Clinical trial NCT03085836
Conditions: Healthy Participants
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2017-04-19; Completion date: 2017-08-17
Enrollment: 33 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the pharmacokinetics (PK) of TAK-438 in healthy adult Chinese participants after both single and multiple dose administration.

Detailed description:
The drug being tested in this study is called TAK-438. TAK-438 is being tested in healthy participants in order to evaluate the PK of single and multiple oral dose.

The study will enroll approximately 36 healthy participants. Participants will be assigned to one of the three treatment groups:

* TAK-438 10 mg tablet once daily
* TAK-438 20 mg tablet once daily
* TAK-438 20 mg tablet twice daily All participants will be asked to take TAK-438 tablet at the same time on Day 1 and Days 3-9.

This single-centre trial will be conducted in China. The overall time to participate in this study is 18 days. Participants will remain confined to the clinic from Day 1 up to Day 11 and will be followed-up by telephone or visit on Day 18.

Arms: arm 1: TAK-438 10 mg, tablets, orally, once daily on Days 1, 3-9. Participants were required to fast for a minimum of 10 hours prior administration of assigned treatment. arm 2: TAK-438 20 mg, tablets, orally, once daily on Days 1, 3-9. Participants were asked to fast for a minimum of 10 hours prior administration of assigned treatment. arm 3: TAK-438 20 mg, tablets, orally, once on Day 1 and twice daily on Days 3-9. Participants were asked to fast for a minimum of 10 hours prior to breakfast, followed by administration of assigned treatment 0.5 hours after breakfast and dinner.
Interventions: intervention 1: TAK-438
Intervention descriptions: intervention 1: TAK-438 tablets.

Protocol documents:
Prot_000.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title:  An Open-Label, Single-center, Parallel, Phase 1 Study to Determine the Pharmacokinetics 
of Single- and Multiple- Oral Doses of TAK-438 10 mg and 20 mg in Healthy Adult Chinese 
NCT Number: NCT03085836
Protocol Approve Date: 21 December 2016
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. 
Named persons or organizations associated with the study.
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.


1.0 TITLE PAGE
PHASE 1 PROTOCOL
An Open-Label, Single-center, Parallel, Phase 1 Study to Determine the Pharmacokinetics 
of Single- and Multiple- Oral Doses of TAK-438 10 mg and 20 mg in Healthy Adult Chinese 
Subjects
Pharmacokinetic Study of TAK-438 in Healthy Adult Chinese Subjects
Sponsor:
Takeda Development Center Asia Pte Ltd.
21 Biopolis Road
Nucleos North Tower, Level 4
Singapore 138567
Study Number:
TAK-438_114
IND Number:
Not applicable
EudraCT Number:
Not applicable
Compound:
TAK-438
Date:
21 December 2016
Amendment History
Date
Amendment Number
Region
01 August 2012
Initial Protocol
Asia Pacific
29 August 2016
01
Asia Pacific
21 December 2016
02
Asia Pacific
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided.
TDC sponsored Asian Pacific investigators will be provided with emergency medical contact 
information cards to be carried by each subject. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Issue
China Contact
Serious adverse event, pregnancy and 
special interest adverse event reporting
Quintiles Lifecycle Safety
(Refer to the Study Team Contact list)
Medical Monitor (medical advice on 
protocol, compound, and medical 
management of subjects)
Quintiles Asia Medical Sciences Group
(Refer to the Study Team Contact list)
Responsible Medical Officer (carries 
overall responsibility for the conduct of 
the study)
sia, Pte Ltd
21 Biopolis Road
Nucleos North Tower, Level 4
Singapore 138567
Tel: 
Fax: PPD
PPD
PPD


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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES 
Date
Date
Date
Date
PPD
PPD
PPD
PPD


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1.3
Protocol Amendment 02 Summary of Changes
Rationale for Amendment No. 02
This document describes the changes in reference to the protocol incorporating Amendment No. 
02. In addition, minor grammatical, editorial, and formatting changes were included for 
clarification purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix G.
Changes in Amendment No. 02
1. Reduced the fasting period after dosing from 4 hours to 2 hours in the once daily dosing 
regimen only.
2. For the collection of demographic data, replaced the requirement to collect date of birth with a 
requirement to collect age.
3. Clarified clinical laboratory sample collection volume and time points.
4. Change in compounds or parameters tested during clinical laboratory testing.
5. Reduced the frequency in 12-lead electrocardiogram monitoring, and revised procedure for 
abnormal (not clinically significant) ECGs at Screening.
6. Clarified that genotyping will be conducted at the local laboratory.
7. Clarified liver function test monitoring.
8. Removed the requirement for genitourinary monitoring as part of the physical examination.
9. Clarified the Chinese population eligible for inclusion into the study.
10. Minor updates for protocol consistency. 
11. Clarified the time point for vital sign measurements.
12. Follow-up Visit changed from a site visit to a Telephone Contact.
13. Clarification of 4-digit enrollment number assignment.
14. Addition of table describing window for urine sample collection.
15. Clarification of meals given during the Confinement Period.
16. Clarification for urinalysis on Day 3 and Day 9.


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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also protect the rights, safety, privacy, and well-being of 
study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State)
China
Location of Facility (Country)


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 02 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study Related Responsibilities.................................................................................14
3.2
Principal Investigator...............................................................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Corporate Identification...........................................................................................16
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.2
Rationale for the Proposed Study.............................................................................19
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................20
5.1
Objectives................................................................................................................20
5.1.1
Primary Objective .......................................................................................20
5.1.2
Additional Objectives..................................................................................20
5.2
Endpoints.................................................................................................................20
5.2.1
Primary Endpoints.......................................................................................20
5.2.2
Additional Endpoints ..................................................................................21
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................22
6.1
Study Design ...........................................................................................................22
6.2
Justification for Study Design, Dose and Endpoints .................................................23
6.3
Premature Termination or Suspension of Study or Investigational Site.....................24
6.3.1
Criteria for Premature Termination or Suspension of the Study...................24
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites ..24
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s).........................................................25
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............26
7.1
Inclusion Criteria .....................................................................................................26
7.2
Exclusion Criteria ....................................................................................................26
7.3
Excluded Medications and Dietary Products ............................................................28
7.4
Diet, Fluid, and Activity Control..............................................................................29
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................30


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7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................30
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................32
8.1
Study Medication and Materials...............................................................................32
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................32
8.1.1.1
Investigational drug................................................................................32
8.1.2
Storage........................................................................................................32
8.1.3
Dose and Regimen ......................................................................................32
8.1.4
Overdose.....................................................................................................33
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................33
8.3
Accountability and Destruction of All Study Medication .........................................34
9.0
STUDY PLAN ..............................................................................................................36
9.1
Study Procedures.....................................................................................................36
9.1.1
Informed Consent Procedure.......................................................................36
9.1.1.1
Pharmacogenomic Informed Consent Procedure.....................................36
9.1.2
Demographics, Medical History, and Medication History Procedure...........36
9.1.3
Physical Examination Procedure .................................................................36
9.1.4
Weight, Height, and BMI............................................................................37
9.1.5
Vital Sign Procedure ...................................................................................37
9.1.6
Documentation of Concomitant Medications...............................................37
9.1.7
Documentation of Concurrent Medical Conditions......................................37
9.1.8
Procedures for Clinical Laboratory Samples................................................38
9.1.9
Contraception and Pregnancy Avoidance Procedure....................................40
9.1.10
Pregnancy ...................................................................................................41
9.1.11
ECG Procedure ...........................................................................................41
9.1.12
Sample Collection for Genotype Analysis ...................................................42
9.1.13
Pharmacokinetic Sample Collection ............................................................42
9.1.13.1
Collection of Blood for Pharmacokinetic Sampling ................................42
9.1.13.2
Collection of Urine for Pharmacokinetic Sampling.................................43
9.1.13.3
Bioanalytical Methods............................................................................43
9.1.14
Pharmacokinetic Parameters........................................................................43
9.1.15
Documentation of Screen Failure ................................................................44
9.1.16
Documentation of Study Entrance...............................................................45
9.2
Monitoring Subject Treatment Compliance..............................................................45
9.3
Schedule of Observations and Procedures................................................................45
9.3.1
Screening (Day -28 to Day -2).....................................................................45


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9.3.2
Check-in (Day -1) .......................................................................................46
9.3.3
Study Entrance (Day 1)...............................................................................47
9.3.4
Day 2 and Day 10 .......................................................................................47
9.3.5
Multiple Dosing Phase (Days 3-9)...............................................................47
9.3.6
Check-Out (Day 11)....................................................................................48
9.3.7
Early Termination .......................................................................................49
9.3.8
Follow-up (Telephone Contact)...................................................................49
9.4
Blood Volume .........................................................................................................49
9.5
Biological Sample Retention and Destruction ..........................................................50
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................51
10.1
Definitions...............................................................................................................51
10.1.1
Pretreatment Events ....................................................................................51
10.1.2
AEs.............................................................................................................51
10.1.3
Additional Points to Consider for PTEs and AEs.........................................51
10.1.4
SAEs...........................................................................................................53
10.1.5
Special Interest AEs....................................................................................54
10.1.6
Severity of PTEs and AEs ...........................................................................54
10.1.7
Causality of AEs .........................................................................................54
10.1.8
Relationship to Study Procedures................................................................55
10.1.9
Start Date....................................................................................................55
10.1.10
Stop Date ....................................................................................................55
10.1.11
Frequency ...................................................................................................55
10.1.12
Action Concerning Study Medication..........................................................55
10.1.13
Outcome .....................................................................................................55
10.2
Procedures...............................................................................................................56
10.2.1
Collection and Reporting of AEs.................................................................56
10.2.1.1
PTE and AE Collection Period ...............................................................56
10.2.1.2
PTE and AE Reporting ...........................................................................56
10.2.2
Collection and Reporting of SAEs...............................................................57
10.2.3
Reporting of Abnormal Liver Function Tests ..............................................57
10.3
Follow-up of SAEs ..................................................................................................58
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................58
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................59
12.0
DATA HANDLING AND RECORDKEEPING............................................................60
12.1
CRFs (Electronic)....................................................................................................60


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12.2
Record Retention .....................................................................................................60
13.0
STATISTICAL METHODS..........................................................................................62
13.1
Statistical and Analytical Plans ................................................................................62
13.1.1
Analysis Sets...............................................................................................62
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................62
13.1.3
Pharmacokinetic Analysis ...........................................................................62
13.1.4
Safety Analysis ...........................................................................................62
13.1.4.1
Safety endpoints and analytical methods.................................................62
13.2
Interim Analysis and Criteria for Early Termination ................................................63
13.3
Determination of Sample Size..................................................................................63
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................64
14.1
Study-Site Monitoring Visits ...................................................................................64
14.2
Protocol Deviations..................................................................................................64
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................65
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................66
15.1
IRB and/or IEC Approval ........................................................................................66
15.2
Subject Information, Informed Consent, and Subject Authorization .........................67
15.3
Subject Confidentiality ............................................................................................68
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................68
15.4.1
Publication and Disclosure..........................................................................68
15.4.2
Clinical Trial Registration...........................................................................69
15.4.3
Clinical Trial Results Disclosure .................................................................69
15.5
Insurance and Compensation for Injury....................................................................69
16.0
REFERENCES..............................................................................................................70
LIST OF IN-TEXT TABLES
Table 6.a
Summary of Dose Cohorts .................................................................................22
Table 6.b
Schematic of Dosing and PK Sampling, by Cohort.............................................23
Table 7.a
Prohibited Medications ......................................................................................28
Table 8.a 
Investigational Drug...........................................................................................32
Table 8.b
Sponsor-Supplied Drug......................................................................................33
Table 9.a
Clinical Laboratory Tests...................................................................................39
Table 9.b
Collection of Blood Samples for Pharmacokinetic Analysis ...............................42
Table 9.c
Collection of Urine Samples for Pharmacokinetic Analysis................................43
Table 9.d
Approximate Blood Volume ..............................................................................50


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Table 10.a
Takeda Medically Significant AE List................................................................54
Table 14.a
Windows for Pharmacokinetic Blood Sample Collection....................................64
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................22
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................71
Appendix B
Responsibilities of the Investigator.....................................................................73
Appendix C
Elements of the Subject Informed Consent.........................................................75
Appendix D
Investigator Consent to Use of Personal Information..........................................78
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples for 
Pharmacokinetic Analysis ..................................................................................79
Appendix F
Collection, Storage, and Shipment of Plasma Samples for Genotyping Analysis
..........................................................................................................................82
Appendix G
Detailed Description of Amendments to Text.....................................................83


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Asia Pte Ltd.
Compound:
TAK-438 (vonoprazan)
Title of Protocol: An Open-Label, Single-center, Parallel, Phase 1 Study to 
Determine the Pharmacokinetics of Single- and Multiple- Oral Doses of 
TAK-438 10 mg and 20 mg in Healthy Adult Chinese Subjects
IND No.:
Not applicable
EudraCT No.:
Not applicable
Study Number: TAK-438_114
Phase: 1
Study Design:
This is a phase 1, parallel, open-label, single- and multiple-dose study of TAK-438 involving 36 healthy Chinese 
subjects between the ages of 18 and 45, inclusive, and considered eligible based on the inclusion and exclusion entry 
criteria.
Screening for potential subjects will occur between 28 and 2 days prior to confinement at the phase 1 unit. Selected 
eligibility criteria will be reconfirmed on Day -1 prior to assignment to the 10 mg or 20 mg once daily or 20 mg twice 
daily cohort, predose blood and urine sampling for PK measurements will also be taken. Having fasted for a minimum 
of 10-hours a single oral dose of TAK-438 will be administered on Day 1 followed by a pharmacokinetic sampling 
period of 48 hours. On Days 3 through to Day 9 subjects will receive their assigned daily dose(s) of TAK-438 
followed by another 12- or 48-hour pharmacokinetic sampling period (for the BID or QD regimens respectively). 
Besides monitoring concomitant medications and adverse events, physical examination, ECG, vital signs and clinical 
laboratory tests will be conducted to monitor safety. A schedule of assessments in listed in Appendix A. 
A schematic of the study design follows; routine diet and fluid controls are listed in Section 7.4
Screening
Check
-In
Single Dose and 
PK
48-
hour 
PK
Multiple 
Dosing 
(a)
Dosing 
and PK
48-
hour 
PK
Check
-Out
Follow-Up (b) 
Telephone 
Contact
Study Day 
-28 to -2
Day -1
Day 1
Day 2
Days 3-8
Day 9
Day 10
Day 11
Day 18 ±3 days
TAK-438 single 
dose 10 mg or 20 
mg
TAK-438 once daily 
10 mg or 20 mg or 
twice daily 20 mg
Confinement
(a) Dosing on Day 3 will be after the 48-hour PK sample collection.
(b) The follow-up telephone contact will assess adverse events, serious adverse events and any concomitant 
medications since the Day 11 visit (study exit).
Primary Objective:
To determine the pharmacokinetics of TAK-438 in healthy adult Chinese subjects after both single and multiple dose 
administration. 
Secondary Objectives:
To determine the safety and tolerability of TAK-438 in healthy adult Chinese subjects after both single and multiple 
dose administration.
Subject Population: 
Healthy subjects aged 18-45 inclusive. 
Number of Subjects:
Per cohort: 12: 
Estimated Total: 36 enrolled
Number of Sites:
1 site in China


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Dose Level(s):
TAK-438 10 mg QD; TAK-438 20 mg QD
TAK-438 20 mg BID 
Route of Administration:
Oral
Duration of Treatment:
Single dose on Day 1 followed by 7 days from Day 3 until 
Day 9
Period of Evaluation:
Approximately 18 days after completion of the 
screening period
Main Criteria for Inclusion:
1.
Healthy (male or non-pregnant, non-lactating female) Chinese adults.
2.
Subject has BMI of ≥19 and ≤ 26kg/m2 and weighs ≥50 kg.
A complete list of study inclusion criteria is provided in Section 7.1.
Main Criteria for Exclusion:
Subjects who have a clinically significant history of hypersensitivity to any drug or food or any excipients of 
TAK-438, a history of gastroesophageal reflux disease (GERD), symptomatic GERD, erosive esophagitis, duodenal 
ulcer, gastric ulcer, dyspepsia, Barrett’s esophagus, or Zollinger-Ellison syndrome, and subjects with a liver function 
test > upper limit of normal are excluded. A complete list of Exclusion criteria can be found in Section 7.2 and 
standard concomitant medications to be excluded in Section 7.3.
Main Criteria for Evaluation and Analyses:
- Pharmacokinetics: 
The concentrations of TAK-438F (free base of TAK-438) and the four major metabolites (M-I, M-II, M-III and 
M-IV-Sul) in plasma and urine will be measured as per the following summary:
Sample Type
Dosing Day
Time Postdose (hours)
Plasma
Day 1, *Day 9
Predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 
hours postdose
Plasma
*Days 4-8
Predose
Urine
Day 1, *Day 9
Predose, 0 to 6, 6 to 12, 12 to 24, 24 to 36 and 36 to 48 hours postdose
*note that for the 20 mg twice daily cohort: from Day 4 to Day 8 PK sampling should be drawn relative to the morning 
dose and, on Day 9 PK samples should only be taken until the 12-hour time point following the morning dose.
The primary pharmacokinetic variables will be assessed after the single dose on Day 1 and after the multiple dose on 
Day 9.
Pharmacokinetic variables will be derived from the plasma concentrations of TAK-438F and its metabolites M-I, 
M-II, M-III, M-IV-Sul as required. These will include, where appropriate, maximum observed plasma concentration 
(Cmax), time to reach Cmax (tmax), area under the plasma concentration-time curve from time 0 to infinity (AUC∞), area 
under the plasma concentration-time curve during a dosing interval (AUCτ) and terminal disposition half-life (t1/2z) on 
Day 1, and maximum observed plasma concentration, at steady state (Cmax,ss), time to reach Cmax at steady state (tmax,ss),
and area under the plasma concentration-time curve during a dosing interval, at steady state (AUCτ,ss) on Day 9.
Pharmacokinetic variables derived from the urine concentrations of TAK-438 and its metabolites M-I, M-II, M-III and 
M-IV-Sul will include amount excreted in urine from time 0 to time t (Aet), fraction of administered dose of drug 
excreted in urine from time 0 to time t (fe,t), and renal clearance (CLR) on Day 1, and amount of drug excreted in urine 
during a dosing interval (Aeτ), the fraction of the dose excreted unchanged in urine (fet), and renal clearance (CLR)on 
Day 9.
- Pharmacogenomics:
CYP2C19 genotype will be tested for each subject in order to ensure that we can fully interpret the study results. 
Although it is noted that cytochrome P450 3A4 (CYP3A4) is the main enzyme responsible for TAK-438 metabolism, 
the polymorphic CYP2C19 also has a minor contribution. 


