Clinical trial NCT02388724
Conditions: Erosive Esophagitis
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2015-03-24; Completion date: 2017-07-27
Enrollment: 481 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to demonstrate the efficacy of vonoprazan (TAK-438) versus lansoprazole in the treatment of erosive esophagitis classified as Los Angeles (LA) classification grades A to D at Week 8.

Detailed description:
The drug being tested in this study is called vonoprazan. Vonoprazan is being tested to treat people who have erosive esophagitis. This study will look at mucosal healing of people who take vonoprazan versus lansoprazole.

This study will enroll approximately 480 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Vonoprazan 20 mg
* Lansoprazole 30 mg

All participants will be asked to take one tablet and one capsule at the same time each day throughout the study. All participants will be asked to record daytime and nighttime (during sleep) subjective symptoms in a diary on a daily basis.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is up to 11 weeks. Participants will make multiple visits to the clinic, and will be contacted by telephone 7-14 days after last dose of study drug for a follow-up assessment.

Arms: arm 1: Vonoprazan 20 mg, tablet, orally, once daily and lansoprazole placebo-matching capsule, orally, once daily for up to 8 weeks. arm 2: Lansoprazole 30 mg, capsule, orally, once daily and vonoprazan placebo-matching tablet, orally, once daily for up to 8 weeks.
Interventions: intervention 1: Vonoprazan intervention 2: Lansoprazole intervention 3: Vonoprazan Placebo intervention 4: Lansoprazole Placebo
Intervention descriptions: intervention 1: Vonoprazan tablets intervention 2: Lansoprazole capsules intervention 3: Vonoprazan placebo-matching tablets intervention 4: Lansoprazole placebo-matching capsules

Protocol documents:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A Randomized, Double-Blind, Double-Dummy Phase 3 Study to Evaluate the Efficacy and Safety 
of Oral Once-Daily administration of TAK-438 20 mg compared to Lansoprazole 30 mg in the 
Treatment of Subjects with Erosive Esophagitis
NCT Number: NCT02388724
Protocol Approve Date: 01-September-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
PROTOCOL AMENDMENT
A Randomized, Double-Blind, Double-Dummy Phase 3 Study to Evaluate the Efficacy and 
Safety of Oral Once-Daily administration of TAK-438 20 mg compared to Lansoprazole 
30 mg in the Treatment of Subjects with Erosive Esophagitis
Sponsor:
Takeda Development Center Asia, Pte. Ltd.
21 Biopolis Road, Nucleos North Tower, Level 4, Singapore 138567
Study Number:
TAK-438_303
IND Number:
Not Applicable
EudraCT Number:
Not Applicable
Compound:
TAK-438
Date:
01-September-2016
Amendment Number:
05
Amendment History
Date
Amendment Number
Amendment Type
Region
08 Aug 2012
Initial Protocol
Not applicable
Asia Pacific
31 Oct 2014
01
Non-substantial
Asia Pacific
26 Jan 2015
02
Non-substantial
Asia Pacific
11 May 2015
03
Substantial
Asia Pacific
14 Dec 2015
04
Substantial
Asia Pacific
01 Sept 2016
05
Non-substantial
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 to each site.
Takeda Development Center Asia, Pte. Ltd. sponsored Asia 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
Asia Pacific Contact
Serious adverse event pregnancy and special 
interest adverse event reporting
Medical Monitor
(medical advice on protocol, compound, and 
medical management of subjects)
Responsible Medical Officer 
(carries overall responsibility for the conduct of the 
study)
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 
The signature of the responsible Takeda medical officer and other signatories can be found on the 
signature page.
Electronic Signatures may be found on the last page of this document.
ate
Date
Date
PPD
PPD
PPD


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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)
Location of Facility (Country)


