetic (PK) parameters other than AUClast and Cmax of TAK-438F 
in Japanese healthy volunteer male subjects who take a single oral dose of TAK-438 20 mg. 
4.3 
Safety Objective 
To assess the safety in Japanese healthy volunteer male subjects who take a single oral dose 
of TAK-438 20 mg. 
4.4 
Study Design 
This study which consists of two studies, Study 1 and Study 2, is a PK study in healthy 
Japanese subjects to evaluate the bioequivalence of single oral dose of TAK-438 OD 20 mg 
tablet without water and TAK-438 20 mg tablet with water (Study 1), and TAK-438 OD 
20 mg tablet with water and TAK-438 20 mg tablet with water (Study 2) in an open-label and 
crossover (2x2) design. The safety of TAK-438 OD 20 mg tablet, and TAK-438 20 mg tablet 
under fasted conditions without breakfast will also be evaluated. 
Pilot and Pivotal BE studies are planned for Study 1 and Study 2 in accordance with the 
“Guideline for Bioequivalence Studies of Generic Products” (PFSB/ELD Notification 
No.0229-10 dated 29 February 2012) as follows; 
Pilot and Pivotal BE studies will be conducted in the same design (inclusion/exclusion 
criteria, dose, regimen and schedule). Pilot BE studies will be conducted first for the sample 
size estimation to demonstrate the bioequivalence in Pivotal BE study. Pivotal BE study with 
the estimated sample size will be conducted to demonstrate the bioequivalence. The data 
from Pilot BE studies can be merged with the data from Pivotal BE study as needed when the 
bioequivalence is evaluated. Pivotal BE studies will not be conducted in the case the 
bioequivalence is demonstrated in Pilot BE study, or the results from Pilot BE study indicate 
that it is not feasible to demonstrate the bioequivalence. 
In the Pilot BE study, 24 subjects will be enrolled in each study (12 subjects in each treatment 
sequence). Subjects will be randomly assigned to either Treatment Sequences with 1:1 
allocation in each study. 
In the Pivotal BE study, 26 to 48 subjects will be enrolled in each study (13 to 24 subjects in 
each treatment sequence depending on outcome of the pilot BE study). Subjects will be 
randomly assigned to either Treatment Sequences with 1:1 allocation in each study. 
In each treatment sequence of Pilot and Pivotal BE studies, subjects will receive a single dose 
of either of TAK-438 OD 20 mg tablet without water or TAK-438 20 mg tablet with water 
(Study 1), and either of TAK-438 OD 20 mg tablet with water or TAK-438 20 mg tablet with 


 
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CONFIDENTIAL 
water (Study 2) on Day 1 in Period 1 and 2. If a subject discontinues from the study, a 
replacement subject may be enrolled, if deemed appropriate by the investigator and sponsor. 
The study site should contact the sponsor for the replacement of subject’s treatment 
assignment and medication identification number. 
The planned dose levels and dosing schedules of TAK-438 OD to be evaluated are outlined 
in Figure 4.a. 
Study 1: BE study when administered without water for TAK-438 OD tablet 
Pilot BE Study 
Sequence 
Period 1 
Period 2 
Number of 
subjects 
A 
One TAK-438 OD 20 mg tablet 
without water 
One TAK-438 20 mg tablet 
with 150 mL water  
12 
B 
One TAK-438 20 mg tablet 
with 150 mL water 
One TAK-438 OD 20 mg tablet 
without water 
12 
Dosing Condition: Fasted (without breakfast) condition 
 
Pivotal BE Study 
Sequence 
Period 1 
Period 2 
Number of 
subjects 
A 
One TAK-438 OD 20 mg tablet 
without water 
One TAK-438 20 mg tablet 
with 150 mL water 
13- 24 
B 
One TAK-438 20 mg tablet 
with 150 mL water 
One TAK-438 OD 20 mg tablet 
without water 
13-24 
Dosing Condition: Fasted (without breakfast) condition 
 
Study 2: BE study when administered with water for TAK-438 OD tablet 
Pilot BE Study 
Sequence 
Period 1 
Period 2 
Number of 
subjects 
C 
One TAK-438 OD 20 mg tablet 
with 150 mL water 
One TAK-438 20 mg tablet 
with 150 mL water 
12 
D 
One TAK-438 20 mg tablet 
with 150 mL water 
One TAK-438 OD 20 mg tablet 
with 150 mL water 
12 
Dosing Condition: Fasted (without breakfast) condition 
 