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- Safety: 
Standard safety assessments for phase 1 studies will be collected which include physical examinations, vital signs, and 
ECG as described in Section 9.1.
- Laboratory tests: 
Standard laboratory tests will be assessed as provided in Section 9.1.8. The total volume of blood to be drawn for study 
participants is 328.5 mL if a catheter is used.
Statistical Considerations:
For TAK-438F and its four metabolites M-I, M-II, M-III and M-IV-Sul plasma and urine concentration and 
pharmacokinetic parameters will be tabulated and descriptive statistics computed.
Sample Size Justification: 
The sample size of 12 subjects per cohort is sufficient to evaluate the PK profile after single- and multiple-dose 
administration of TAK-438 10 mg and 20 mg. And, it is also consistent with CFDA guideline “Technical guideline for 
clinical pharmacokinetics study of chemicals”.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator
Zhongshan Hospital, Fudan University
180 Fenglin Road, Xuhui District,
Shanghai, P.R. China
PPD


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3.3
List of Abbreviations
ADME
absorption, distribution metabolism, excretion
AE
adverse event
Aet
amount of drug excreted in urine time 0 to t, 
Aeτ
amount of drug excreted in urine time 0 to tau,
ALT
alanine aminotransferase
ANOVA
analysis of variance
aPTT
activated prothrombin time
AST
aspartate aminotransferase
AUC∞
area under the plasma concentration-time curve from time 0 to infinity.
AUCτ
area under the plasma concentration-time curve during the dosing interval.
AUClast
area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration (tlqc).
Cav,ss
average plasma concentration during a dosing interval, at steady state
CFR
Code of Federal Regulations
CL/F
apparent clearance.
CLR
renal clearance.
Cmax
maximum observed plasma concentration
eCRF
case report form (electronic)
CRO
contract research organization
Cmax,ss
maximum observed plasma concentration during a dosing interval, at steady state.
Cmin,ss
minimum observed plasma concentration during a dosing interval, at steady state
ECG
electrocardiogram
EDC
electronic data capture
EMEA
European Medicines Agency
FDA
Food and Drug Administration
FAS
full analysis set
fe
fraction of administered dose of drug excreted in urine, from time 0 to time t. 
fe,τ
fraction of administered dose of drug excreted in urine during a dosing interval
GCP
Good Clinical Practice
GGT
-glutamyl transferase
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IVRS
interactive voice response system
IWRS
interactive web response system
LDH
lactate dehydrogenase


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LLN
lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
MRT
mean residence time 
PTE
pretreatment event
PTF%
peak/trough fluctuation during a dosing interval, at steady state.
PT/INR
prothrombin time/international normalized ratio
Rac(AUC)
accumulation ratio based on AUC.
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
t1/2z
terminal disposition phase half-life.
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
Vz/F
apparent volume of distribution.
WBC
white blood cell
WHO
World Health Organization
λz
terminal disposition phase rate constant.
3.4
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
The proton pump inhibitors (PPIs), such as lansoprazole, represent the drugs of first choice for 
gastric and duodenal ulcers, as well as non-erosive or erosive esophagitis and are being widely 
used.
The PPIs inhibit the H+, K+-ATPase enzyme (proton pump) which represents the final step in acid 
secretion by the parietal cells in the gastric mucosa, and produce potent anti-secretory efficacy for 
acid-related disorders. 
However, even with these potent acid-inhibitory effects, the PPIs are not without their limitations 
and have not necessarily produced adequate improvements in extent and speed of symptom relief 
[1]. Indeed, the PPIs appear to leave room for improvement, the reasons being that: 
1. Being less resistant to acid exposure and provided as enteric-coated drugs, the PPIs vary in 
time for onset of their action; 
2. About 3 to 5 days are required to obtain maximum acid-inhibitory effects with the PPIs; 
3. Acid-inhibitory effects with the PPIs appear to be satisfactory during daytime, but not 
adequate to inhibit acid regurgitations from the stomach to the esophagus occurring during 
nighttime, leading to nocturnal acid breakthroughs in some individuals; 
4. Metabolized by CYP2C19 associated with polymorphisms, the PPIs are associated with 
varying serum concentrations, thus producing disparate acid-inhibitory effects in extensive 
metabolizers (EM) versus poor metabolizers (PM). 
Developed at Takeda Pharmaceutical Company Ltd, TAK-438 belongs to a new class of 
acid-inhibitory agents called “potassium-competitive acid blockers” (P-CAB). TAK-438 is shown 
not only to inhibit the H+,K+-ATPase enzyme in the final step of acid secretion, as the PPIs do, but 
does not require the presence of acid for its activation and inhibits the H+,K+-ATPase enzyme in a 
potassium-competitive fashion. Furthermore, TAK-438 is shown to be stable in the presence of 
acid and is water-soluble, requires no particular pharmacological preparations, such as an enteric 
coating, suggesting that TAK-438 may likely vary less in time for onset of action than the PPIs 
among those receiving the drug. Furthermore, in contrast to the PPIs which take 3 to 5 days to 
produce their maximum acid-inhibitory effects, TAK-438 is expected to produce its maximum 
acid-inhibitory effects in a much shorter time and to produce better outcomes than the PPIs with its 
potent and sustained acid-inhibitory effects. 
In Japan, TAK-438 has been evaluated for the doses ranging between 1 mg and 120 mg in a phase 
I study (TAK-438/CPH-001) as well as for safety, pharmacokinetics, and acid-inhibitory effects in 
a 7-day repeated-dose study (TAK-438/CPH-002) at the doses ranging between 10 mg and 40 mg. 
TAK-438 has been found to be well tolerated when given at the dose of 40 mg in the 7-day 
repeated-dose study, where the pH4 holding time ratio (pH4 HTR) with TAK-438 10 mg on day 7 
was shown to be similar to that with lansoprazole 30 mg. However pH4 HTR was found to 
increase greatly with TAK-438 15 mg and 20 mg, and exceed 90% and remain stable with 


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TAK-438 30 mg and 40 mg, thus providing evidence of TAK-438’s potent and sustained 
acid-inhibitory effects. Furthermore, no specific trend was found with any of the CYP2C19 
polymorphisms, suggesting that these polymorphisms lead to very little difference in the 
pharmacokinetics of TAK-438. Additionally, in a study evaluating interactions between TAK-438 
and various non-steroidal anti-inflammatory drugs (NSAIDs) (eg, loxoprofen sodium, diclofenac 
sodium, meloxicam) (TAK-438/CPH-003), none of these drugs were shown to significantly affect 
the pharmacokinetics of TAK-438.
Studies of single-dose (TAK-438_101) and repeated-dose (TAK-438_107) TAK-438 were 
conducted in the UK as well, where TAK-438 was evaluated for its safety, pharmacokinetics and 
acid-inhibitory effects in the 7-day repeated-dose study at the doses ranging between 10 mg and 
40 mg. TAK-438 was shown to be well tolerated at the dose of 40 mg in the repeated-dose study, 
with the pH4 HTR on day 7 shown to be similar to that in the repeated-dose study conducted in 
Japan at either of the doses examined, supporting the potent and sustained acid-inhibitory effects 
of TAK-438. Again, in a study evaluating interactions between TAK-438 and clarithromycin 
conducted in the UK (TAK-438_110), repeated-dose clarithromycin was examined for its 
influence on the pharmacokinetics of TAK-438, where, while the plasma concentration of 
TAK-438F increased by 1.35-fold for Cmax and by 1.58-fold for AUC in combination with 
clarithromycin, a potent inhibitor of the CYP3A4 enzyme, TAK-438 was shown to be well 
tolerated.
In a phase II dose-ranging study of TAK-438 in subjects with erosive esophagitis 
(TAK-438/CCT-001), TAK-438, given once daily at doses 5 mg, 10 mg, 20 mg, and 40 mg for 
8 weeks, was evaluated for its dose-response efficacy and safety in a randomized, double-blind, 
parallel-group comparison with lansoprazole serving as control, demonstrating that the rate of 
endoscopic healing of erosive esophagitis 4 weeks after the start of treatment, the primary endpoint 
of the study, was 92.3%, 92.5%, 94.4%, and 97.0% with TAK-438 5 mg, 10 mg, 20 mg and 40 mg, 
respectively, compared to 93.2% with lansoprazole, showing the non-inferiority of TAK-438 to 
lansoprazole 30 mg at the doses examined. No particular safety concerns were identified with 
TAK-438 at the doses examined.
TAK-438 has been studied in a number of acid-related diseases and noninferiority with 
lansoprazole has been confirmed in several phase 3 studies including reflux esophagitis healing 
and prevention of recurrence studies, gastric ulcer (GU)/duodenal ulcer (DU) healing and for the 
prevention of recurrence of a gastric or duodenal ulcer during NSAID or aspirin administration 
and has subsequently been launched in Japan for these indications. Of note, in a phase 3 
Helicobacter pylori eradication study, 7-day treatment with TAK-438 20 mg (n=329) or 
lansoprazole 30 mg (n=321) in combination with amoxicillin 750 mg plus clarithromycin 200 or 
400 mg, Helicobacter pylori eradication rates were 92.6% and 75.9%, respectively. Furthermore, 
the first 50 treatment failures with good compliance received second-line triple-therapy with 
TAK-438 20 mg (in combination with amoxicillin 750 mg and metronidazole 250 mg) in an 
open-label manner and an eradication rate of 98% was observed. All treatments were 
well-tolerated.


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4.2
Rationale for the Proposed Study
TAK-438 has been evaluated in both Japanese healthy volunteers (TAK-438/CPH-001, 
TAK-438/CPH-002, and TAK-438/CPH-003 and non-Japanese healthy volunteers 
(TAK-438_101, TAK-438_103, TAK-438_107, TAK-438_109 and TAK-438_110). TAK-438 
has been evaluated in single-dose studies at doses of 1 to 120 mg, in multiple-dose studies at doses 
of 10, 15, 20, 30, and 40 mg, and in a phase 2 study at doses of 5, 10, 20 and 40 mg for 8 weeks. 
TAK-438 has also been evaluated for the effect of food at 10 and 40 mg doses in Japanese subjects, 
and for the effect of food and gender at a 20 mg dose in non-Japanese subjects. An ADME study 
using the 20 mg dose and a clarithromycin drug-drug interaction study using single doses of 40 mg
TAK-438 and multiple doses of 500 mg clarithromycin have also been completed.TAK-438 is 
considered safe and has been well-tolerated at all doses administered and at doses ≥20 mg had a 
rapid onset and prolonged duration of action. The effects of food and gender have no clinically 
relevant effect on the PK profile, however the use of the strong CYP3A4 inhibitor increased the 
exposure of TAK-438F and its metabolites by up to 2-fold. Completed PK studies indicate that 
four major metabolites should be assessed: M-I, M-II, M-III and M-IV-Sul. 
This study is designed based on the requirements of the China Food and Drug Administration 
(CFDA) for successful registration of TAK-438 in China. Phase 3 efficacy and safety trials will be 
performed concurrently in China and other countries within the Asian region. This single- and 
multiple-dose study design will provide adequate information on the pharmacokinetic profile of 
TAK-438 in adult Chinese subjects at the 10 mg, 20 mg and 40 mg dose levels.
This study will evaluate the PK of unchanged TAK-438F and the 4 metabolites following single-
and multiple-doses of 10 mg and 20 mg, ie, the doses used in the concurrent Asian Phase 3 efficacy 
and safety studies.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective 
To determine the pharmacokinetics of TAK-438 in healthy adult Chinese subjects after both single 
and multiple dose administration.
5.1.2
Additional Objectives
5.2
Endpoints
5.2.1
Primary Endpoints
The Primary endpoints for this study are the pharmacokinetic parameters derived from the plasma 
and urine concentrations of TAK-438F and its metabolites M-I, M-II, M-III, M-IV-Sul assessed 
after the first dose on Day 1 and after the final repeat dose on Day 9 as required. 
The following pharmacokinetic parameters will be calculated from plasma concentrations of 
TAK-438F, M-I, M-II, M-III and M-IV-Sul:
Day 1
!
Maximum observed plasma concentration (Cmax).
!
Time to reach Cmax (tmax).
!
Area under the plasma concentration-time curve from time 0 to infinity (AUC∞).
!
Area under the plasma concentration-time curve during a dosing interval (AUCτ).
!
Terminal disposition half-life (t1/2z).
Day 9
!
Maximum observed plasma concentration, at steady state (Cmax,ss).
!
Time to reach Cmax at steady state (tmax,ss).
!
Area under the plasma concentration-time curve during a dosing interval, at steady state
(AUCτ,ss).
The following pharmacokinetic parameters will be calculated from urine concentrations of 
TAK-438F, M-I, M-II, M-III and M-IV-Sul:
Day 1
!
Amount of drug excreted in urine from time 0 to time t (Aet).
CCI


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!
Fraction of administered dose of drug excreted in urine from time 0 to time t (fe,t).
!
Renal clearance (CLR).
Day 9
!
Amount of drug excreted in urine during a dosing interval (Aeτ).
!
Fraction of administered dose of drug excreted in urine during a dosing interval (fe,τ).
!
Renal clearance (CLR).
5.2.2
Additional Endpoints
CCI


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 1, parallel, open-label, single- and multiple-dose study of oral TAK-438 involving 
36 healthy Chinese subjects between the ages of 18 and 45, inclusive, and considered eligible 
based on the inclusion and exclusion entry criteria.
Screening for potential subjects will occur between 28 and 2 days prior to confinement at the phase 
1 unit. Selected eligibility criteria will be reconfirmed on Day -1 prior to assignment to the 10 mg 
or 20 mg once daily or 20 mg twice daily cohort, predose blood and urine sampling for PK 
measurements will also be taken. Having fasted for a minimum of 10-hours a single oral dose of 
TAK-438 will be administered on Day 1 followed by a pharmacokinetic sampling period of 48 
hours. On Days 3 through 9 subjects will receive their assigned daily dose(s) of TAK-438 followed 
by another pharmacokinetic sampling period of 48 hours (for subjects on a once daily regimen), or 
12 hours (for those assigned to the 20 mg twice daily regimen). The subject will be confined to the 
phase 1 unit from Day -1 (Check-In) through to Day 11 (Check-Out) and will be contacted by the 
study site for a follow-up telephone visit on Day 18.
Besides monitoring concomitant medications and adverse events, physical examination, ECG, 
vital signs and clinical laboratory tests will be conducted to monitor safety. A schedule of 
assessments is listed in Appendix A. A schematic of the study design follows; routine diet and 
fluid controls are listed in Section 7.4.
Figure 6.a
Schematic of Study Design
Screening Period
Treatment Period
Follow-Up
Screening
Check-
In
Single Dose/
PK
48-hour 
PK
Multiple 
Dosing (a)
Dosing 
and PK
48-hour PK / 
Observation
Check-
Out
Follow-up 
Telephone
Visit
Days -28
to -2
Day -1
Day 1
Day 2
Days 3-8
Day 9
Day 10
Day 11
Day 18 ± 3 
days
TAK-438 
single dose 10 
mg or 20 mg
TAK-438 once daily 
10 mg or 20 mg or 
twice daily 20 mg
Confinement 
PK=pharmacokinetic.
A summary of the dose cohorts is presented in Table 6.a.
Table 6.a
Summary of Dose Cohorts
Cohort
TAK-438 Dose (shown as free base amount)
Subjects
1
TAK-438 10 mg once daily
12
2
TAK-438 20 mg once daily
12
3
TAK-438 20 mg twice daily
12


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A schematic of the dosing schedule and sampling, by cohort, is provided in Table 6.b.
Table 6.b
Schematic of Dosing and PK Sampling, by Cohort
6.2
Justification for Study Design, Dose and Endpoints
For the patient population studied
This study will be performed in healthy subjects rather than the target subject population (ie, 
disease patients) in order to collect pharmacokinetic, safety and tolerability information that will 
not be biased by any comorbidities. This is also in compliance with CFDA data requirements.
For study design, sample size and genotyping used
1. Study design.
The study design is open label, since the primary objective is to assess objective variables, ie, 
pharmacokinetics. This is not a subjective measurement and there is consequently no risk of 
potential bias of the study results; hence there are no requirements for blinding and a placebo 
group.
2. Sample size.
The sample size is sufficient to establish the complete pharmacokinetic profile for TAK-438 and 
its major metabolites. It is also selected to be compliant with CFDA requirements.
3. CYP2C19 genotyping.
CYP2C19 genotype will be tested for each subject in order to ensure that we can fully interpret the 
study results. Although it is noted that cytochrome P450 3A4 (CYP3A4) is the main enzyme 
responsible for TAK-438 metabolism, the polymorphic CYP2C19 also has a minor contribution. 
For doses of the study medications used
This study supports the ongoing development program for the TAK-438 in Asia which includes 
planned Phase 3 studies in peptic ulcer diseases, and erosive esophagitis. The 10 mg and 20 mg 
once daily and 20 mg twice daily dose levels are selected as they are consistent with the planned 
phase 3 studies.


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For duration of treatment used
The half-life (mean) of a single oral dose of 20 mg of TAK-438 in healthy adult male subjects is 
5.8 hours for unchanged drug, 9.6 hours for M-I, 8.2 hours for M-II, 5.2 hours for M-III and 
3.8 hours for M-IV-Sul. Therefore a pharmacokinetic sampling period of 48 hours is considered 
sufficient to characterize the pharmacokinetic profile following a single dose of TAK-438. In 
addition it would be expected that following repeat dosing steady state would be achieved after 
5 half-lives, therefore the collection of samples to determine the pharmacokinetic profile 
following Day 7 should capture the steady state pharmacokinetic parameters. 
As supported by ADME study TAK-438_103, a follow-up examination (as an onsite visit) will be 
conducted 7 days after dosing, at which time the drug is considered to be completely eliminated 
from the body.
For endpoints used
The plasma concentration and urinary excretion rate of unchanged drug and major metabolites 
TAK-438 will be examined to establish the pharmacokinetics of dosing at 10 and 20 mg once daily 
and 20 mg twice daily. 
The commonly used safety endpoints of adverse events, vital signs, ECG findings, and laboratory 
test results are used in this study determined as safety endpoints.
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.


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6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/ independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to first dose of study medication 
on Day 1.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria:
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures. 
3. The subject is a healthy adult male or female Chinese subject.
4. The subject is aged 18 to 45 years, inclusive, at the time of signing the informed consent form.
5. The subject weighs at least 50 kg and has a body mass index (BMI) between 19 and 26kg/m2, 
inclusive at Screening (Check-In Day -1).
6. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
throughout the duration of the study and for 4 weeks after last dose of study medication.
*Definitions and acceptable methods of contraception are defined in Section 9.1.9
Contraception and Pregnancy Avoidance Procedure and reporting responsibilities 
are defined in Section 9.1.10 Pregnancy.
7. The subject is willing to abstain from caffeine and alcohol from 72 hours before first dose 
(Day 1) until the Follow-up Visit on Day 18.
8. The subject is willing to abstain from strenuous exercise from 72 hours before first dose 
(Day 1) until the Follow-up Visit on Day 18.
9. The subject is willing to provide a sample for pharmacogenetic analysis (for CYP2C19 
genotyping).
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 90 days prior to providing their 
informed consent.
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, study site employee, or in a dependant 
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. 


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4. The subject has uncontrolled, clinically significant cardiovascular disease or other
abnormality, which may impact the ability of the subject to participate or potentially confound 
the study results.
5. Subject is lactose intolerant or has a known hypersensitivity to any component of the 
formulation of TAK-438.
6. The subject has a positive urine drug result for drugs of abuse at Screening or Check-in 
(Day -1).
7. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse at any time prior to the screening visit or is unwilling to agree to abstain from alcohol 
and drugs throughout the study.
8. Subject has taken any excluded medication, supplements, or food products listed in the 
Excluded Medications and Dietary Products table listed in Section 7.3.
9. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after participating in this study; or intending to donate ova during such time 
period. 
10. Subject has evidence of current cardiovascular, central nervous system, hepatic, hematopoietic 
disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma 
hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the subject’s 
medical history, physical examination, or safety laboratory tests giving reasonable suspicion of 
a disease that would contraindicate taking TAK-438 or contraindicate any drug used to reduce 
acid secretion by the stomach or that might interfere with the conduct of the study. This 
includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias.
11. The subject has a history of symptomatic GERD, GERD, Erosive Esophagitis, DU, GU, 
dyspepsia, Barrett’s Esophagus, or Zollinger-Ellison (ZE) syndrome or has current or recent 
(within 6 months) gastrointestinal disease that would be expected to influence the absorption 
of drugs.
12. Subject has a history of cancer, other than basal cell or Stage 1 squamous cell carcinoma of the 
skin which has been in remission for at least 5 years prior to Day 1.
13. Subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody 
(HCV), human immunodeficiency virus (HIV) antibody/antigen at Screening.
14. Subject has used nicotine-containing products (including but not limited to cigarettes, pipes, 
cigars, chewing tobacco, nicotine patch or nicotine gum) within 6 weeks prior to Check-in 
Day -1. Cotinine test is positive at Screening or Check-in (Day -1).
15. The subject has poor peripheral venous access.
16. Subject has donated or lost 400 mL or more of his or her blood volume (including 
plasmapheresis), or had a transfusion of any blood product within 90 days prior to Day 1; or 
subject has donated or lost more than 200 mL or more of his or her blood in the last 28 days.


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17. Subject has a Screening or Check-in (Day -1) abnormal (clinically significant) ECG. Entry of 
any subject with an abnormal (not clinically significant) ECG must be approved, and 
documented by signature by the GCP-trained study doctor. Also refer to Section 9.1.11 for 
further instructions on ECG review.
18. Subject has abnormal Screening or Day -1 laboratory values that suggest a clinically 
significant underlying disease or subject with the following laboratory abnormalities: 

Creatinine levels: >2 mg/dL (>177 µmol/L).

Alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total bilirubin > the 
upper limit of normal (ULN).
7.3
Excluded Medications and Dietary Products
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until completion of all study activities.
Table 7.a
Prohibited Medications
6 weeks prior to
Check-In (Day -1)
28 days prior to Check-In 
(Day -1)
14 days prior to 
Check-In 
(Day -1)
7 days prior to Check-In 
(Day -1)
72 hours prior 
to Check-In 
(Day -1)
Nicotine-containin
g products
Prescription medications
OTC medications
including 
salicylates (a)
Foods or beverages containing 
grapefruit or grapefruit 
products, Seville-type (sour) 
oranges and marmalade or 
other Seville orange products.
Alcohol-
containing 
products or 
medications
Immunization/
vaccines
St. John’s wort, ginseng, kava, 
ginkgo biloba, Chinese herbs, 
melatonin, other herbal or 
homeopathic preparations or 
other nutraceuticals.
Vitamin 
supplements
Products or 
medications 
containing 
caffeine or 
xanthine
OTC=over-the-counter. 
(a) Occasional use of paracetamol (2 g/day) is allowed or other OTC medication as approved by Takeda’s or designated CRO’s 
Medical Monitor on a case-by-case basis during the 14 days prior to Day -1. Neither paracetamol nor any other OTC medication is 
allowed from Day 1 to Day 11 (after last PK sample collection).
Subjects must be instructed not to take any medications, including over-the-counter medications, 
without first consulting with the investigator.
Use of concomitant medications will not be allowed during the study except for those approved by 
Takeda’s (or designated CRO’s) Medical Monitor on a case-by-case basis during the screening
phase. No concomitant medications will be allowed from Day 1 until Day 11 (after last PK 
sampling time point) unless deemed necessary in a medical emergency. Concomitant medications 
will include all medications the subject has taken from signing of informed consent to the end of 
the study (Day 18).
The use of oral hormonal contraceptives and hormone replacement therapy is not allowed. 
Exceptions to the above prohibited medication will be reviewed on a case-by-case basis by the 
Takeda (or designated CRO) Medical Monitor.


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If the subject reports taking any medication or if administration of any medication becomes 
necessary during the course of this study, the Takeda (or designated CRO) Medical Monitor must 
be notified. All medications must be recorded in the source documents as well as on the 
appropriate electronic case report form (eCRF) along with dosage information, dates of 
administration, and reasons for use.
7.4
Diet, Fluid, and Activity Control
Subjects will be confined to the clinic for the duration of each treatment period (Day -1 through 
Day 11).
During the confinement period, subjects will be given a menu for the dosing period that includes 
3 meals. Each meal will contain approximately 20% to 25% fat (relative to the total calories), 
according to the local phase 1 unit standard. The menu of the standardized meals from the clinical 
research site will be approved by Takeda before the implementation. The study menu should be 
recorded and submitted to the study file with a copy provided to the sponsor prior to the start of the 
study.
If a blood draw or any study procedure coincides with a meal, the study procedure will take 
precedence followed by the blood draw and then the meal.
For subjects receiving QD regimen, they should be fasted overnight for a minimum of 10 hours 
prior to dosing and will continue to fast for 2 hours after dosing. They should take the dose with 
240 mL water and refrain from drinking for at least 1 hour postdose, after which water can be 
given ad libitum.
For subjects receiving BID regimen they should be fasted overnight for a minimum of 10 hours 
prior to breakfast. Breakfast and dinner should be given at approximately the same time each day 
on Day 1 to Day 10. Breakfast and dinner should be completed within 0.5 hours and then TAK-438 
should be administered 0.5 hours after the start of breakfast/dinner on the day of dosing. Subjects 
will continue to fast for 4 hours after dosing. They should take the dose with 240 mL water and 
refrain from drinking for at least 1 hour postdose, after which water can be given ad libitum.
Subjects will refrain from strenuous exercise for 72 hours prior to the first dose and for the 
duration of their participation in the study (Day 18).
Subjects will be informed that blood donation is not allowed for at least 12 weeks after the final 
examination of this study.
If a subject visits another medical institution during the study period, the investigator should be 
informed of the circumstances and therapy, and should communicate with the medical institution 
about the subject’s participation in the study.


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7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study should be 
recorded in the case report form ([e]CRF) using the following categories. For screen failure 
subjects, refer to Section 9.1.15.
1. Pretreatment event or adverse event (AE). The subject has experienced a pretreatment event or 
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 pretreatment 
event or AE.

Liver Function Test Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any time 
during study medication treatment:
–
ALT, AST, or total bilirubin >2 × ULN.
2. Significant protocol deviation. The discovery after administration of the first dose of study 
medication that the subject failed to meet protocol entry criteria or did not adhere to protocol
requirements, and continued participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) 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).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may terminate a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded. In 


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addition, efforts should be made to perform all procedures scheduled for the Final/Study Exit 
Visit.
Discontinued or withdrawn subjects will not be replaced after treatment assignment.


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to TAK-438 10 mg and 20 mg tablets. 
8.1.1.1
Investigational drug
The chemical name of TAK-438 is: 
1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrrol-3-yl]-N-methyl methanamine 
monofumarate. Note that there is no generic name assigned at the time of writing this protocol.
Table 8.a
Investigational Drug
Name, strength and 
dose form
Description
Manufacturer
TAK-438 10 mg 
tablets
Pale yellow film-coated tablet
Takeda Pharmaceutical Company Limited, Osaka, Japan
TAK-438 20 mg 
tablets
Pale red film-coated tablet
scored on both sides
Takeda Pharmaceutical Company Limited, Osaka, Japan
TAK-438 investigational drug will be foil/foil blistered packaged into 10-dose child-resistant 
blister cards, containing a total of 10 tablets. Each blister card will be labeled in an open fashion 
with a single panel label which will include the investigational drug Name, strength and dose form, 
pertinent study information and the country-specific regulatory caution statement.
8.1.2
Storage
TAK-438 should be stored at 25°C; with excursions permitted 15°C to 30°C. Protect from 
moisture and humidity. Study medication is to remain in the blister card until time of dosing.
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. All study medication must be stored under 
the conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day. 
Temperature excursion must be reported to the sponsor or designee.
8.1.3
Dose and Regimen
Each subject who qualified to enter into the open label treatment on Day 1 will be assigned to 
receive a single dose of TAK-438 at either the 10 mg or 20 mg dose level. Subjects will 


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subsequently receive additional multiple doses of TAK-438 from Day 3 to Day 9 at the same dose 
level, note that for subjects in Cohort 3 this will be a 20 mg single dose, on Day 1, followed by a 20 
mg dose on a BID regimen, for total 40 mg daily dose from Day 3 to 9.
Table 8.b describes the dose and tablet count that will be provided to each group.
Table 8.b
Sponsor-Supplied Drug
Cohort
Group 
Description
Single Dose
(Day 1)
Multiple Dose 
(Days 3-9)
Regimen
1
TAK-438 10 
mg
One 10 mg 
TAK-438 tablet
One 10 mg TAK-438
tablet daily
After fasting for 10 hours (continue 
fasting for 2 hours after dosing)
2
TAK-438 20 
mg
One 20 mg 
TAK-438 tablet
One 20 mg TAK-438
tablet daily
After fasting for 10 hours (continue 
fasting for 2 hours after dosing)
3
TAK-438 20 
mg twice
One 20 mg 
TAK-438 tablet
One 20 mg TAK-438
tablet twice daily
After fasting for 10 hours, 1 tablet 0.5 
hours after breakfast and 1 tablet 
approximately 12 hours later and 0.5 
hours after dinner
8.1.4
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.
All cases of overdose (with or without associated adverse events) will be documented on an 
Overdose page of the eCRF, in order to capture this important safety information consistently in 
the database. Adverse events associated with an overdose will be documented on AE CRF(s) 
according to Section 10.0, Pretreatment Events and Adverse Events.
Serious adverse events (SAEs) of overdose should be reported according to the procedure outlined 
in Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically. 
8.2
Investigational Drug Assignment and Dispensing Procedures
Subjects will be assigned to receive a 4-digit enrollment number. The number will be assigned by 
the clinic site personnel in sequential order as follows:
Cohort 1: 10mg TAK-438 QD beginning with 1001
Cohort 2: 20mg TAK-438 QD beginning with 2001
Cohort 3: 20mg TAK-438 BID beginning with 3001
This 4-digit number will be used by the clinical site to facilitate the prelabeling of pharmacokinetic 
samples, and will be the only subject identifier used on all sample collections. It should also be 
contained on the pharmacokinetic transport vials shipped to the bioanalytical laboratory, and will 


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be used by the laboratory to report the subject data results. This 4-digit number should only be used 
for the purposes described in this section. It does not replace the 3-digit subject number which is 
assigned at the time the informed consent is obtained and which is used for all other procedures to 
identify the subjects throughout the study.
8.3
Accountability and Destruction of All Study Medication
Drug supplies will be counted and reconciled at the site before being returned to Takeda or 
designee or being destroyed. 
The investigator or designee must ensure that the study medication is used in accordance with the 
approved protocol and is dispensed only to subjects enrolled in the study. To document appropriate 
use of study medication (TAK-438 10 mg and 20 mg), the investigator must maintain records of all 
study medication delivery to the site, site inventory, use by each subject, and return to the sponsor 
or designee.
Upon receipt of study medication, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct and is in 
good condition. If quantity and conditions are acceptable, investigator or designee should 
acknowledge the receipt of the shipment by signing bottom half of the packing list and faxing per 
instructions provided on the form. If there are any discrepancies between the packing list versus 
the actual product received, Takeda must be contacted to resolve the issue. The packing list should 
be filed in the investigator’s essential document file.
The investigator must maintain 100% accountability for all study medication received and 
dispensed during his or her entire participation in the study. Proper drug accountability includes, 
but is not limited to:

Continuously monitoring expiration dates (drug label).

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator must record the current inventory of all study medication, TAK-438 10 mg and 
20 mg on a sponsor-approved drug accountability log. The following information will be recorded 
at a minimum: protocol number and title, name of investigator, site identifier/number, description 
of study medication, expiry or retest date, date and amount dispensed including the initials of the 
person dispensing and receiving the study medication. The same information will also be captured 
in the subject-level documentation.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the sponsor or its designee for destruction or destroyed at the site, as 


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applicable. The investigator will retain the original documentation regarding clinical study 
material accountability, return, and/or destruction, and copies will be sent to the sponsor or 
designee.
The investigator will be notified of any expiry date or retest date extension of clinical study 
material during the study conduct. On expiry date notification from the sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the sponsor or its designee for destruction.
In the event of expiry date extension of supplies already at the study site, supplies may be relabeled 
with the new expiry date at that site. In such cases, Takeda or its designee will prepare additional 
labels and all necessary documentation for completion of the procedure at the sites.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.1.1
Pharmacogenomic Informed Consent Procedure
The sampling of whole blood for CYP2C19 genotyping analysis is mandatory; every subject must 
sign the informed consent in order to participate in this study. The informed consent for the 
CYP2C19 genotyping analysis is a component of the overall study informed consent.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include age, sex, race, alcohol and caffeine 
consumption and smoking status of the subject at Screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the condition/disease under study that stopped at or prior to 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.7).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 28 days prior to signing of informed consent.
9.1.3
Physical Examination Procedure
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes and 
(11) other.
Any abnormal finding on a pretreatment physical examination assessment must be assessed as Not 
Clinically Significant (NCS) or Clinically Significant (CS) by the investigator and recorded in the 
source document and eCRF. All CS findings may be recorded either as a pretreatment event (only 
if they occurred after informed consent and before first dose of study medication) or as a 


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concurrent medical condition (if they were present before informed consent) in the source 
document and on the appropriate eCRF described in Section 10.0 or Section 9.1.7. 
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately prior to the start of the investigational drug (Day 1) must be 
assessed as NCS or CS by the investigator and recorded in the source document and eCRF. Any 
CS change, as determined by the investigator, will be recorded as an AE in source documentation 
and on the pretreatment event/AE eCRF described in Section 10.0. 
9.1.4
Weight, Height, and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated, using metric units with the formula provided below:
Metric:
BMI = weight (kg)/height (m)2
Height will be collected in centimeters to 1 decimal place and weight will be collected in 
kilograms to 1 decimal place. Results for BMI will be expressed with 1 decimal place.
Example:
-Height=176.2 cm (or 1.762 m), weight=79.2 kg; BMI=79.2/1.76.22=25.5 kg/m2.
9.1.5
Vital Sign Procedure
Vital signs will include body temperature (oral, tympanic, or axillary measurement), sitting blood 
pressure (after 5 minutes resting), respiration rate and pulse (bpm). On dosing days, vital sign 
measurements should be taken at predose in the morning, and it is recommended that for the 
remaining days, measurements should be taken at approximately the same time as on the dosing 
days.
If a blood draw or any study procedure coincides with a meal, the study procedure will take 
precedence, followed by the blood draw and then the meal.
9.1.6
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication, including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. Documentation will 
include dose and frequency (although only ‘total daily dose’ may be captured on the eCRF), as 
well as generic medication name, unit, route of administration, start and end dates, and reason for 
use. 
9.1.7
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, electrocardiogram 