Pivotal BE Study 
Sequence 
Period 1 
Period 2 
Number of 
subjects 
C 
One TAK-438 OD 20 mg tablet 
with 150 mL water 
One TAK-438 20 mg tablet 
with 150 mL water 
13- 24 
D 
One TAK-438 20 mg tablet 
with 150 mL water 
One TAK-438 OD 20 mg tablet 
with 150 mL water 
13-24 
Dosing Condition: Fasted (without breakfast) condition 
Figure 4.a 
Schematic of Study Design 


 
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CONFIDENTIAL 
5.0 
ANALYSIS ENDPOINTS 
5.1 
Primary Endpoints 
• PK (plasma concentration): AUClast and Cmax of TAK-438F. 
5.2 
Secondary Endpoints 
• PK (plasma concentration): AUCinf, tmax, MRTinf,ev and Lambda z of TAK-438F. 
5.3 
Safety Endpoints 
• TEAEs, clinical laboratory tests, vital signs, weight, and ECG parameters. 


 
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6.0 
DETERMINATION OF SAMPLE SIZE 
In Studies 1 and 2, the planned number of subjects is 12 per sequence (total of 24 subjects) in 
the pilot study, and 24 per sequence (total of 48 subjects) in the pivotal study. Statistical basis 
for the sample size is presented below. 
Assuming a root mean square error of 0.195 for PK parameters in the pilot study, the power 
of two one-sided t-tests to verify the bioequivalence [H0: ln(μ)≤ln(θ1), ln(μ)≥ln(θ2); H1: 
ln(θ1)<ln(μ)<ln(θ2); where μ=μt/μs, μt is the mean for TAK-438 OD tablet, μs is the mean for 
the concomitant administration of TAK-438 tablet, θ1=0.80, and θ2=1.25] at a one-sided 
significance level of 5% and μ=0.95 to 1.05 would be ≥90% with a sample size of 12 subjects 
per sequence (total of 24 subjects). 
In the case that the pivotal study will be implemented, the number of subjects will be 
recalculated based on the results from the pilot study. Assuming a maximal root mean square 
error of 0.195 for PK parameters in the pivotal study, two one-sided t-tests with a one-sided 
significance level of 5% and μ=0.90 to 1.11 would need a maximum of 24 subjects per 
sequence (total of 48 subjects) to provide 90% power to verify the bioequivalence. 


 
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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
7.1.1 Study Definitions 
The following definitions and calculation formulas will be used. 
• Treatment-emergent adverse event (TEAE): An adverse event whose date of onset occurs 
on or after the start of study drug. 
• Pretreatment event (PTE): Any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study but prior to 
administration of study drug. 
• Descriptive statistics: Number of subjects, mean, standard deviation, maximum, 
minimum, and quartiles. 
• Coefficient of variation (CV) (%): Standard deviation / mean * 100. 
• Formulation. 
 TAK-438 OD 20 mg tablet. 
 TAK-438 20 mg tablet. 
• Sequence. 
 A: TAK-438 OD 20 mg tablet without water => TAK-438 20 mg tablet with water. 
 B: TAK-438 20 mg tablet with water => TAK-438 OD 20 mg tablet without water. 
 C: TAK-438 OD 20 mg tablet with water => TAK-438 20 mg tablet with water. 
 D: TAK-438 20 mg tablet with water => TAK-438 OD 20 mg tablet with water. 
7.2 
Analysis Sets 
• Safety analysis set: All subjects who received at least one dose of study drug. 
• Pharmacokinetic analysis set: All subjects who received at least one dose of study drug, 
and whose PK data are evaluable (e.g., withdrawal subjects who had no PK data in 
Period 2 will be excluded from this analysis set).  
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 of Last Subject’s Last Visit/Contact 
 
MedDRA Version 
 
SAS Version Used for Creating the Datasets 


 
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CONFIDENTIAL 
Analytical 
Method(s): 
 
(1) Study Information 
Study information shown in the analysis variables section will be provided. 
7.3.2 Screen Failures 
Analysis Set: 
All Subjects Who Were Not Randomized 
Analysis 
Variable(s): 
 
Age (years)  
 
 
Analytical 
Method(s): 
 
(1) Screen Failures 
Descriptive statistics will be provided. 
7.3.3 Subject Eligibility 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s): 
 
Eligibility Status 
 
[Eligible for Randomization,  
Not Eligible for Randomization] 
 