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(ECG), or physical examination abnormalities noted at Screening or Day -1 examinations. The 
condition (ie, diagnosis) should be described.
9.1.8
Procedures for Clinical Laboratory Samples
All samples for clinical laboratory testing will be collected in accordance with acceptable 
laboratory procedures. The maximum volume of blood at any single visit is approximately 
14.7 mL, and the approximate total volume of blood is 53.5 mL. Except for urinalysis on Day 3 
and Day 9, laboratory samples will be taken following a minimum 10-hour overnight fast on the 
days stipulated in the Schedule of Study Procedures (Appendix A). On dosing days, samples for 
clinical laboratory testing should be drawn at predose in the morning (except for urinalysis on Day 
3 and Day 9 when urine PK collection shall be taken as priority). At the Screening Visit, Day-1 and 
Day 11, it is recommended that samples are drawn at approximately the same time as the dosing 
days.
Table 9.a lists the tests that will be obtained for each laboratory specimen.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cells
White blood cells (with 
differential: neutrophils, 
eosinophils, basophils, 
monocytes, lymphocytes)
Hemoglobin
Hematocrit
Platelets
PT/INR
aPTT
Reticulocyte percentage
Alanine aminotransferase (a, b)
Albumin
Alkaline phosphatase
Amylase
Aspartate aminotransferase (a, b)
GGT
Total bilirubin (a, b, c)
Direct bilirubin (b)
Uric Acid
Total protein
Triglycerides (a)
Serum creatinine
Blood urea 
Creatine kinase
Potassium
Sodium
Glucose (a)
Chloride
Calcium
Magnesium
Cholesterol (HDL and LDL)
Lactose dehydrogenase
pH
Specific gravity
Protein
Glucose
Nitrites
Bilirubin
Ketones
Urobilinogen
Microscopic Analysis:
RBC/high power field
WBC/high power field
Hyaline casts/low power 
field 
Granular casts/ low power 
field
Epithelial cells
Diagnostic Screening:
Serum
Urine
HIV test
Hepatitis panel, including HBsAg and anti-HCV Ab
Drug screen, including amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine, 
opiates, and cotinine
Female subjects of child-bearing potential only:
-
hCG (for pregnancy)
Female subjects of child-bearing potential only when 
menopause is suspected:
-
Follicle-stimulating hormone (FSH)
Breath Test
Alcohol (d)
(a) To be measured under fasting conditions.
(b) Included in liver function tests.
(c) Direct bilirubin will be measured if total bilirubin is >1.5xULN.
(d) A breathalyzer test will be performed and must be negative for alcohol at the Initial and preconfinement Screen 
Visits and at Check-in (Day -1).
The phase 1 unit’s local laboratory will perform laboratory tests for hematology, serum 
chemistries, and urinalysis. The results of laboratory tests will be returned to the investigator, who
is responsible for reviewing and filing these results.
If subjects experience an increase in any one of ALT, AST, or total bilirubin >2 ×ULN the study 
medication shall be stopped according to the discontinuation criteria. Follow-up laboratory tests 
(at a minimum, serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be 
performed within a maximum of 7 days and preferably within 48 to 72 hours after the abnormality 
was found.


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(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests.)
All laboratory safety data will be transferred electronically to Takeda or designee in the format 
requested by Takeda. If the laboratory is unable to electronically transfer data, the study site 
coordinator or designee is responsible for transcribing laboratory results to the eCRF. The 
investigator will maintain a copy of the laboratory accreditation and the reference ranges for the 
laboratory used.
Laboratory reports must be signed and dated by the principal investigator or subinvestigator 
indicating that the report has been reviewed and any abnormalities have been assessed for clinical 
significance.
All clinically significant laboratory abnormalities must be recorded as a PTE/AE in the subject’s 
source documents and on the appropriate eCRF. A clinically significant laboratory abnormality 
that has been verified by retesting will be followed until the abnormality returns to an acceptable
level or a satisfactory explanation has been obtained.
9.1.9
Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 4 weeks after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as at least 1 year since last regular menses with an FSH>40 IU/L or at least 5 years since last 
regular menses, confirmed before any study medication is implemented).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are excluded, the only 
acceptable methods of contraception are: 
Barrier methods (each time the subject has 
intercourse):
Intrauterine devices (IUDs):

Cap (plus spermicidal cream or jelly) PLUS 
male condom.

Diaphragm (plus spermicidal cream or jelly) 
PLUS male condom.

Copper T.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 


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understand the requirements for avoidance of pregnancy and donation of ova during the course of 
the study.
During the course of the study, regular urine human chorionic gonadotropin (hCG) pregnancy tests 
will be performed only for women of childbearing potential and subjects will receive continued 
guidance with respect to the avoidance of pregnancy as part of the study procedures (Appendix A). 
In addition to a negative urine hCG pregnancy test at Screening, subjects also must have a negative 
urine hCG pregnancy test at Day -1 prior to receiving any dose of study medication.
9.1.10 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (TAK-438 10 mg or 20 mg tablets) should be immediately discontinued. 
If the pregnancy occurs during administration of active study medication, eg, after Day 1 or within 
30 days of the last dose of active study medication, the pregnancy should be reported immediately, 
using a pregnancy notification form, to the contact listed in Section 1.0.
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time 
she became pregnant and provide details of treatment the subject received (blinded or unblinded, 
as applicable).
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.
9.1.11 ECG Procedure
12-lead ECGs printed in standard format, will be collected at Screening, Check-in (Day -1), and on 
Confinement Days (Days 1-11/Early Termination). On dosing days, ECGs should be collected 
after dosing. 
The investigator will be responsible for providing the interpretation of all safety ECGs 
(normal/abnormal). These results will be reviewed by the investigator for subject safety and will 
be provided in an appropriate format with the clinical study report. The time that the ECG was 
performed will be recorded. The following parameters will be recorded on the (e)CRF from the 
subject’s ECG trace: heart rate, QT interval, PR interval, QRS interval and RR interval.
During Screening periods (Screening visit and Day -1), ECGs deemed abnormal but not clinically 
significant by the study doctor, should be sent to the CRO Medical Monitor for review in 24 hours 
(with subject de-identified). If consensus is not reached between site investigators and CRO 
Medical Monitor, the CRO medical monitor will consult Takeda Clinical Science on the same 
working day. 
If ECG tracings are printed out on thermal paper which fades over time, any such tracings should 
be completely photocopied and both the original tracing and the counter-signed copy should be 
filed in the subject’s medical record.


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9.1.12 Sample Collection for Genotype Analysis
The sample of whole blood for CYP2C19 genotyping analysis is mandatory. Every subject must 
sign the informed consent in order to participate in this study.
One 2 mL whole blood sample for DNA isolation will be collected on Day -1 from each subject in 
the study, into plastic K2EDTA spray-coated tubes, and stored under frozen condition. A second 
aliquot of blood may be taken if isolation of DNA from the first sample was not successful or 
possible.
Detailed instructions for the handling of samples are provided in Appendix F.
9.1.13 Pharmacokinetic Sample Collection
9.1.13.1 Collection of Blood for Pharmacokinetic Sampling
Blood samples (one 6-mL sample per scheduled time) for pharmacokinetic analysis of TAK-438
and its metabolites will be collected into chilled vacutainers containing anticoagulant sodium 
heparin according to the schedule in Appendix A. Instructions for sample processing and shipment 
are provided in Appendix E.
Serial blood samples for determination of TAK-438F and its metabolites will be collected 
according to Table 9.b.
Table 9.b
Collection of Blood Samples for Pharmacokinetic Analysis
Cohorts
Matrix
Dosing Day
Scheduled Time (hours)
TAK-438 10 mg QD 
and 
TAK-438 20 mg QD
Blood
1 and 9
Predose (0 hours), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 
4, 6, 8, 10, 12, 16, 24, 36, and 48 hours 
postdose
Blood
4-8
Predose
TAK-438 20 mg BID
Blood
1
Predose (0 hours), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 
4, 6, 8, 10, 12, 16, 24, 36, and 48 hours 
postdose
Blood
4-8
Predose (relative to morning dose)
Blood
9
Predose (0 hours), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 
4, 6, 8, 10 and 12 hours postdose (relative to 
morning dose)
The actual time of sample collection will be recorded on the source document and eCRF.
Sampling time points may be adjusted based on the preliminary emerging pharmacokinetic data 
collected from prior cohort(s), but the total number of samples collected per subject should not 
exceed the planned number. 


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9.1.13.2 Collection of Urine for Pharmacokinetic Sampling
Serial urine samples for determination of TAK-438F and its metabolites will be collected 
according to Table 9.c.
Table 9.c
Collection of Urine Samples for Pharmacokinetic Analysis
Cohorts
Matrix
Dosing Day
Time Postdose (hours)
TAK-438 10 mg QD 
and 
TAK-438 20 mg QD
Urine
1 and 9
Predose (spot urine), 0 to 6, 6 to 12, 12 to 24 hours, 24 to 36 hours 
and 36 to 48 hours postdose
TAK-438 20 mg 
BID 
Urine
1
Predose (spot urine), 0 to 6, 6 to 12, 12 to 24 hours, 24 to 36 hours 
and 36 to 48 hours postdose
Urine
9
Predose (spot urine), 0 to 6 and 6 to 12 hours postdose (relative to 
morning dose)
Instructions for sample processing and shipment are provided in Appendix E.
9.1.13.3 Bioanalytical Methods
Plasma and urine concentrations of TAK-438F and its metabolites will be measured by 
high-performance liquid chromatography with tandem mass spectrometry.
9.1.14 Pharmacokinetic Parameters 
The pharmacokinetic parameters of TAK-438F and its metabolites 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 involving sampling times. The 
following pharmacokinetic parameters will be calculated for plasma concentration values of 
TAK-438F and its metabolites: 
Symbol/Term
Definition
Plasma
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity, calculated using 
the observed value of the last quantifiable concentration.
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration.
AUClast,ss
Area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration, at steady state.
AUCt
Area under the plasma concentration-time curve from time 0 to time t.
AUCτ
Area under the plasma concentration-time curve during a dosing interval.
AUCτ,ss
Area under the plasma concentration-time curve during a dosing interval, at steady state.
Cav,ss
Average plasma concentration during a dosing interval, at steady state.
Cmax
Maximum observed plasma concentration.
Cmax,ss
Maximum observed plasma concentration during a dosing interval, at steady state.
Cmin,ss
Minimum observed plasma concentration during a dosing interval, at steady state.


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Symbol/Term
Definition
Plasma
CL/F
Apparent clearance after extravascular administration, calculated using the observed 
value of the last quantifiable concentration.
CL/Fss
Apparent clearance after extravascular administration, at steady state, calculated using 
AUCτ.
λz
Terminal disposition phase rate constant.
MRT∞,ev
Mean residence time after extravascular administration, calculated using the observed 
value of the last quantifiable concentration.
PTF%
Peak trough fluctuation during a dosing interval, at steady state, expressed as a 
percentage of Cav,ss.
Rac(AUC)
Accumulation ratio based on AUCτ.
Rac(Cmax)
Accumulation ratio based on Cmax.
t1/2z
Terminal disposition phase half-life.
tmax
Time of first occurrence of Cmax.
tmax,ss
Time of first occurrence of Cmax, at steady state.
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration.
Vz/Fss
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using AUCτ.
The following urine pharmacokinetic parameters of TAK-438F and its metabolites will be derived 
from urine concentrations of TAK-438F and its metabolites:
Urine
Aet
Amount of drug excreted in urine from time 0 to time t.
Aeτ
Amount of drug excreted in urine during a dosing interval.
fe,t
Fraction of administered dose of drug excreted in urine from time 0 to time t. Molecular 
weight adjustment needed for metabolites.
fe,τ
Fraction of administered dose of drug excreted in urine during a dosing interval. 
Molecular weight adjustment needed for metabolites.
CLR
Renal clearance.
9.1.15 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If the subject is found to be 
not eligible at this visit, the investigator should complete the eCRF.
The primary reason for screen failure is recorded in the eCRF using the following categories:

Pretreatment event/AE.

Did not meet inclusion criteria or did meet exclusion criteria <specify reason>.

Significant protocol deviation.


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
Lost to follow-up.

Voluntary withdrawal <specify reason>.

Study termination.

Other <specify reason>.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.16 Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the treatment phase.
If the subject is found to be not eligible for entrance, the investigator should record the primary 
reason for failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
Study medication will be administered while subjects are under observation in the clinical research 
unit. Following administration of the study medication, appropriate mouth and/or hand checks will 
be performed to ensure that the dose is swallowed and noted in the source document. The date and 
time of each dose will be recorded in the source documents and on the eCRFs. An inventory of the 
study medication supplies dispensed will be performed by the site pharmacist or authorized study 
designee and recorded onto the Drug Accountability Log in the subject’s source document records 
or equivalent. The exact dose time of consecutive subjects may be staggered to facilitate logistics 
at the site.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening (Day -28 to Day -2)
Subjects will be screened for the study within 28 days prior to the first dose of study medication. 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria as 
described in Section 7.0. See Section 9.1.15 for procedures for documenting screening failures.
Procedures to be completed at the Screening Visit include:

Informed consent.

Demographics, medical history, and medication history.

Physical examination.

Vital signs.

Weight, height and BMI.


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
Concomitant medications.

Concurrent medical conditions.

Pretreatment event assessment.

Fasting clinical laboratory tests and HIV, Hepatitis panel and urine drug, cotinine screening 
tests. Also, a urine pregnancy test will be done for female subjects of child-bearing potential or 
FSH will be measured for female subjects where menopause is suspected.

Fasting liver function tests.

ECG procedure.

Breath test for alcohol.

Guidance on avoidance of strenuous exercise, pregnancy, ova or blood donation.
9.3.2
Check-in (Day -1)
Screening will be completed at the Check-in Day -1 visit. The following procedures will be 
performed and documented during this Check-in Visit:

Confinement begins (and will continue until Check-Out Day 11).

Physical examination.

Vital signs.

Weight and BMI.

Concomitant medications.

Concurrent medical conditions.

Pretreatment event assessment.

Fasting clinical laboratory tests (hematology, chemistry, and urinalysis) additionally urine 
drug and cotinine screening tests.

Fasting liver function tests.

Urine pregnancy test for females of child-bearing potential.

Collection of blood sample for CYP2C19 genotyping.

ECG procedure.

Breath test for alcohol.

Reconfirm study eligibility (ie, inclusion and exclusion criteria).

Guidance on avoidance of strenuous exercise, pregnancy, ova or blood donation.


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9.3.3
Study Entrance (Day 1)
Study entrance will take place on Day 1 while the subject remains confined to the phase 1 unit. The 
following procedures will be performed and documented during Study Entrance:

Vital signs (predose).

Concomitant medications.

ECG procedure (postdose).

Collection of predose and postdose blood samples for PK analysis.

Collection of predose and postdose urine samples for PK analysis.

Pretreatment event and adverse event assessment.
The subject should be assigned to treatment as described in Section 8.2. Subjects will be 
administered the first dose (ie, single dose) of study medication in the unit under the supervision of 
the investigator or designee, as described in Section 8.2. 
9.3.4
Day 2 and Day 10
While remaining confined at the phase 1 unit, the following procedures will be performed on 
Day 2 and also on Day 10:

Vital signs.

Concomitant medications.

ECG procedure.

Collection of postdose blood samples for PK analysis (not required on Day 10 for subjects 
assigned to 20 mg BID regimen in multiple dosing phase).

Collection of postdose urine samples for PK analysis (not required on Day 10 for subjects 
assigned to 20 mg BID regimen in multiple dosing phase).

Adverse event assessment.
9.3.5
Multiple Dosing Phase (Days 3-9) 
While remaining confined at the phase 1 unit, the following procedures will be performed between 
Day 3-9:

Vital signs (predose).

Concomitant medications.

Fasting clinical laboratory tests (hematology, and chemistry) at pre-dose on Days 3 and 9 only.

Urinalysis on Day 3 and 9 only

Fasting liver function tests at pre-dose on Days 3 and 9 only.


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
ECG procedure (postdose).

Collection of predose blood samples for PK analysis Days 3-9 inclusive, and also of postdose 
blood samples on Day 9 only. 
Note that the predose time point for Day 3 is actually the 48-hour postdose time point 
following the Day 1 dose. Note also that for subjects assigned to the 20 mg BID multiple dose 
regimen PK draws should be taken relative to the morning dose.

Collection of urine samples for PK analysis at predose and postdose on Day 9.
Note also that for subjects assigned to the 20 mg BID multiple dose regimen PK draws should 
be taken relative to the morning dose.

Adverse event assessment.

Administration of study medication.
9.3.6
Check-Out (Day 11)
The Check-Out will be performed on Day 11 and after completion of all required study procedures 
the subject will be released from the phase 1 unit (ie, confinement period ends). The following 
procedures will be performed and documented:

Physical examination.

Vital signs.

Weight and BMI.

Concomitant medications.

Fasting clinical laboratory tests (hematology, chemistry, urinalysis); additionally a urine 
pregnancy test only for females of child-bearing potential. 

Fasting liver function tests.

ECG procedure.

Collection of postdose blood and urine samples for PK analysis (not required for subjects 
assigned to 20 mg BID regimen in the multiple dosing phase).

Adverse event assessment.

Guidance on avoidance of strenuous exercise, pregnancy, ova or blood donation.
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.


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9.3.7
Early Termination
The reason for discontinuation must be documented in the source document and eCRF. The 
following procedures will be performed and documented:

Physical examination.

Vital signs (predose).

Concomitant medications.

Fasting clinical laboratory tests at pre-dose (hematology, chemistry, urinalysis); additionally 
urine pregnancy test for female subjects of child-bearing potential only. 

Fasting liver function tests at pre-dose.

ECG procedure postdose.

Collection of predose or postdose blood samples for PK analysis as required by study schedule.

Collection of predose or postdose urine samples for PK analysis as required by study schedule.

Adverse event assessment.

Guidance on avoidance of strenuous exercise, pregnancy, ova or blood donation.
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
9.3.8
Follow-up (Telephone Contact)
Follow-up will begin the first day after the Check-out or Early Termination and the telephone visit 
will be at Day 18 (± 3 days). The follow-up will document the following:

Concomitant medications.

Adverse event assessment.

Guidance on avoidance of strenuous exercise, pregnancy, ova or blood donation.
9.4
Blood Volume
Total blood sampling volume for an individual subject is shown in Table 9.d.