Primary Reason for Subject Not 
Being Eligible 
[Adverse Event, Death, Lost to 
Follow-up, Protocol Deviation, 
Sample Size Sufficient, Screen 
Failure, Study Terminated by 
Sponsor, Withdrawal by Subject, 
Other] 
Analytical 
Method(s): 
 
(1) Eligibility for Randomization 
Frequency distributions will be provided. When calculating percentages for 
the primary reasons for subject not being eligible, the total number of 
ineligible subjects will be used as the denominator. 
7.3.4 Disposition of Subjects 
Analysis Set: 
Randomized Set 
Analysis 
Variable(s): 
 
Study Completion Status 
 
[Completed Study, Prematurely 
Discontinued Study ] 
 
Reason for Discontinuation of 
Study Visits 
[Adverse Event, Death, Lost to 
Follow-up, Protocol Deviation, 


 
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CONFIDENTIAL 
Study Terminated by Sponsor, 
Withdrawal by Subject, Other] 
Analytical 
Method(s): 
 
(1) Disposition of Subjects 
Frequency distributions will be provided for each sequence and overall by 
study. When calculating percentages for the reasons for discontinuation, the 
total number of subjects who did not complete all planned study visits will be 
used as the denominator. 
7.3.5 Protocol Deviations and Analysis Sets 
7.3.5.1 Protocol Deviations 
Analysis Set: 
Randomized Set 
Analysis 
Variable(s): 
 
Significant Protocol Deviation 
 
[Entry Criteria, Concomitant Medication, 
Procedure Not Performed Per Protocol, 
Study Medication, Withdrawal Criteria, 
Major GCP Violations] 
Analytical 
Method(s): 
 
(1) Protocol Deviations 
Frequency distribution will be provided for each sequence and overall by 
study. A subject who has several deviations will be counted once in each 
appropriate category. A subject who has several deviations that can be 
classified into the same category will be counted only once. 
7.3.5.2 Analysis Sets 
Analysis Set: 
Randomized Set 
Analysis 
Variable(s): 
 
Handling of Subjects 
 
[Categories are based on the specifications 
in List of Subject Evaluability 
Assignments] 
 
Analysis Sets 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
 
[Included] 
[Included] 
Analytical 
Method(s): 
 
(1) Subjects Excluded from Analysis Sets 
Frequency distributions will be provided for each sequence by study.  


 
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CONFIDENTIAL 
A subject who has several reasons for exclusion will be counted once in each 
appropriate category. A subject who has several reasons for exclusion that 
can be classified into the same category will be counted only once. 
(2) Analysis Sets 
Frequency distributions will be provided for each sequence and overall by 
study. 
7.4 
Demographic and Other Baseline Characteristics 
Analysis Set: 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
 
Age (years) 
 
 
Height (cm) 
 
 
Weight (kg) (Predose of Period 1) 
 
 
BMI (kg/m2) (Predose of Period 1) 
 
 
Caffeine Classification 
[Yes, No] 
 
Alcohol Classification 
[Daily, A Few Times Per Week,  
A Few Times Per Month, No]  
 
Smoking Classification 
[Never, Current, Former] 
Analytical 
Method(s): 
 
(1) Summary of Demographics and Baseline Characteristics 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided for each sequence and overall by study. 
7.5 
Medical History and Concurrent Medical Conditions 
Not applicable. 
7.6 
Medication History and Concomitant Medications 
Not applicable. 
7.7 
Study Drug Exposure and Compliance 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s): 
 
Number of Times the Study Drug was Taken 
 
[1, 2] 
Analytical 
Method(s): 
 
(1) Study Drug Exposure 
Frequency distributions will be provided for each sequence by study. 