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Table 9.d
Approximate Blood Volume
Sample Type
Sample 
Volume
Volume per Period (mL)
Total 
Volume
Screening
and 
Day -1
Single 
Dose
Multiple 
Dose
Study 
Exit
Follow-Up
Clinical laboratory (safety) tests
9.7-14.7
mL
24.4
0
19.4
9.7
(only if 
clinically 
significant at 
last draw)
53.5
CYP2C19 genotyping
2 mL
2
0
0
0
0
2
PK blood collection
6 mL
0
102
132
0
0
234
Total Approximate Blood Sampling Volume
289.5
Direct venipuncture is the preferred method of blood collection; however, a catheter with a single 
saline flush may be used.
A catheter with a heparin-containing saline flush may be used; however, the 289.5-mL total blood 
volume does not include discarded blood from predraws (assuming approximately 1 mL of blood 
is discarded each time a sample is collected from a catheter). Should a catheter be used, the total 
blood volume taken during the study must not exceed 328.5 mL.
9.5
Biological Sample Retention and Destruction
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.12. 
The genetic material will be sent to the local laboratory to determine the CYP2C19 metabolic 
status of each subject. Any remaining sample after testing will be destroyed.


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
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.


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
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 a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). 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 a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, 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 PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 


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worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as adverse events.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as adverse 
events.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 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
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
PTEs that fulfill 1 or more of the serious criteria above are also to be considered as serious and 
should be reported and followed up in the same manner as SAEs (see Sections 10.2.2 and 10.3).
10.1.5 Special Interest AEs 
A Special Interest AE (serious or nonserious) is one of scientific and medical concern specific to 
the compound or program, for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. Such events may require further investigation in order 
to characterize and understand them and would be described in protocols and instructions provided 
for investigators as to how and when they should be reported to Takeda. There are no Special 
Interest AEs for this study.
10.1.6 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.7 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.


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Not Related
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related.
10.1.9 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.10 Stop Date 
The stop date of the AE/ PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.11 Frequency
Episodic AEs/ PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.12 Action Concerning Study Medication 

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE.
10.1.13 Outcome 

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/ PTE.

Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/ PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 


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study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/ PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/ PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/ PTEs which are considered as the cause of death.

Unknown – the course of the AE/ PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication 
(Day 1) or until screen failure. For subjects who discontinue prior to study medication 
administration, PTEs are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication (Day 1). Routine collection of AEs will continue until the follow-up visit on Day 18.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
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 PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:

Event term.

Start and stop date.

Severity.


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
Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (related or not related) (not completed for PTEs).

Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.

Action concerning study medication (not applicable for PTEs).

Outcome of event.

Seriousness.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. 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 name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation. Also, investigators should 
report any SAE in appropriate format (ie, locally required form) to related authorities, IRB/IECs in 
accordance with local GCP and/or local regulations.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal Liver Function Tests 
If during the treatment or follow-up period a subject is noted to have ALT or AST >3 ×ULN and
total bilirubin >2 ×ULN for which an alternative etiology has not been identified, the event should 
be recorded as an SAE and reported as per Section 10.2.2. The investigator must contact the 
Medical Monitor for discussion of the relevant subject details and possible alternative etiologies, 
such as acute viral hepatitis A or B or other acute liver disease. Follow-up laboratory tests as 
described in Section 9.1.8 must also be performed. In addition, a Liver Function Test Abnormality 
Form must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).


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10.3
Follow-up of SAEs
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs or IECs, 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 or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. 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 investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.


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


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary.
12.1
CRFs (Electronic)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
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.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper should be 
copied and certified, source worksheets, all original signed and dated informed consent forms, 
subject authorization forms regarding the use of personal health information (if separate from the 
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. Furthermore, International Conference on Harmonisation (ICH) E6 Section 4.9.5 
requires the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 
2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 


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discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Study Site Agreement between the investigator 
and sponsor.
Refer to the Phase 1 Site Specifications document for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor before 
disposing of any such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
13.1.1 Analysis Sets
In this study, two kinds of analysis sets are defined: PK analysis set and safety analysis set. The PK
analysis set used for primary analysis will consist of subjects who received the study drug, 
completed the minimum protocol specified procedures with no significant protocol deviations, and 
were evaluable for the pharmacokinetics. 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 as well as the rules for 
handling data, consulting medical experts as needed. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized overall and by cohort using 
the PK analysis set and safety analysis set.
13.1.3 Pharmacokinetic Analysis
The plasma concentration of TAK-438F and its metabolites M-I, M-II, M-III, and M-IV-Sul will 
be summarized by cohort over each scheduled sampling point using descriptive statistics
(arithmetic mean, SD, median, minimum and maximum). Mean concentration-time profiles with
SDs of TAK-438F and its metabolites M-I, M-II, M-III and M-IV-Sul will be provided by cohort. 
Individual plasma concentration data versus time will be presented in a data listing.
Descriptive statistics (arithmetic mean, SD, median, minimum and maximum) will be used to 
summarize the plasma and urine PK parameters for TAK-438F and its metabolites M-I, M-II, 
M-III, and M-IV-Sul. In addition, geometric mean and coefficient of variation will be computed 
for Cmax and AUCs from plasma pharmacokinetics.
A more detailed analysis will be presented in the SAP.
13.1.4 Safety Analysis
13.1.4.1 Safety endpoints and analytical methods
All summaries of safety data will be presented based on the safety analysis set. No statistical 
testing or inferential statistics will be generated.


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Adverse Events
A treatment-emergent adverse event (TEAE) is defined as an adverse event (AE) whose date of 
onset occurs on or after the start of study drug.
All TEAEs will be coded using MedDRA. Data will be summarized using preferred term and 
primary system organ class. All TEAEs, drug-related TEAEs and serious TEAEs will be 
summarized by cohort.
Clinical Laboratory Evaluations, Vital Signs and 12-lead ECGs
Observed values and changes (from baseline) for continuous variables will be summarized by 
cohort over time using descriptive statistics.
For categorical variables, shift tables will be presented for each cohort.
Method of data conversion and handling of missing data
No imputation of missing data or of excluded data in accordance with the Statistical Analysis Plan
will be applied. Values below the lower limit of quantification will be handled as 0.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
The sample size of 12 subjects per cohort is sufficient to evaluate the PK profile after single- and 
multiple-dose administration of TAK-438 10 mg and 20 mg. The sample size chosen for this study 
is based on precedent set by other pharmacokinetic studies of similar nature and guidelines issued 
by the CFDA; it was not based on statistical considerations of power and sample size of TAK-438. 
The sample size is considered though to be sufficient for investigating the objectives of the study. 


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), 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.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the medical 
monitor (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospective approved deviation) from the inclusion or exclusion criteria.
Every attempt will be made to collect each pharmacokinetic blood sample at the designated time 
point, and the actual time of each blood sample will be recorded on the source document and 
eCRF. However, blood samples not collected within the interval specified for the scheduled 
sample time should be reported to Takeda using the Protocol Deviation Form.
Protocol Deviation Forms are to be completed for pharmacokinetic samples collected outside of 
the following intervals:
Table 14.a
Windows for Pharmacokinetic Blood Sample Collection
Minutes
Nominal Sampling Time
no more than 30 minutes predose
0 hour
±5
immediately postdose to ≤6 hours
±10
>6 hours postdose


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Table 14.b
Windows for Pharmacokinetic Urine Sample Collection
Minutes
Nominal Sampling Time
-60
0 hour
-30*
0 to 6 hours postdose
-60*
6 to 12 hours postdose
-60*
12 to 24 hours postdose
-60*
24 to 36 hours postdose
-60*
36 to 48 hours postdose
*Only refers to the last defined timepoint in each period.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs 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 or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those US sites unwilling to provide names and titles of all members due to 
privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC 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 or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC 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 ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received written permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include
notification to the IRB or IEC 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 or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC 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 or IEC and sponsor.


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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe 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 and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, 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, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical 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, and subject initials 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, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s [e]CRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During 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, other 
than study recruitment materials and/or advertisements, 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. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Master Services Agreement or equivalent agreement. In the event of any 
discrepancy between the protocol and the Master Services Agreement or equivalent agreement the 
Master Services Agreement or equivalent agreement will prevail.


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15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, Takeda will, at a minimum, register all 
clinical trials conducted in patients that it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before trial initiation. 
15.4.3 Clinical Trial Results Disclosure
Takeda will minimally post the results of clinical trials conducted in patients, regardless of 
outcome, on ClinicalTrials.gov or other publicly accessible websites, as required by applicable 
laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Master Services Agreement or equivalent agreement regarding the sponsor’s policy on 
subject compensation and treatment for injury. If the investigator has questions regarding this 
policy, he or she should contact the sponsor or sponsor’s designee.


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16.0
REFERENCES
1. Fass R, Shapiro M, Swell J. Systematic review: proton-pump inhibitor failure in 
gastro-oesophageal reflux disease—where next? Aliment Pharmacol Ther. 2005;22:79-94.
2. Peter J, et al. A randomized, comparative study of three doses of AZD0865 and esomeprazole 
for healing of reflux esophagitis. Clin Gastroenterol Hepatol. 2007;5:12.


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Appendix A
Schedule of Study Procedures
Screening
Treatment
Discontinuation
Follow-Up
Phone 
Call
Single Dose
Multipl
e Dose
Study Exit
Study Day:
Days 
-28 to 
-2
Day -1 
(Check-
in)
Day 1 
(a)
Day 
2
Days 
3-9
Day 
10
Day 11
(Check-
Out)
Early 
Termination 
Visit (b)
Final 
Contact
Day 18 ±3 
days
Confinement
X
X
X
X
X
X
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical 
history
X
Medication history
X
Physical examination
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Weight, height and BMI
X
X (n)
X (n)
Concomitant medications
X
X
X
X
X
Concurrent medical 
conditions
X
X
Clinical laboratory tests (c)
X
X
X (d)
X
X
Liver function tests (e)
X
X
X
X
X
HIV test
X
Hepatitis panel
X
Urine pregnancy test (f)
X
X
X
X
FSH (g)
X
Urine drug, cotinine screen 
(h)
X
X
Breath (alcohol) test
X
X
CYP2C19 genotyping
X
ECG (i)
X
X
X
X
X
X
X
X
PK blood collection
X
X
X (j)
X (o)
X (o)
X
PK urine collection
X
X
X (k)
X (o)
X (o)
X
Assignment to 10 mg or 20 
mg cohort (l)
X
Administer study 
medication (m)
X (p)
X
Guidance on avoidance of 
strenuous exercise, 
pregnancy, ova or blood 
donation
X
X
X
X
X
PTE assessment
X
X
AE assessment
X
X
Footnotes are on last table page.


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(a) The day of first study medication administration for Treatment period is Day 1.
(b) Conduct procedures for subjects discontinued early per protocol Section 7.6. Any PK sampling due should be collected at the 
Early Termination Visit, if possible. 
(c) Hematology, serum chemistries, and urinalysis tests after fasting for 10 hours (except for urinalysis on Day 3 and Day 9); for 
dosing days should be taken predose in the morning (except for urinalysis on Day 3 and Day 9 when urine PK sampling shall take 
priority), for non-dosing days, it is recommended that sample be taken at approximately the same time as on the dosing days. 
(d) Safety sample for clinical hematology, chemistry and urinalysis should be taken on Day 3 and Day 9 only. Hematology and 
chemistry shall be after fasting for 10 hours predose.
(e) Liver function tests are comprised of AST, ALT, total and direct bilirubin and measurements are to be taken at Screening,
Day -1, Day 3, Day 9, Day 11, and Early Termination predose.
(f) Women of childbearing potential. 
(g) Only when menopause is suspected.
(h) Drug screen including: amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, cotinine methadone, and opiates.
(i) A single 12-lead ECG will be performed once daily at the Screening Visit (Day -28 to -2), Day -1, and on all confinement days 
(Days 1-11/ Early Termination). On dosing days, ECGs should be performed after dosing. 
(j) Plasma PK sampling is only predose on Days 4 to 8. PK sampling on Day 3 is actually the 48 hours postdose sampling of Day 1
(k) Urine PK samples collection is required during Day 3 and Day 9 (not on Day 4 to Day 8 inclusive). Urine PK sampling on Day 3 
is actually the 48 hours post dose sampling of Day 1. 
(l) Assignment to a dosing group (10 mg or 20 mg once daily or 20 mg twice daily).
(m) Study medication should be administered to subjects at a single dose or QD regimen after fasting for 10 hours, subjects should 
continue to fast for 2 hours after the dose. (throughout the study); for subjects assigned to the BID regimen in the multiple dosing 
phase (Days 3-9) subjects will be fed 0.5 hours prior to the dosing however note that those subjects are required to fast for 10 hours 
before clinical laboratory blood test sample collections which can be drawn before being fed.
(n) Only measure height at Screening Visit
(o) Not required for subjects assigned to 20 mg BID regimen.
(p) All subjects will receive a single dose of TAK-438 at the dose level to which they are assigned, ie, for those subjects assigned to 
20 mg BID in multiple dosing phase they will receive a single 20 mg dose on Day 1.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs and return all unused sponsor-supplied drugs to the sponsor.


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12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and assignment to each treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
14. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
15. The anticipated prorated payment(s), if any, to the subject for participating in the study.
16. The anticipated expenses, if any, to the subject for participating in the study.
17. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
18. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.


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19. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
20. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
21. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
24. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening and throughout the duration of the study. Regular pregnancy tests will be 


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performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study medication will be discontinued. 


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Appendix D
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples for 
Pharmacokinetic Analysis
Instructions for Processing of Plasma Samples for Pharmacokinetic Analysis of TAK-438
1. Collect 6 mL of venous blood for the plasma into a chilled Becton-Dickinson Vacutainer. All 
TAK-438 blood samples should be collected into Vacutainers containing sodium heparin.
2. Gently invert the Vacutainer several times to mix the additive with the collected blood prior to 
centrifugation and place immediately on ice.
3. Within 45 minutes of the sample collection, centrifuge the Vacutainers for 10 minutes at 
approximately 1100 to 1300 (RCF) at approximately 4°C. Note: if using a collection device 
other than Becton-Dickinson, refer to manufacturer’s instruction for proper centrifugation 
force and time.
4. Immediately following centrifugation, gently remove plasma from the packed cells. To ensure 
a more homogeneous sample, all plasma should first be transferred into 1 aliquot. From there, 
split the plasma evenly between the 2 aliquots. A minimum of 1.0 mL needs to be obtained for 
each sample. Labeling may include protocol number (TAK-438_114), sample matrix 
(ie, plasma) randomization/enrollment number, period, nominal day and time, and either “SET 
1” (for original sample) or “SET 2” (for duplicate sample).
5. Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately -70°C or lower until shipment to 
 
 No more than 60 minutes will elapse between blood collection and 
freezing the plasma sample.
Instructions for Processing of Urine Samples for Pharmacokinetic Analysis of TAK-438
1. Collect urine into polypropylene containers. During the collection interval, the urine will be 
stored at approximately 4°C.
2. Stir the urine in the polypropylene container vigorously.
3. Measure the urine volume at the end of the collection period.
4. Place two 5 mL aliquots of urine in polypropylene containers. Labeling may include protocol 
number (TAK-438_114), sample matrix (ie, urine), randomization number, nominal day and 
time, and either “SET 1” (for original sample), or “SET 2” (for duplicate sample).
5. Freeze the urine samples and store frozen at approximately -70°C or lower. Keep samples 
frozen at approximately -70°C or lower until shipment to 
 
. No more than 2 hours will elapse between the end of 
the collection period and freezing the urine samples. .
Shipping of Plasma and Urine Samples 
The following instructions are recommended unless they differ from the site’s SOPs for labeling, 
packaging, or shipping of pharmacokinetic samples.
PPD
PPD


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1. Biological samples (ie, plasma or urine) should be shipped on dry ice to prevent thawing 
during transit. Samples should be shipped only on Monday, Tuesday, or Wednesday, and at 
least 2 days prior to a national holiday, in order to minimize the possibility of samples in transit 
over a weekend or holiday. If duplicate samples are to be shipped, send SET 1 samples and 
await confirmation of arrival before shipping the duplicate SET 2 samples.
2. Before shipping, make sure the sample tubes are tightly sealed. Separate each subject’s 
samples as follows:
3. Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc®) containing additional 
absorbent material.
4. Using a permanent marker, write the 4-digit enrollment number, sample matrix (ie, plasma or 
urine), number of samples, and “SET 1” on each self-sealing bag.
5. Place the bags of individual subject’s samples into a larger plastic bag so that samples are 
double bagged. Duplicate SET 2 samples should be returned to the freezer for storage. Repeat 
steps 3 through 5 above when preparing duplicate samples for shipment, except self-sealing 
bags should be marked “SET 2.”
6. An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study medication (TAK-438), protocol number (TAK-438_114), 
investigator’s name, sample type (ie, plasma or urine), subject enrollment number, period, 
nominal collection day and time, and intended sample storage conditions. When duplicate SET 
2 samples are being shipped, make a copy of the original SET 1 sample inventory and mark as 
“SET 2.” Place the inventory paperwork into a large self-sealing bag. SET 1 samples will be 
shipped first on dry ice, followed by shipment of duplicate SET 2 samples after SET 1 samples 
have been received by the analytical laboratory.
7. For sample packing, utilize dry ice generously (eg, 20-25 pounds or 10-11 kg per day of 
transit) to safeguard against longer than expected shipping times and delays. Use newspaper or 
other material to insulate the double-bagged samples from direct contact with the dry ice. Place 
the sample bundles into a Styrofoam container (or other suitable container) and fill the excess 
space with dry ice slabs or ice pellets (preferably the latter). Make a note of the estimated 
weight of the dry ice used per shipping container.
8. Place the inventory paperwork (in a large self-sealing bag) on top of the dry ice in the 
Styrofoam container. Place the lid on the Styrofoam container and seal completely with 
strapping tape. Place the Styrofoam container in a cardboard shipping carton and seal securely 
with strapping tape.
9. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).


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10. Affix an address label to each shipping carton. Complete the address label with the following 
information:
Plasma and Urine Samples for TAK-438
Contact Name: 
Address: 
Phone: 
11. Affix a carbon dioxide label on each carton, specifically:
Carbon Dioxide Solid UN-1845
Class 9 PKG GR III
Quantity _____________________
(fill in weight to nearest lb/kg and specify unit of measure used)
12. Affix 2 dry ice symbol labels on opposite sides of the carton. Mark “KEEP FROZEN” on 
each carton. Specify a return address and contact person on the carton.
13. Obtain the airway bill number and a receipt of shipment from the carrier.
14. After shipping of the TAK-438 samples, please contact
at e-mail:
to notify him/her of next day delivery. When calling, provide the 
following information:
!
Name of courier or transport company.
!
Time and date the shipment left the clinical site.
!
Airway bill number.
PPD
PPD
PPD
PPD
PPD


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Appendix F
Collection, Storage, and Shipment of Plasma Samples for Genotyping 
Analysis
Instructions for processing and shipping of plasma samples for genotyping analysis 
1. Collect one 2 mL tube of venous blood into a plastic tube containing K2EDTA.
2. Mix immediately by gently inverting the tube several times (at least 8-10 times) to mix the 
additive with the collected blood.
3. Send to the local laboratory in 2 hours upon collection for testing according to local site 
operating procedure. The alleles to be tested are *1/*1, *1/*2,*1/*3, *2/*2, *2/*3, *3/*3.


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Appendix G
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 02 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Reduced the fasting period after dosing from 4 hours to 2 hours in the once daily dosing 
regimen only.
The primary change occurs in Section 7.4 Diet, Fluid, and Activity Control:
Initial 
wording
For subjects receiving QD regimen, they should be fasted overnight for a minimum of 
10 hours prior to dosing and will continue to fast for 4 hours after dosing. They should 
take the dose with 240 mL water and refrain from drinking for at least 1 hour postdose, 
after which water can be given ad libitum.
Amended 
or new 
wording:
For subjects receiving QD regimen, they should be fasted overnight for a minimum of 
10 hours prior to dosing and will continue to fast for 4 hours 2 hours after dosing. 
They should take the dose with 240 mL water and refrain from drinking for at least 1 
hour postdose, after which water can be given ad libitum.
Rationale for Change:
This change has been made to allow subjects to have breakfast 2 hours after the dose (having 
already fasted for 10 hours predose). Given that TAK-438 is not known to show a food effect, and 
the peak plasma concentrations occur <2 hours postdose, it is not expected that this change will 
markedly impact the pharmacokinetic results of the study.
The following sections also contain this change:

Section 8.1.3 Dose and Regimen

Appendix A Schedule of Study Procedures (footnote m).


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Change 2: For the collection of demographic data, replaced the requirement to collect date of birth 
with a requirement to collect age.
The primary change occurs in Section 9.1.2 Demographics, Medical History, and Medication 
History Procedure:
Initial 
wording
Demographic information to be obtained will include date of birth, sex, alcohol and 
caffeine consumption and smoking status of the subject at Screening.
Amended 
or new 
wording:
Demographic information to be obtained will include date of birth age, sex, race, 
alcohol and caffeine consumption and smoking status of the subject at Screening.
Rationale for Change:
China-FDA Technical Guidelines for Clinical Trial Data Management state that for reasons of 
subject privacy, the date of birth should not be collected if this is not necessary.
Change 3: Clarified clinical laboratory sample collection volume and time points.
The primary change occurs in Section 9.1.8 Procedures for Clinical Laboratory Samples:
Initial 
wording:
All samples will be collected in accordance with acceptable laboratory procedures. 
The maximum volume of blood at any single visit is approximately 20 mL, and the 
approximate total volume of blood for the study is 316 mL. Laboratory samples will 
be taken following a minimum 10-hour overnight fast on the days stipulated in the 
Schedule of Study Procedures (Appendix A).
Amended 
or new 
wording:
All samples for clinical laboratory testing will be collected in accordance with 
acceptable laboratory procedures. The maximum volume of blood at any single visit is 
approximately 20 mL 14.7 mL, and the approximate total volume of blood for the 
study is 316 mL 53.5 mL. Except for urinalysis on Day 3 and Day 9, laboratory 
samples will be taken following a minimum 10-hour overnight fast on the days 
stipulated in the Schedule of Study Procedures (Appendix A). On dosing days, 
samples for clinical laboratory testing should be drawn at predose in the 
morning (except for urinalysis on Day 3 and Day 9 when urine PK collection 
shall be taken as a priority). At the Screening Visit, Day-1 and Day 11, it is 
recommended that samples are drawn at approximately the same time as the 
dosing days.
Rationale for Change:
To correct the single visit and total blood volume for clinical laboratory sample testing, and 
clarified the time point when collections should be made for consistency with Appendix A.
The following sections also contain this change:


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
2.0 STUDY SUMMARY

Section 9.4 Blood Volume.

Appendix A Schedule of Study Procedures (footnotes c, d, e, and k).
Change 4: Change in compounds or parameters tested during clinical laboratory testing.
The primary change occurs in Table 9.a Clinical Laboratory Tests
Amended 
wording:
Hematology
Red blood cells
White blood cells (with differential: neutrophils, eosinophils, basophils, monocytes, 
lymphocytes)
Hemoglobin
Hematocrit
Platelets
PT/INR
aPTT
Reticulocyte count percentage
Urinalysis
pH
Specific gravity
Protein
Glucose
Nitrites
Bilirubin
Hemoglobin
Ketones
Urobilinogen
Microscopic Analysis:
RBC/high power field
WBC/high power field
Hyaline casts/ low power field
Granular casts/ low power field
Epithelial cells casts, crystals and organisms
Rationale for Change:
Minor changes have been made to be consistent with the local clinical laboratory’s testing 
procedure. These changes will have no impact on subject safety monitoring. 


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Change 5: Reduced the frequency in 12-lead electrocardiogram monitoring, and revised 
procedure for abnormal (not clinically significant) ECGs at Screening.
The primary change occurs in Section 9.1.11 ECG Procedure:
Initial 
wording:
12-lead ECGs printed in standard format, will be collected at Screening, Check-in 
(Day-1), and on Dosing Days (ie, Day 1 and 3-9 inclusive) at predose (0 hours) and 1, 
2, 4, 8, 12, 24 and 48 hours post dose, and at the Early Termination of the study for 
safety assessment. Note however that during the multiple dosing phase some 24-hour 
or 48-hour postdose ECG time points will coincide with subsequent dose ECG time
points (ie, 24-hour post-dose ECG following the Day 3 dose coincides with the Day 4 
pre-dose ECG) and in such cases it is only necessary to record one ECG trace at the 
appropriate time point.
The investigator will be responsible for providing the interpretation of all safety ECGs 
(normal/abnormal). These results will be reviewed by the investigator for subject 
safety and will be provided in an appropriate format with the clinical study report. The 
time that the ECG was performed will be recorded. The following parameters will be 
recorded on the (e)CRF from the subject’s ECG trace: heart rate, QT interval, PR 
interval, QRS interval and RR interval.
As ECG tracings on thermal paper fade over time, any such tracings should be 
completely photocopied and both the original tracing and the counter-signed copy 
should be filed in the subject’s medical record.


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Amended 
or new 
wording:
12-lead ECGs printed in standard format, will be collected at Screening, Check-in 
(Day -1). and on Dosing Days (ie, Day 1 and 3-9 inclusive) at predose (0 hours) and 1, 
2, 4, 8, 12, 24 and 48 hours post dose, and at the Early Termination of the study for 
safety assessment. Note however that during the multiple dosing phase some 24-hour 
or 48-hour postdose ECG time points will coincide with subsequent dose ECG time
points (ie, 24-hour post-dose ECG following the Day 3 dose coincides with the Day 4 
pre-dose ECG) and in such cases it is only necessary to record one ECG trace at the 
appropriate time point. Confinement Days (Days 1-11/Early Termination). On 
dosing days, ECGs should be collected after dosing.
The investigator will be responsible for providing the interpretation of all safety ECGs 
(normal/abnormal). These results will be reviewed by the investigator for subject 
safety and will be provided in an appropriate format with the clinical study report. The 
time that the ECG was performed will be recorded. The following parameters will be 
recorded on the (e)CRF from the subject’s ECG trace: heart rate, QT interval, PR 
interval, QRS interval and RR interval.
During Screening periods (Screening visit and Day -1), ECGs deemed abnormal 
but not clinically significant by the study doctor, should be sent to the CRO 
Medical Monitor for review in 24 hours (with subject de-identified). If consensus 
is not reached between site investigators and CRO Medical Monitor, the CRO 
medical monitor will consult Takeda Clinical Science on the same working day. 
As If ECG tracings are printed out on thermal paper which fades over time, any such 
tracings should be completely photocopied and both the original tracing and the 
counter-signed copy should be filed in the subject’s medical record.
Rationale for Change:
This change in frequency of ECGs is to reduce the number of interventions, and will have no 
impact on subject safety monitoring. The change in procedure for abnormal ECGs at Screening is 
to permit the immediate confirmation by a qualified study doctor of a subject’s eligibility for 
whom their ECG is abnormal but not clinically significant, in addition to a second ECG review by 
the CRO Medical Monitor to ensure consistency in the ECG assessment. Revisions to the text 
pertaining to ECG tracings have been made as the selected phase 1 unit does not use thermal paper.
The following sections also contain this change:

Section 7.2 Exclusion Criteria

Section 9.3.3 Study Entrance (Day 1)

Section 9.3.5 Multiple Dosing Phase (Days 3-9)

Section 9.3.7 Early Termination

Appendix A Schedule of Study Procedures (footnote i).


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Change 6: Clarified that genotyping will be conducted at the local laboratory
The primary change occurs in Section 9.5 Biological Sample Retention and Destruction:
Initial 
wording:
The genetic material will be sent to a testing laboratory to determine the CYP2C19 
metabolic status of each subject. Any remaining sample after testing will be destroyed.
Amended 
or new 
wording:
The genetic material will be sent to a testing the local laboratory to determine the 
CYP2C19 metabolic status of each subject. Any remaining sample after testing will be 
destroyed.
Rationale for Change:
Given the regulations in China on the shipment of biosamples containing human genetic 
information, it was determined that the local laboratory at the selected institution would perform 
the genetic testing.
The following sections also contain this change:

Appendix F Collection, Storage, and Shipment of Plasma Samples for Genotyping Analysis.
Change 7: Clarified liver function test monitoring.
The primary change occurs in Table 9.a Clinical Laboratory Tests
Description 
of change:
In the column Serum Chemistry: alanine aminotransferase, aspartate 
aminotransferase, total bilirubin, and direct bilirubin have been highlighted as being 
included in liver function tests, with a new footnote:
(b) Included in liver function tests.
Rationale for Change:
Highlight the tests involved in liver function monitoring.
The following sections also contain this change:

Section 9.3 Schedule of Observations and Procedures

Appendix A Schedule of Study Procedures.


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Change 8: Removed the requirement for genitourinary monitoring as part of the physical 
examination.
The primary change occurs in Section 9.1.3 Physical Examination Procedure:
Initial 
wording:
A physical examination will consist of the following body systems: (1) eyes; (2) ears, 
nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal 
system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) 
nervous system; (10) lymph nodes; (11) genitourinary system and (12) other.
Amended 
or new 
wording:
A physical examination will consist of the following body systems: (1) eyes; (2) ears, 
nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal 
system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) 
nervous system; (10) lymph nodes ; (11) genitourinary system and (12) (11) other.
Rationale for Change:
An examination of the genitourinary system is only required to be included if applicable to the 
indication under study. As the genitourinary system is not applicable to the proposed indication of 
TAK-438, an examination of this system is not necessary.
Change 9: Clarified the Chinese population eligible for inclusion into the study.
The primary change occurs in Section 7.1 Inclusion Criteria:
Initial 
wording:
3. The subject is a healthy adult male or female subject of Chinese descent.
5. The subject weighs at least 50 kg and has a body mass index (BMI) between 19
and 24, inclusive at Screening (Check-In Day -1).
Amended 
or new 
wording:
3. The subject is a healthy adult male or female Chinese subject of Chinese descent.
5. The subject weighs at least 50 kg and has a body mass index (BMI) between 19
and 26 kg/m2 24, inclusive at Screening (Check-In Day -1).
Rationale for Change:
To reflect the demography in China, and not limit the inclusion criteria to any one ethnic group in 
China, and to reflect the updated China FDA regulations for recommended BMI inclusion criteria
in a phase 1 study.
The following sections also contain this change:

2.0 STUDY SUMMARY


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Change 10: Minor updates for protocol consistency.
The primary change occurs in 2.0 STUDY SUMMARY:
Deleted 
text:
Healthy subjects aged 18-45 inclusive (it is recommended that there will be an equal 
number of males and females in each cohort).
Rationale for Change:
Removed to maintain consistency with the rest of the protocol. The study will still recruit both 
male and female subjects.
Change 11: Clarified the time point for vital sign measurements.
The primary change occurs in Section 9.1.5 Vital Sign Procedure:
Initial 
wording:
Vital signs will include body temperature (oral, tympanic, or axillary measurement), 
sitting blood pressure (after 5 minutes resting), respiration rate and pulse (bpm).
Amended 
or new 
wording:
Vital signs will include body temperature (oral, tympanic, or axillary measurement), 
sitting blood pressure (after 5 minutes resting), respiration rate and pulse (bpm). On 
dosing days, vital sign measurements should be taken at predose in the morning, 
and for the remaining days, measurements should be taken at approximately the 
same time as on the dosing days.
Rationale for Change:
To clarify the time for each vital sign measurement in the study procedure.


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Change 12: Follow-up Visit changed from a site visit to a Telephone Contact.
The primary change occurs in Section 9.3.8 Follow-up (Telephone Contact)
Initial 
wording:
9.3.8
Follow-up (Final Visit)
Follow-up will begin the first day after the Check-out or Early Termination and the 
onsite visit will be at Day 18 (± 3 days). The follow-up will document the following:
Amended 
or new 
wording:
9.3.8
Follow-up (Final Visit) (Telephone Contact)
Follow-up will begin the first day after the Check-out or Early Termination and the 
onsite visit telephone contact will be at Day 18 (± 3 days).
Rationale for Change:
Clarification of study site usual procedures. Procedures during the Final Visit can be conducted 
over the phone in accordance with the original protocol and will not have an impact on subject 
safety.
The following sections also contain this change:

Section 6.1 Study Design

2.0 STUDY SUMMARY

Appendix A Schedule of Study Procedures.
Change 13: Clarification of 4-digit enrollment number assignment.
The primary change occurs in 8.2 Section Investigational Drug Assignment and Dispensing 
Procedures
Initial 
wording:
Subjects will be assigned to receive a 4-digit enrollment number. The number will be 
assigned by the clinic site personnel in sequential order beginning with 1001.
Amended 
or new 
wording:
Subjects will be assigned to receive a 4-digit enrollment number. The number will be 
assigned by the clinic site personnel in sequential order beginning with 1001as 
follows:
Cohort 1: 10mg TAK-438 QD beginning with 1001
Cohort 2: 20mg TAK-438 QD beginning with 2001
Cohort 3: 20mg TAK-438 BID beginning with 3001
Rationale for Change:
Request from phase 1 study unit to use enrollment numbers to differentiate between cohorts.


TAK-438
Study No. TAK-438_114
Page 92 of 95
Protocol Incorporating Amendment No. 02
21 December 2016
CONFIDENTIAL
Change 14: Addition of table describing window for urine sample collection.
The primary change occurs in Section 14.2 Protocol Deviations
Amended 
or new 
wording:
[New Table 14.b
Windows for Pharmacokinetic Urine Sample Collection]
Rationale for Change:
Upon request from the site, in accordance with their rountine practice,the window for urine 
collection time has been clarified.


TAK-438
Study No. TAK-438_114
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21 December 2016
CONFIDENTIAL
Change 15: Clarification of meals given during the Confinement Period
The primary change occurs in Section7.4 Diet, Fluid, and Activity Control
Initial 
wording:
During the confinement period, subjects will be given a menu for the dosing period 
that includes 3 meals and an evening snack, each containing approximately 20% to 
25% fat (relative to the total calories), according to the local phase 1 unit standard. The 
menu of the standardized meals from the clinical research site will be approved by 
Takeda before the implementation. The meals served on the day of dosing should be 
identical for each cohort in the study. The study menu should be recorded and 
submitted to the study file with a copy provided to the sponsor prior to the start of the 
study.
Amended 
or new 
wording:
During the confinement period, subjects will be given a menu for the dosing period 
that includes 3 meals. and an evening snack, each Each meal will containing
approximately 20% to 25% fat (relative to the total calories), according to the local 
phase 1 unit standard. The menu of the standardized meals from the clinical research 
site will be approved by Takeda before the implementation. The meals served on the 
day of dosing should be identical for each cohort in the study. The study menu should 
be recorded and submitted to the study file with a copy provided to the sponsor prior to 
the start of the study.
Rationale for Change:
Given that subjects are required to fast for 4 hours post-dose, and an overnight fast is required to be 
more than 10 hours, subjects would need to quickly consume an evening snack at 2200 in order to 
be able to draw fasted blood at 0800. As this was not practical, the evening snack was removed 
from the study protocol.
The requirement for identical meals on dosing days was removed as subjects receiving once daily 
dosing would not receive breakfast (only a morning snack), while subjects receiving twice daily 
dosing will receive breakfast.
Change 16: Clarification of meals given during the Confinement Period 3 and Day 9
The primary change occurs in Section 9.3.5 Multiple Dosing Phase (Days 3-9)


TAK-438
Study No. TAK-438_114
Page 94 of 95
Protocol Incorporating Amendment No. 02
21 December 2016
CONFIDENTIAL
Initial 
wording:
While remaining confined at the phase 1 unit, the following procedures will be 
performed between Day 3-9:

Vital signs.

Concomitant medications.

Fasting clinical laboratory tests (hematology, chemistry, and urinalysis) on days 3 
and 9 only.

ECG procedure.