 
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7.8 
Efficacy Analysis 
Not applicable. 
7.8.1 Primary Efficacy Endpoint(s) 
Not applicable. 
7.8.2 Secondary Efficacy Endpoint(s) 
Not applicable. 
7.8.3 Additional Efficacy Endpoint(s) 
Not applicable. 
7.8.4 Statistical/Analytical Issues 
7.8.4.1 Adjustments for Covariates 
Not applicable. 
7.8.4.2 Handling of Dropouts or Missing Data 
Missing test results and data determined to be non-evaluable according to this document will 
not be used for hypothesis testing and estimations.  
For plasma concentrations and laboratory test results, values below the lower limit of 
quantification will be treated as zero when calculating the descriptive statistics. For 
laboratory test results, values above the upper limit of quantification will be treated as the 
upper limit value when calculating the descriptive statistics. 
7.8.4.3 Multicenter Studies 
Not applicable. 
7.8.4.4 Multiple Comparison/Multiplicity 
Not applicable. 
7.8.4.5 Use of an "Efficacy Subset" of Subjects 
Not applicable. 
7.8.4.6 Active-Control Studies Intended to Show Equivalence or Non-Inferiority 
In each of Study 1 and Study 2, the study drugs will be assessed for bioequivalence according 
to the Guideline for Bioequivalence Studies of Generic Products. If any of the following 
criteria is satisfied, TAK-438 OD tablet and TAK-438 tablet will be concluded to be 
bioequivalent. 
• For AUClast and Cmax of TAK-438F, the two-sided 90% CI of the difference in the 
means of log-transformed (natural log) parameter between the formulations is between 
0.8 and 1.25, inclusive. 


 
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• For AUClast and Cmax of TAK-438F, the difference in the means of log-transformed 
(natural log) parameter between the formulations is between 0.90 and 1.11, inclusive. 
Furthermore, the results of the elution test satisfy the requirements specified in the 
Guideline for Bioequivalence Studies of Generic Products. 
7.8.4.7 Examination of Subgroups 
Not applicable. 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis 
7.9.1 Pharmacokinetic Analysis 
7.9.1.1 Plasma Concentrations 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
 
Plasma Concentrations of TAK-438F 
Visit: 
Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 Hours Postdose 
Analytical 
Method(s): 
 
The following summaries will be provided by study. 
 
(1) Summary of Plasma Concentrations by Visit 
Descriptive statistics will be provided for each formulation by visit. 
 
(2) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each formulation. Visit 
will be plotted on the horizontal axis and each of the analysis variables 
will be plotted on the vertical axis. The vertical axis will be a normal 
scale. 
 
(3) Mean Plot of Plasma Concentrations 
Mean will be plotted for each formulation. Visit will be plotted on the 
horizontal axis and each of the analysis variables will be plotted on the 
vertical axis. The vertical axis will be a common logarithmic scale. 


 
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CONFIDENTIAL 
7.9.1.2 Pharmacokinetic Parameters 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
 
Pharmacokinetic parameters of TAK-438F 
 
AUClast 
Cmax 
AUCinf 
 
AUC48 
tmax 
CL/F 
 
Vz/F 
t1/2z 
Lambda z 
 
MRTinf,ev 
MRTlast,ev 
R(AUClast) 
 
R(Cmax) 
 
 
Analytical 
Method(s): 
 
The following summaries will be provided by by study. 
 
(1) Summary of Pharmacokinetic Parameters 
For AUClast, Cmax, AUCinf and AUC48, descriptive statistics, 
geometric mean, and CV will be provided for each formulation. 
For tmax, descriptive statistics will be provided for each formulation. 
For R(AUClast) and R(Cmax), descriptive statistics will be provided. 
For all other variables, descriptive statistics and CV will be provided for 
each formulation. 
7.9.1.3 Assessment of Bioequivalence 
Primary Endpoints 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
 
Pharmacokinetic parameters of TAK-438F 
 
AUClast 
Cmax 
 
Analytical 
Method(s): 
 
The following analyses will be performed by study. 
(1) The difference in the least square means between the formulations 
(TAK-438 OD 20 mg tablet - TAK-438 20 mg tablet) and the two-sided 
90% confidence interval will be provided using an ANOVA model. The 
ANOVA model will include log-transformed (natural log) analysis 
variable as dependent variable, and formulation, sequence, and period as 
independent variables. 
(2) For reference, the same analyses will be performed for untransformed 
analysis variables. 


 
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Secondary Endpoints 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
 
Pharmacokinetic parameters of TAK-438F 
 
AUCinf 
tmax 
MRTinf,ev 
 
Lambda z 
 
 
Analytical 
Method(s): 
 
The following analyses will be performed by study. 
(1) The difference in the least square means between the formulations 
(TAK-438 OD 20 mg tablet - TAK-438 20 mg tablet) and the two-sided 
90% confidence interval will be provided using an ANOVA model. The 
ANOVA model will include log-transformed (natural log) analysis 
variable as dependent variable, and formulation, sequence, and period as 
independent variables. 
 
(2) For reference, the same analyses will be performed for untransformed 
analysis variables. 
7.9.1.4 Individual Plasma Concentrations 
Analysis Set: 
Randomized Set 
Analysis 
Variable(s): 
 
Plasma Concentrations of TAK-438F 
Visit: 
Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 Hours Postdose 
Analytical 
Method(s): 
 
The following case plots will be provided by study. 
 
(1) Individual Plasma Concentrations of TAK-438F (vertical axis: normal 
scale) 
7.9.2 Pharmacodynamic Analysis 
Not applicable. 
7.10 
Other Outcomes 
Not applicable.  


 
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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] 
Analytical 
Method(s): 
 
The following summaries will be provided for each formulation by study. 
 
(1) Overview of Treatment-Emergent Adverse Events 
 
1) All Treatment-Emergent Adverse Events (number of events, number 
and percentage of subjects)  
 
2) Relationship of Treatment-Emergent Adverse Events to study drug 
(number of events, number and percentage of subjects)  
 
3) Intensity of Treatment-Emergent Adverse Events (number of events, 
number and percentage of subjects)  
 
4) Treatment-Emergent Adverse Events leading to study drug 
discontinuation (number of events, number and percentage of 
subjects)  
 
5) Serious Treatment-Emergent Adverse Events (number of events, 
number and percentage of subjects)  
 
6) Relationship of Serious Treatment-Emergent Adverse Events to 
study drug (number of events, number and percentage of subjects)  
 
7) Serious Treatment-Emergent Adverse Events leading to study drug 
discontinuation (number of events, number and percentage of 
subjects)  
 
8) Treatment-Emergent Adverse Events resulting in death (number of 
events, number and percentage of subjects)  
 
TEAEs will be counted according to the rules below. Percentages for each 
formulation will be based on the number of subjects who were treated by that 
formulation in the safety analysis set. 
Number of subjects 
• Summaries for 2) and 6)  
A subject with occurrences of TEAE in both categories (i.e., Related and 


 
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Not Related) will be counted once in the Related category. 
• Summary for 3)  
A subject with multiple occurrences of TEAE will be counted once for the 
TEAE with the maximum intensity. 
• Summaries other than 2) , 3) , and 6)  
A subject with multiple occurrences of TEAE will be counted only once. 
Number of events 
For each summary, the total number of events will be calculated. 
7.11.1.2 Displays of Treatment-Emergent Adverse events 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s): 
 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Analytical 
Method(s): 
 
The following summaries will be provided using frequency distribution for 
each formulation by study. 
TEAEs will be coded using the MedDRA and will be summarized using SOC 
and PT. SOC will be sorted alphabetically and PT will be sorted in 
decreasing frequency for tables provided by SOC and PT. SOC and PT will 
be sorted in decreasing frequency for tables provided by System Organ Class 
only or PT only. 
 
(1) Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
 
(2) Treatment-Emergent Adverse Events by System Organ Class 
 
(3) Treatment-Emergent Adverse Events by Preferred Term 
 
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
(5) Intensity of Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
 
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by 
System Organ Class, and Preferred Term 
 
(7) Serious Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
 
(8) Special Interest Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 


 
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The frequency distribution will be provided according to the rules below. 
Percentages for each formulation will be based on the number of subjects 
who were treated by that formulation in the safety analysis set. 
Number of subjects 
• Summary tables other than (5) and (6) 
A subject with multiple occurrences of TEAE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences of 
TEAE within a PT will be counted only once in that PT. 
• Summary tables for (5) and (6)  
A subject with multiple occurrences of TEAE within a SOC or a PT will 
be counted only once for the TEAE with the maximum intensity. 
7.11.1.3 Displays of Pretreatment Events 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s): 
 
PTE 
Analytical 
Method(s): 
 
The following summaries will be provided using frequency distribution. 
PTEs 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. 
 
(1) Pretreatment Events by System Organ Class and Preferred Term 
(2) Serious Pretreatment Events by System Organ Class and Preferred Term 
 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
A subject with multiple occurrences of PTE within a SOC will be counted 
only once in that SOC. A subject with multiple occurrences of PTE within a 
PT will be counted only once in that PT. 
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  
 
 
WBC Differentials (Neutrophils, Eosinophils, Basophils, Monocytes, 


 
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Lymphocytes) 
 
Hemoglobin 
Hematocrit 
Platelets 
 
Serum Chemistry 
 
ALT 
Albumin 
ALP 
 
AST 
Total Bilirubin 
Total Protein 
 
Creatinine 
BUN 
Creatine Kinase 
 
GGT 
Potassium 
Sodium 
 
Glucose 
Chloride 
 
Visit: 
Predose, 48 Hours Postdose 
Analytical 
Method(s): 
 
The following summaries will be provided for each formulation by study. 
 