Collection of predose blood samples for PK analysis Days 3-9 inclusive, and also 
of postdose blood samples on Day 9 only. 
Note that the pre-dose time point for Day 3 is actually the 48-hour post-dose time
point following the Day 1 dose. Note also that for subjects assigned to the 20 mg 
BID multiple dose regimen PK draws should be taken relative to the morning 
dose.

Collection of urine samples for PK analysis predose on day 3, predose and 
postdose on Day 9.
Note that the pre-dose time point for Day 3 is actually the 48-hour post-dose time
point following the Day 1 dose. Note also that for subjects assigned to the 20 mg 
BID multiple dose regimen PK draws should be taken relative to the morning 
dose.

Adverse event assessment.

Administration of study medication.


TAK-438
Study No. TAK-438_114
Page 95 of 95
Protocol Incorporating Amendment No. 02
21 December 2016
CONFIDENTIAL
Amended 
or new 
wording:
While remaining confined at the phase 1 unit, the following procedures will be 
performed between Day 3-9:

Vital signs (predose).

Concomitant medications.

Fasting clinical laboratory tests (hematology, and chemistry , and urinalysis) at 
pre-dose on Days 3 and 9 only.

Urinalysis on Day 3 and 9 only

Fasting liver function tests at pre-dose on Days 3 and 9 only.

ECG procedure (postdose).

Collection of predose blood samples for PK analysis Days 3-9 inclusive, and also 
of postdose blood samples on Day 9 only. 
Note that the predose time point for Day 3 is actually the 48-hour postdose time
point following the Day 1 dose. Note also that for subjects assigned to the 20 mg 
BID multiple dose regimen PK draws should be taken relative to the morning 
dose.

Collection of urine samples for PK analysis at predose and postdose on Day 9. 
Note that the pre-dose time point for Day 3 is actually the 48-hour post-dose time 
point following the Day 1 dose. Note also that for subjects assigned to the 20 mg 
BID multiple dose regimen PK draws should be taken relative to the morning 
dose.

Adverse event assessment.

Administration of study medication.
Rationale for Change:
Given that subjects are required to have urine PK 48 hours postdose, a timepoint which will be 
quite close to fasted urinalysis, urine PK shall be taken as priority in this PK study. Thus, fasting 
requirement for urinalysis is removed to facilitate the urine PK collection.  


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PPD
PPD
PPD
PPD

SAP_001.pdf: 
This may include, but is not limited to, redaction of the following: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: An Open-Label, Single-center, Parallel, Phase 1 Study to Determine the 
Pharmacokinetics of Single- and Multiple- Oral Doses of TAK-438 10 mg and 20 mg in 
Healthy Adult Chinese
NCT Number: NCT03085836
SAP Approve Date:  30 August 2017
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. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-438_114
An Open-Label, Single-center, Parallel, Phase 1 Study to Determine the Pharmacokinetics
of Single- and Multiple- Oral Doses of TAK-438 10 mg and 20 mg in Healthy Adult Chinese
Subjects
PHASE 1
Version: Final 2
Date: 30 August 2017
Prepared by:
Based on:
Protocol Version: Amendment 02
Protocol Date: 21 December 2016
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-438_114
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CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
Study Title:
An Open-Label, Single-center, Parallel, Phase 1 Study to Determine the 
Pharmacokinetics of Single- and Multiple- Oral Doses of TAK-438 10 mg 
and 20 mg in Healthy Adult Chinese
Approvals:
Date
Date
Date
Date
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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2.0
TABLE OF CONTENTS
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
List of In-Text Tables............................................................................................................4
List of In-Text Figures...........................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Additional Objectives ................................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoints .....................................................................................................9
5.2
Additional Endpoints ...............................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Study Definitions ...............................................................................................12
7.1.2
Definition of Study Days....................................................................................12
7.1.3
Definition of Study Visit Windows ....................................................................12
7.1.4
Method of Data Conversion and Handling of Missing Data................................13
7.2
Analysis Sets ...........................................................................................................14
7.3
Disposition of Subjects ............................................................................................14
7.3.1
Study Information..............................................................................................14
7.3.2
Screen Failures...................................................................................................14
7.3.3
Subject Eligibility ..............................................................................................15
7.3.4
Disposition of Subjects ......................................................................................15
7.3.5
Protocol Deviations and Analysis Sets ...............................................................16
7.4
Demographic and Other Baseline Characteristics.....................................................17
7.5
Medical History and Concurrent Medical Conditions...............................................17
7.6
Medication History and Concomitant Medications...................................................17
7.7
Efficacy Analysis.....................................................................................................18
7.8
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................18
7.8.1
Pharmacokinetic Analysis ..................................................................................18
7.8.2
Pharmacodynamic Analysis ...............................................................................19


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7.9
Other Outcomes.......................................................................................................19
7.10
Safety Analysis........................................................................................................20
7.10.1 Adverse Events ..................................................................................................20
7.10.2 Clinical Laboratory Evaluations .........................................................................22
7.10.3 Vital Signs .........................................................................................................24
7.10.4 12-Lead ECGs ...................................................................................................24
7.10.5 Other Observations Related to Safety.................................................................25
7.11
Interim Analysis ......................................................................................................25
7.12
Changes in the Statistical Analysis Plan...................................................................25
8.0
REFERENCES..............................................................................................................26
9.0
APPENDIX...................................................................................................................27
9.1
Criteria for Markedly Abnormal Values...................................................................27
9.1.1
Hematology, Serum Chemistry, Vital Signs, and 12-lead ECG (except Upper 
MAV Criteria of QTcF Interval) ........................................................................27
9.1.2
12-lead ECG (Upper MAV Criteria of QTcF Interval) .......................................29
LIST OF IN-TEXT TABLES
Table 4.a
Summary of Dose Cohorts ...................................................................................8
Table 4.b
Schematic of Dosing and PK Sampling, by Cohort...............................................8
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ..................................................................................8


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
Aet
amount of drug excreted in urine from time 0 to time t
Aeτ 
amount of drug excreted in urine during a dosing interval
aPTT
activated partial thromboplastin time
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUCτ
area under the plasma concentration-time curve during a dosing interval
AUCτ,ss
area under the plasma concentration-time curve during a dosing interval, at steady 
state
BID
twice daily
BMI
body mass index
CFDA
China Food and Drug Administration
CLR
renal clearance
Cmax
maximum observed plasma concentration
Cmax,ss
maximum observed plasma concentration, at steady state
CRF
case report form
CV
coefficient of variation
CYP
cytochrome P450
ECG
electrocardiogram
fe,t
Fraction of administered dose of drug excreted in urine from time 0 to time t. 
Molecular weight adjustment needed for metabolites
fe,τ
Fraction of administered dose of drug excreted in urine during a dosing interval. 
Molecular weight adjustment needed for metabolites.
GGT
-glutamyl transferase
HDL
high density lipoprotein
LDH
lactate dehydrogenase
LDL
low density lipoprotein
LLN
lower limit of normal
MAV
markedly abnormal values
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PK
pharmacokinetics
PT
Preferred Term
PT
prothrombin time
PT/INR
prothrombin time/international normalized ratio
PTE
pretreatment event
QD
once daily
QTcF
QT interval corrected by Fridericia’s method
SAP
statistical analysis plan
SOC
System Organ Class
TAK-438F
freebase of TAK-438


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TEAE
treatment-emergent adverse event
t1/2z
terminal disposition phase half-life
tmax
time of first occurrence of Cmax
tmax,ss
time of first occurrence of Cmax, at steady state
ULN
upper limit of normal
WHO Drug
World Health Organization Drug Dictionary


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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective is to determine the pharmacokinetics of TAK-438 in healthy adult 
Chinese subjects after both single and multiple dose administration.
4.2
Secondary Objectives
Not applicable.
4.3
Additional Objectives
4.4
Study Design
This is a phase 1, parallel, open-label, single- and multiple-dose study of oral TAK-438 
involving 36 healthy Chinese subjects between the ages of 18 and 45, inclusive, and considered 
eligible based on the inclusion and exclusion entry criteria.
Screening for potential subjects will occur between 28 and 2 days prior to confinement at the 
phase 1 unit. Selected eligibility criteria will be reconfirmed on Day -1 (Check In) prior to 
assignment to the 10 mg or 20 mg once daily or 20 mg twice daily cohort, predose blood and 
urine sampling for pharmacokinetic (PK) measurements will also be taken. Having fasted for a 
minimum of 10-hours a single oral dose of TAK-438 will be administered on Day 1 followed by 
a pharmacokinetic sampling period of 48 hours. On Days 3 through 9, subjects will receive their 
assigned daily dose(s) of TAK-438 followed by another pharmacokinetic sampling period of 
48 hours (for subjects on a once daily regimen), or 12 hours (for those assigned to the 20 mg 
twice daily regimen). The subject will be confined to the phase 1 unit from Day -1 (Check-In) 
through to Day 11 (Check-Out) and will be contacted by the study site for a follow-up phone call
on Day 18.
Besides monitoring concomitant medications and adverse events (AE), physical examination, 
electrocardiogram (ECG), vital signs and clinical laboratory tests will be conducted to monitor 
safety. A schematic of the study design is presented in Figure 4.a.
CCI


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Figure 4.a
Schematic of Study Design
A summary of the dose cohorts is presented in Table 4.a.
Table 4.a
Summary of Dose Cohorts
A schematic of the dosing schedule and sampling, by cohort, is provided in Table 4.b.
Table 4.b
Schematic of Dosing and PK Sampling, by Cohort


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The Primary endpoints for this study are the pharmacokinetic parameters derived from the 
plasma and urine concentrations of TAK-438F and its metabolites M-I, M-II, M-III and 
M-IV-Sul assessed after the first dose on Day 1 and after the final repeat dose on Day 9 as 
required. 
The following pharmacokinetic parameters will be calculated from plasma concentrations of 
TAK-438F, M-I, M-II, M-III and M-IV-Sul:
Day 1

Maximum observed plasma concentration (Cmax).

Time to reach Cmax (tmax).

Area under the plasma concentration-time curve from time 0 to infinity (AUC∞).

Area under the plasma concentration-time curve during a dosing interval (AUCτ).

Terminal disposition half-life (t1/2z).
Day 9

Maximum observed plasma concentration, at steady state (Cmax,ss).

Time to reach Cmax at steady state (tmax,ss).

Area under the plasma concentration-time curve during a dosing interval, at steady state 
(AUCτ,ss).
The following pharmacokinetic parameters will be calculated from urine concentrations of TAK-
438F, M-I, M-II, M-III and M-IV-Sul:
Day 1

Amount of drug excreted in urine from time 0 to time t (Aet).

Fraction of administered dose of drug excreted in urine from time 0 to time t (fe,t).

Renal clearance (CLR).
Day 9

Amount of drug excreted in urine during a dosing interval (Aeτ).

Fraction of administered dose of drug excreted in urine during a dosing interval (fe,τ).

Renal clearance (CLR).


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5.2
Additional Endpoints
CCI


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6.0
DETERMINATION OF SAMPLE SIZE
The sample size of 12 subjects per cohort is sufficient to evaluate the PK profile after single- and
multiple-dose administration of TAK-438 10 mg and 20 mg. The sample size chosen for this 
study is based on precedent set by other pharmacokinetic studies of similar nature and guidelines 
issued by the China Food and Drug Administration (CFDA); it was not based on statistical 
considerations of power and sample size of TAK-438. The sample size is considered though to 
be sufficient for investigating the objectives of the study.


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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.

TEAE: An AE whose date of onset occurs on or after the start of study drug. A TEAE whose 
relationship to study drug is missing will be considered drug-related. A TEAE whose 
intensity is missing will be considered severe.

PTE: An AE whose date of onset occurs before the start of study drug.

Significant TEAE: Any AEs (not including serious TEAEs) that led to an intervention, 
including withdrawal of drug treatment or significant additional concomitant therapy.

Descriptive statistics: number of subjects with non-missing values, mean, standard deviation, 
maximum, minimum, and quartiles

Duration of exposure to study medication (days): date of last dose of study medication - date 
of first dose of study medication + 1

QTcF interval (msec): QT interval (msec) / (RR interval (msec)/1000)0.33 (rounded to the 
nearest whole number)

Baseline values: The last evaluable observation (ie, non-missing) before the first dose of 
study medication. If no evaluable observation is obtained before the first dose, the baseline 
value will be missing. 
7.1.2
Definition of Study Days
Study Day: The day before the first dose of the study medication will be defined as Study Day -1 
and the day of the first dose will be defined as Study Day 1. Other study days are defined relative 
to Study Day 1, eg, the day 2 days prior to Study Day 1 is Day -2 and the day after Study Day 1 
is Day 2.
7.1.3
Definition of Study Visit Windows
7.1.3.1
Plasma Concentrations of TAK-438F and Its Metabolites M-I, M-II, M-III and M-IV-
Sul
For each time, all evaluable observation (ie, non-missing) obtained in the corresponding time 
interval will be used. If more than one observation lies within the same time window, the 
observation with the closest sampling time to the scheduled time will be used. If there are two 
observations equidistant to the scheduled time, the later observation will be used.


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Visit: Days 1 and 9
Visit
Time
Scheduled Time 
(min)
Time Interval (min)
Sampling Time
Days 1 and 9
Pre–morning dose
0
-30 – 0
0.25 hours post–morning dose
15
10 – 20
0.5 hours post–morning dose
30
25 – 35
0.75 hours post–morning dose
45
40 – 50
1 hour post–morning dose
60
55 – 65
1.5 hours post–morning dose
90
85 – 95
2 hours post–morning dose
120
115 – 125
3 hours post–morning dose
180
175 – 185
4 hours post–morning dose
240
235 – 245
6 hours post–morning dose
360
355 – 365
8 hours post–morning dose
480
470 – 490
10 hours post–morning dose
600
590 – 610
12 hours post–morning dose
720
710 – 730
16 hours post–morning dose*
960
950 – 970
24 hours post–morning dose*
1440
1430 – 1450
36 hours post–morning dose*
2160
2150 – 2170
48 hours post–morning dose*
2880
2870 – 2890
* Blood samples collection at these time points on Day 9 is not scheduled for Cohort 3, ie, subjects assigned to the 
20 mg BID regimen.
Visit: Days 4-8
Visit
Time
Scheduled Time
(min)
Time Interval (min)
Sampling Time
Days 4 - 8
Pre–morning dose
0
-30 – 0
7.1.3.2
Other Endpoints
The baseline visit is defined as the period before the first dose of study medication, and 
post-baseline visits are defined in line with CRF-recorded visits. The last evaluable observation
(ie, non-missing) in the baseline visit will be used as the baseline value, and all evaluable 
observation will be used for each post-baseline visit. 
7.1.4
Method of Data Conversion and Handling of Missing Data
No imputation of missing data or of excluded data will be applied. Values below the lower limit 
of quantification will be handled as 0.


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7.2
Analysis Sets
The safety analysis set used for primary analysis will consist of subjects who received at least 1 
dose of the study drug.
The PK analysis set will consist of subjects who received the study drug, who have sufficient 
plasma/urine concentration data to calculate at least 1 pharmacokinetic parameter, and completed 
the minimum protocol specified procedures with no significant protocol deviations, which are
listed below:

Subjects who did not meet inclusion criteria #3, #4 or #5.

Subjects who met exclusion criteria #1, #4, #6, #7, #8, #10, #11, #12, #13, #14, or #18.

Subjects who have violated the rules specified in section 7.3 (excluded medications and 
dietary products) of the protocol up to 48 hours after the last dose on Day 9.

Subjects who did not receive the study drug at some scheduled time of administration.
7.3
Disposition of Subjects
7.3.1
Study Information
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables:
Date First Subject Signed Informed Consent Form
Date of Last Subject’s Last Visit/Contact
MedDRA Version
WHO Drug Version
SAS Version Used for Creating the Datasets
Analytical Methods:
(1) Study Information
Study information shown in the analysis variables section will be provided.
7.3.2
Screen Failures
Analysis Set:
All Subjects Who Did Not Enter the Treatment Period
Analysis Variables:
Age (years) 
[Min<= - <30, 30<= - <40, 40<= - <=Max]
Gender
[Male, Female]
Race
[American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White]
Analytical Methods:
(1) Screen Failures
Frequency distributions for categorical variables and descriptive statistics for continuous 
variables will be provided.


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7.3.3
Subject Eligibility
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables:
Eligibility Status
[Yes, No]
Primary Reason for Subject Not Being Eligible
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation, 
Lost to Follow-Up, 
Voluntary Withdrawal, 
Study Termination, 
Did Not Meet Entrance Criteria, 
Other]
Analytical Methods:
(1) Eligibility for Entrance into the Treatment Period
Frequency distributions will be provided. When calculating the 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:
All Subjects Who Entered the Treatment Period
Analysis Variables:
Study Drug Administration Status
[No]
Reason for Not Being Treated
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation,
Lost to Follow-Up, 
Voluntary Withdrawal, Study Termination, 
Pregnancy, Other]
Study Drug Completion Status
[Completed Study Drug, 
Prematurely Discontinued Study Drug]
Reason for Discontinuation of Study Drug
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation,
Lost to Follow-Up, 
Voluntary Withdrawal, Study Termination, 
Pregnancy, Other]
Analytical Methods:
(1) Disposition of Subjects
Frequency distributions will be provided for each cohort and overall. When calculating 
percentages for the reasons for not being treated, the total number of subjects not treated by 
the study drug will be used as the denominator. When calculating percentages for the reasons 
for discontinuation of study drug, the total number of subjects who prematurely discontinued 
the study drug will be used as the denominator.
(2) Flow Chart of Subject Distribution
Flow chart will be provided.


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7.3.5
Protocol Deviations and Analysis Sets
Protocol Deviations
Analysis Set:
All Subjects Who Entered the Treatment Period
Analysis Variables:
Protocol Deviation
[Entry Criteria, Concomitant Medication, 
Procedure Not Performed Per Protocol, 
Study Medication, Withdrawal Criteria]
Analytical Methods:
(1) Protocol Deviations
Frequency distribution will be provided by cohort and overall for each deviation category. A 
subject who has several deviations will be counted once in each appropriate category. A 
subject who has several deviations that can be classified into the same category will be 
counted only once.
Analysis Sets
Analysis Set:
All Subjects Who Entered the Treatment Period
Analysis Variables:
Analysis Sets
PK Analysis Set
Safety Analysis Set
[Included]
[Included] 
Analytical Methods:
(1) Analysis Sets
Frequency distributions will be provided by cohort and overall.