(1) Summary of Laboratory Test Results and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline (48 
Hours Postdose - Predose) will be provided by visit. 
 
(2) Case Plots of Laboratory Test Results 
Plots over time for each subject will be presented. 
 
(3) Summary of Shifts of Laboratory Test Results 
Shift tables showing the number of subjects in each category at Predose 
visit and 48 Hours Postdose visit will be provided. 
For each laboratory test, the laboratory values will be classified as 
"Low", "Normal" or "High" relative to the normal reference range. The 
shift tables will be based on these classifications. 
7.11.2.2 Urinalysis 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s): 
 
pH 
 
 
Specific Gravity 
 
 
Protein 
 
 
Glucose 
 
Visit: 
Predose, 48 Hours Postdose 
Analytical 
Method(s): 
 
For specific gravity, summaries (1) to (3) will be provided for each 
formulation by study. 
For each variable other than specific gravity, summaries (3) will be provided 
for each formulation by study. 


 
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(1) Summary of Urine Laboratory Test Results and Change from Baseline 
by Visit 
Descriptive statistics for observed values and changes from baseline (48 
Hours Postdose - Predose) will be provided by visit. 
 
(2) Case Plots of Urine Laboratory Test Results 
Plots over time for each subject will be presented. 
 
(3) Number of Subjects in Categories of Urine Laboratory Test Results 
Shift tables showing the number of subjects in each category at Predose 
visit and 48 Hours Postdose visit will be provided. 
7.11.3 Vital Signs and Weight 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s): 
 
Temperature 
 
 
Respiration Rate 
 
 
Systolic Blood Pressure 
 
 
Diastolic Blood Pressure 
 
 
Pulse 
 
 
Weight 
 
Visit: 
Predose, 48 Hours Postdose 
Analytical 
Method(s): 
 
The following summaries will be provided for each formulation by study. 
 
(1) Summary of Vital Signs Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline (48 
Hours Postdose - Predose) will be provided by visit. 
 
(2) Case Plots of Vital Signs Parameters and Weight 
Plots over time for each subject will be presented. 
7.11.4 12-Lead ECGs 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s): 
 
Heart Rate 
 
 
RR Interval 
 
 
PR Interval 
 
 
QT Interval 
 
 
QRS Interval 
 


 
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QTcF Interval 
 
 
Interpretation 
[Within Normal Limits, Abnormal but not Clinically 
Significant, Abnormal and Clinically Significant] 
Visit: 
Predose, 48 Hours Postdose 
Analytical 
Method(s): 
 
For each variable other than 12-lead ECG interpretations, summaries (1) and 
(2) will be provided for each formulation by study. 
For 12-lead ECG interpretation, summary (3) will be provided for each 
formulation by study. 
 
(1) Summary of ECG Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline (48 
Hours Postdose - Predose) will be provided by visit. 
 
(2) Case Plots of ECG Parameters 
Plots over time for each subject will be presented. 
 
(3) Summary of Shift of 12-lead ECG Interpretation 
Shift table showing the number of subjects in each category at Predose 
visit and 48 Hours Postdose visit will be provided. 
7.11.5 Other Observations Related to Safety 
Not applicable. 
7.12 
Interim Analysis 
In this study, an analysis will be performed after the completion of the pilot study to 
determine whether the results may warrant further analysis in the pivotal study for both 
Studies 1 and 2. On the basis of bioequivalence assessment in the pilot study, the Sponsor 
will decide, after discussion(s) with the medical experts, on whether to proceed to the pivotal 
study and promptly notify the investigator of the decision (in regard to Criteria of 
bioequivalence, refer to Section 7.8.4.6).  
In the case that the results from the analysis satisfy the criteria of bioequivalence: 
The study (Study 1 or 2) will be completed with the pilot study and without implementing the 
pivotal study. 
In the case that the results from the analysis do not meet the criteria of bioequivalence: 
The pivotal study will be implemented after the number of subjects required to conclude the 
bioequivalence in the study (Study 1 or 2) is calculated based on the results from the pilot 
study. Any evidence from the pilot study suggesting difficulties in bioequivalence testing in 
the pivotal study may lead to the pivotal study not being implemented. 
7.13 
Changes in the Statistical Analysis Plan  
Not applicable. 


 
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8.0 
REFERENCES 
No reference.