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7.4
Demographic and Other Baseline Characteristics
Analysis Set:
PK Analysis Set
Safety Analysis Set
Analysis Variables:
Age (years)
[Min<= - <30, 30<= - <40, 40<= - <=Max]
Gender
[Male, Female]
Race
[American Indian or Alaska Native, Asian, 
Black or African American, 
Native Hawaiian or Other Pacific Islander, 
White]
Height (cm)
[Min<= - <150, 150<= - <160, 
160<= - <170, 170<= - <=Max]
Weight (kg) (Baseline)
[Min<= - <50.0, 50.0<= - <60.0, 
60.0<= - <70.0, 70.0<= - <80.0, 
80.0<= - <=Max]
BMI (kg/m2) (Baseline)
[Min<= - <19.0, 19.0<= - <=24.0, 
24.0< - <=Max]
Smoking Classification
[The Subject Has Never Smoked, 
The Subject Is a Current Smoker, 
The Subject Is an Ex-smoker]
Consumption of Alcohol
[Drink Every day, 
Drink a Couple of Days Per Week,
Drink a Couple of Days Per Month, 
Never Drink]
Consumption of Caffeine
[Yes, No]
CYP2C19 Genotype
[*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, *3/*3]
Analytical Methods:
(1) Summary of Demographics and Other Baseline Characteristics
Frequency distributions for categorical variables and descriptive statistics for continuous 
variables will be provided by cohort and overall.
7.5
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases that stopped at or prior to the time 
of informed consent. Concurrent medical conditions are defined as significant conditions 
ongoing or present at the time of informed consent.
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA, version 19.0) coding system.
There will be no analysis of medical history and concurrent medical conditions.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped 
prior to signing of informed consent. Concomitant medications are recorded on the eCRF and 
include any medications, other than the study drug, taken at any time between informed consent 
and on or prior to the last dose of study drug.


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Medication history and concomitant medications will be coded using the World Health 
Organization Drug Dictionary (WHO Drug) version 2016Q1 or higher.
There will be no analysis of medication history and concomitant medications.
7.7
Efficacy Analysis
Not applicable.
7.8
Pharmacokinetic/Pharmacodynamic Analysis
7.8.1
Pharmacokinetic Analysis
Plasma Concentrations of TAK-438F and Its Metabolites M-I, M-II, M-III and M-IV-Sul
Analysis Set:
PK Analysis Set
Analysis Variable:
Plasma Concentrations of TAK-438F and Its Metabolites M-I, M-II, M-III and M-IV-Sul
Time Point:
Visit: Days 1 and 9
Pre–morning dose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16*, 24*, 36*, 
48* hours post–morning dose (relative to start time of morning dose at Day 1 or 9)
* Blood samples collection at these time points on Day 9 is not scheduled for Cohort 3, 
ie, subjects assigned to the 20 mg BID regimen.
Visit: Days 4-8
Pre–morning dose (0 hours)
Analytical Methods:
The following summaries will be provided for each analyte by cohort.
(1) Summary of Plasma Concentrations by Time Point
Descriptive statistics for observed values will be provided for each time point. In addition, 
geometric mean, and %CV will be provided
(2) Concentration-time Profiles for Individual Subjects
Observed values will be plotted using individual case plot.
(3) Mean Concentration-time Profiles with Standard Deviations
Mean of plasma concentration will be plotted by time point using linear scales and common
log scales for Days 1-9, Day 1 and Day 9 respectively.


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Plasma PK Parameters of TAK-438F and Its Metabolites M-I, M-II, M-III and M-IV-Sul
Analysis Set:
PK Analysis Set
Analysis Visit and 
Variable:
Plasma PK Parameters of TAK-438F and Its Metabolites M-I, M-II, M-III and M-IV-Sul
Visit: Day 1
Cmax
tmax
AUC∞
AUCτ
t1/2z
λz
CL/F
Vz/F
Visit: Day 9
Cmax,ss
tmax,ss
AUCτ,ss
t1/2z
λz
CL/Fss
Vz/Fss
Rac(AUC)
Rac(Cmax)
Analytical Methods:
The following summaries will be provided for each analyte by cohort.
(1) Summary of Plasma PK Parameters
Descriptive statistics for PK parameters will be provided. In addition, geometric mean and 
%CV will be computed for Cmax and AUCs.
Urine PK Parameters of TAK-438F and Its Metabolites M-I, M-II, M-III and M-IV-Sul
Analysis Set:
PK Analysis Set
Analysis Visit and 
Variable:
Urine PK Parameters of TAK-438F, Its Metabolites M-I, M-II, M-III and M-IV-Sul, and the 
Total of TAK-438F and Its Metabolites
Visit: Day 1
Aet
fe,t
CLR
Visit: Day 9
Aeτ
fe, τ
CLR
Analytical Methods:
The following summaries will be provided for each analyte by cohort.
(1) Summary of Urine PK Parameters
Descriptive statistics for PK parameters will be provided. Here, only fe will be summarized 
for the total of TAK-438F and its metabolites. 
7.8.2
Pharmacodynamic Analysis
Not applicable.
7.9
Other Outcomes
Not applicable.


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7.10
Safety Analysis
7.10.1 Adverse Events
7.10.1.1 Overview of Treatment-Emergent Adverse Events
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Relationship to Study Drug
[Related, Not Related]
Intensity
[Mild, Moderate, Severe]
Analytical Methods: The following summaries will be provided for each cohort.
(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) Relationship to Study Drug of Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation (number of events, number and percentage of subjects)
6) Serious Treatment-Emergent Adverse Events (number of events, number and percentage of 
subjects) 
7) Relationship of Serious Treatment-Emergent Adverse Events to Study Drug (number of 
events, number and percentage of subjects) 
8) Serious Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
(number of events, number and percentage of subjects) 
9) Treatment-Emergent Adverse Events Resulting in Death (number of events, number and 
percentage of subjects) 
10) Significant Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)
11) Relationship of Significant Treatment-Emergent Adverse Events to Study Drug (number 
of events, number and percentage of subjects)
TEAEs will be counted according to the rules below.
Number of subjects

Summaries for 2), 5), 7) and 11)
A subject with occurrences of TEAE in both categories (ie, Related and Not Related) will 
be counted once in the Related category.

Summary for 3)
A subject with multiple occurrences of TEAE will be counted once for the TEAE with the 
maximum intensity.

Summaries other than 2), 3), 5), 7) and 11)
A subject with multiple occurrences of TEAE will be counted only once.
Number of events
For each summary, the total number of events will be calculated.


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7.10.1.2 Displays of Treatment-Emergent Adverse Events
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Intensity
[Mild, Moderate, Severe]
Analytical Methods: The following summaries will be provided using frequency distribution for each cohort. 
TEAEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency for tables provided 
by SOC and PT. SOC and PT will be sorted in decreasing frequency for tables provided by 
SOC only or PT only.
(1) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
(2) Treatment-Emergent Adverse Events by System Organ Class
(3) Treatment-Emergent Adverse Events by Preferred Term
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(5) Intensity of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class, and Preferred Term
(7) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term
(8) Drug-Related Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term
(9) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term
(10) Serious Drug-Related Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term
(11) Significant Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(12) Drug-Related Significant Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term
The frequency distribution will be provided according to the rules below.
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. Percentages will be based on the number of subjects in the safety analysis 
set.

Summary tables for (5) and (6)
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted only 
once for the TEAE with the maximum intensity. Percentages will be based on the number 
of subjects in the safety analysis set.


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7.10.1.3 Displays of Pretreatment Events
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables: PTE
Analytical Methods: The following summaries will be provided using frequency distribution.
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.
7.10.2 Clinical Laboratory Evaluations
Hematology and Serum Chemistry
Analysis Set:
Safety Analysis Set
Analysis Variables : Hematology
Red blood cells (×1012/L)
White blood cells (×109/L)
Hemoglobin (g/L)
Hematocrit (%)
Platelets (×109/L)
White blood cell differential (Neutrophils (%), Eosinophils (%), Basophils (%), 
Monocytes (%), Lymphocytes (%))
PT/INR
PT (sec)
aPTT (sec)
Reticulocyte percentage 
(%)
Serum Chemistry
Alanine aminotransferase
(U/L)
Alkaline phosphatase (U/L)
Aspartate aminotransferase
(U/L)
GGT (U/L)
Total bilirubin (μmol/L)
Direct bilirubin (μmol/L)
Lactose dehydrogenase 
(U/L)
Creatine kinase (U/L)
Albumin (g/L)
Total protein (g/L)
Serum creatinine (umol/L)
Blood urea (mmol/L) 
Uric Acid (mmol/L)
HDL Cholesterol (mmol/L) LDL Cholesterol (mmol/L)
Triglycerides (mmol/L)
Glucose (mmol/L)
Potassium (mmol/L)
Sodium (mmol/L)
Magnesium (mmol/L) 
Calcium (mmol/L)
Chloride (mmol/L)
Amylase (U/L)
Visit:
Baseline, Days 3, 9 and 11.
Analytical Methods: The following summaries will be provided for each cohort. Liver function testing 
measurements at local laboratories are not used for the summaries.


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(1) Summary of Laboratory Test Results and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline (each post-baseline visit -
baseline) will be provided for each visit.
(2) Summary of Shifts of Laboratory Test Results
Shift tables showing the number of subjects in each category at baseline and each post-baseline 
visit will be provided. For each laboratory test, the laboratory values will be classified as 
“Low”, “Normal” or “High” relative to the normal reference range provided by the central 
laboratory. The shift tables will be based on these classifications.
(3) Number and Percentage of Subjects with Markedly Abnormal Values of Laboratory 
Test results
Overall frequency distributions of MAV during treatment phase will be provided. If a 
laboratory test result has both lower and upper MAV criteria, analysis will be performed for 
each. Further details are given in Appendix.
Urinalysis
Analysis Set:
Safety Analysis Set
Analysis Variables : pH
[Min<= - <5.0, 5.0<= - <=8.5, 8.5< - <=Max]
Specific gravity
[Min<= - <1.005, 1.005<= - <=1.030, 1.030< - <=Max]
Protein
[Negative, Positive]
Glucose
[Negative, Positive]
Nitrites
[Negative, Positive]
Bilirubin
[Negative, Positive]
Ketones
[Negative, Positive]
Urobilinogen
[Normal, Abnormal]
Microscopic Analysis
RBC (/HPF)
[Negative, Positive]
WBC (/HPF)
[Negative, Positive]
Hyaline casts (/LPF)
[Not Found, Positive]
Granular casts (/LPF)
[Not Found, Positive]
Epithelial cells (×106/L)
[Min<= - <2.0, 2.0<= - <=10.0, 10.0< - <=Max]
Visit:
Baseline, Days 3, 9 and 11.
Analytical Methods: The following summaries will be provided for each cohort. 
(1) Summary of Shifts of Urine Laboratory Test Results
Shift tables showing the number of subjects in each category at baseline and each post-baseline 
visit will be provided.


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7.10.3 Vital Signs
Analysis Set:
Safety Analysis Set
Analysis Variables: Body Temperature (°C)
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Respiratory Rate (bpm)
Pulse (bpm)
Visit:
Baseline, Days 2-11
Analytical Methods: For each variable, following summary will be provided by cohort.
(1) Summary of Vital Signs Parameters and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline (each post-baseline visit –
baseline) will be provided for each visit.
(2) Number and Percentage of Subjects with Markedly Abnormal Values of Vital Signs 
Parameters
Overall frequency distributions of MAV during treatment phase will be provided. If a vital 
sign parameter has both lower and upper MAV criteria, analysis will be performed for each. 
Further details are given in Appendix.
7.10.4 12-Lead ECGs
Analysis Set:
Safety Analysis Set
Analysis Variables: Heart Rate (bpm)
RR Interval (msec)
PR Interval (msec)
QT Interval (msec)
QTcF Interval (msec)
QRS Interval (msec)
12-Lead ECG Interpretation
[“Within Normal Limits”,
“Abnormal, Not Clinically Significant”,
“Abnormal, Clinically Significant”]
Visit:
Baseline, Days 1-11


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Analytical Methods: For each variable other than 12-lead ECG interpretations, summary (1) will be provided by 
cohort.
For 12-lead ECG interpretations, summary (3) will be provided by cohort.
(1) Summary of ECG Parameters and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline (each post-baseline visit –
baseline) will be provided for each visit.
(2) Number and Percentage of Subjects with Markedly Abnormal Values of ECG 
Parameters
Overall frequency distributions of MAV during treatment phase will be provided. If an ECG 
parameter has both lower and upper MAV criteria, analysis will be performed for each. Further 
details are given in Appendix.
(3) Summary of Shifts of ECG Parameters
Shift tables showing the number of subjects in each category at baseline and each post-baseline 
visit will be provided.
7.10.5 Other Observations Related to Safety
Not applicable.
7.11
Interim Analysis
Not applicable.
7.12
Changes in the Statistical Analysis Plan 
From the SAP version 1.0, the following parts were updated. In 7.3.4, the subject flow chart was 
mentioned clearly. In 7.8.1, common log scales were applied to semi-log graphs for mean 
concentration-time profiles instead of natural log scales, and Ae was removed from the summary 
table for the total of TAK-438F and its metabolites. In 7.10.1.1 and 7.10.1.2, several tables for 
drug-related TEAEs were added. In 7.10.2, PT and microscopic analysis parameters were added 
to the analysis variables. In 9.1.1, the MAV criteria of blood urea was removed.


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8.0
REFERENCES
Not applicable.


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9.0
APPENDIX
9.1
Criteria for Markedly Abnormal Values
9.1.1
Hematology, Serum Chemistry, Vital Signs, and 12-lead ECG (except Upper MAV 
Criteria of QTcF Interval)
For each parameter, all evaluable data (ie, non-missing data) obtained up to Day 11 will be 
classified as a MAV or not. The criteria in the table below will be used. 
For each parameter and subject, classifications will be made according to the conditions i) to iii) 
provided below. The lower and the upper criteria will be considered separately.
i)
A subject with at least one evaluable data after baseline that meets the MAV criteria will be 
classified as a subject with MAV.
ii)
A subject who does not meet condition i) and has at least one evaluable data after baseline 
that doesn’t meet the MAV criteria will be considered as a subject without MAV.
iii) A subject who does not meet conditions i) or ii) will be excluded from the analysis of MAV 
for that parameter.
Hematology
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Red blood cells (×1012/L)
<0.8×LLN
>1.2×ULN
White blood cells (×109/L)
<0.5×LLN
>1.5×ULN
Hemoglobin (g/L)
<0.8×LLN
>1.2×ULN
Hematocrit (%)
<0.8×LLN
>1.2×ULN
Platelets (×109/L)
<75
>600
Neutrophils (%）
<0.5×LLN
>1.5×ULN
Eosinophils (%）
-
>2×ULN
Basophils (%）
-
>3×ULN
Monocytes (%）
-
>2×ULN
Lymphocytes (%）
<0.5×LLN
>1.5×ULN
aPTT (sec)
>1.5×ULN
PT/INR
>1.5


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Serum Chemistry
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Alanine aminotransferase (U/L)
-
>3×ULN
Alkaline phosphatase (U/L)
-
>3×ULN
Aspartate aminotransferase (U/L)
-
>3×ULN
GGT (U/L)
-
>3×ULN
Total bilirubin (μmol/L)
-
>34.2
Direct bilirubin (μmol/L)
-
>2×ULN
Creatine kinase (U/L)
-
>5×ULN
Albumin (g/L)
<25
-
Total protein (g/L)
<0.8×LLN
>1.2×ULN
Uric Acid (mmol/L)
-
>0.773
Triglycerides (mmol/L)
-
>2.5×ULN
Glucose (mmol/L)
<2.8
>19.4
Potassium (mmol/L)
<3.0
>6.0
Sodium (mmol/L)
<130
>150
Magnesium (mmol/L)
<0.5
>1.2
Calcium (mmol/L)
<1.75
>2.88
Chloride (mmol/L)
<75
>126
Amylase (U/L)
-
>2×ULN
Serum creatinine (μmol/L)
-
>177
Vital Signs
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Body Temperature (°C)
<35.6
>37.7
Systolic Blood Pressure (mmHg)
<85
>180
Diastolic Blood Pressure (mmHg)
<50
>110
Pulse (bpm)
<50
>120


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12-lead ECG
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Heart Rate (bpm)
<50
>120
QT Interval (msec)
<=50
>=460
QTcF Interval (msec)
<=50
-
9.1.2
12-lead ECG (Upper MAV Criteria of QTcF Interval)
All evaluable data (ie, non-missing data) obtained up to Day 11 will be classified as a MAV or 
not. The criteria in the table below will be used. Note that the observed value and the change 
from baseline used for classification should be measurements taken on the same day.
For each subject, classifications will be made according to the conditions i) to iii) provided 
below.
i)
A subject with at least one evaluable data after baseline that meets the MAV criteria will be 
classified as a subject with MAV.
ii)
A subject who does not meet condition i) and has at least one evaluable data after baseline 
that meets any of the following will be considered as a subject without MAV.

Observed value is less than 450 msec and not missing.

Change from baseline is less than 30 msec and not missing, and observed value is less than 
500 msec and not missing.
iii) A subject who does not meet conditions i) or ii) will be excluded from the analysis of MAV.
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
QTcF Interval (msec)
-
If either of the following conditions is met:

observed value >=500

change from baseline >= 30 and observed value >=450


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&OLQLFDO3KDUPDFRORJ\$SSURYDO
6HS87&
%LRVWDWLVWLFV$SSURYDO
6HS87&
&OLQLFDO$SSURYDO
6HS87&
3KDUPDFRYLJLODQFH$SSURYDO
6HS87&
PPD
PPD
PPD
PPD
PPD