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1.3
Protocol Amendment 05 Summary of Changes
1. The contacts (Section 1.1) have been updated.
2. The protocol approvers (Section 1.2) have been updated.
3. Inclusion criterion #3 (Section 7.1) has been revised to extend the window period for the 
number of days before randomization for endoscopy to 14 days.
4. Main exclusion criteria have been supplemented with hypersensitivity to lansoprazole, in 
Study Summary (Section 2.0) and Section 7.2, and to exclude subjects with liver function test 
(LFT) > upper limit of normal (ULN), in Study Summary (Section 2.0).
5. Information on phase 3 clinical data for TAK-438 has been added to the Background (Section 
4.1).
6. LA classification grading O has been included in Section 9.1.16 (Endoscopy), due to routine 
clinical practice.
7. Section 9.3.1 (Screening Phase procedures) has been revised to include updated wording 
regarding the window period for the number of days before randomization for ECG, Hepatitis 
B and C, and endoscopy, which has been extended to 14 days. Additionally, the process of 
dispensing the Medical Emergency card has been added.
8. For study procedures (Appendix A), the window period for the number of days before 
randomization for ECG, Hepatitis B and C, and endoscopy has been extended to 14 days. 
Additionally, the process of dispensing the Medical Emergency card has been added.
Typographical errors and points for clarification have also been added. A full description and 
supporting rationale for each of the changes implemented in this Protocol Amendment is provided 
in Appendix G.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 05 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Principal Investigator/Coordinating 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(s)..........................................................................................20
5.1.2
Secondary Objectives.........................................................................................20
5.1.3
Additional Objectives.........................................................................................20
5.2
Endpoints.................................................................................................................20
5.2.1
Primary Endpoint...............................................................................................20
5.2.2
Secondary Endpoints..........................................................................................20
5.2.3
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.....................26
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................26
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........26
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................26
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............27
7.1
Inclusion Criteria .....................................................................................................27
7.2
Exclusion Criteria ....................................................................................................27
7.3
Excluded Medications and Treatments.....................................................................29


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7.4
Diet, Fluid, Activity Control ....................................................................................30
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................31
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................32
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................33
8.1
Study Medication and Materials...............................................................................33
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................33
8.1.1.1 Investigational drug......................................................................................33
8.1.1.2 Ancillary Materials.......................................................................................34
8.1.1.3 Sponsor-Supplied Drug ................................................................................34
8.1.1.4 Rescue Medication.......................................................................................34
8.1.2
Storage...............................................................................................................35
8.1.3
Dose and Regimen .............................................................................................35
8.1.3.1 Missed Doses ...............................................................................................36
8.1.4
Overdose............................................................................................................36
8.2
Investigational drug Assignment and Dispensing Procedures...................................36
8.3
Randomization Code Creation and Storage..............................................................37
8.4
Investigational Drug Blind Maintenance ..................................................................37
8.5
Unblinding Procedure..............................................................................................37
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................37
9.0
STUDY PLAN ..............................................................................................................39
9.1
Study Procedures.....................................................................................................39
9.1.1
Informed Consent Procedure..............................................................................39
9.1.2
Demographics, Medical History, and Medication History Procedure..................39
9.1.3
Physical Examination Procedure ........................................................................39
9.1.4
Weight, Height and BMI....................................................................................40
9.1.5
Vital Sign Procedure..........................................................................................40
9.1.6
Documentation of Concomitant Medications......................................................40
9.1.7
Documentation of Concurrent Medical Conditions.............................................40
9.1.8
Procedures for Clinical Laboratory Samples.......................................................40
9.1.9
Contraception and Pregnancy Avoidance Procedure...........................................42
9.1.10 Pregnancy ..........................................................................................................43
9.1.11 ECG Procedure..................................................................................................43
9.1.12 Determination of H. pylori infection status using breath test...............................43
9.1.13 Documentation of Screen Failure .......................................................................43
9.1.14 Documentation of Randomization......................................................................44


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9.1.15
 
.................................................................................................44
9.1.16 Endoscopy .........................................................................................................45
9.2
Monitoring Subject Treatment Compliance..............................................................47
9.3
Schedule of Observations and Procedures................................................................47
9.3.1
Visit 1: Screening Phase (Day -28 to Day-1) ......................................................47
9.3.2
Visit 2: Treatment Phase (Randomization, Day1)...............................................48
9.3.3
Visit 3: Treatment Phase (Day 15 / Week 2).......................................................49
9.3.4
Visit 4: Treatment Phase (Day 29 / Week 4).......................................................50
9.3.5
Visit 5: Treatment Phase (Day 43 / Week 6).......................................................51
9.3.6
Visit 6: End of Treatment (Day 57 / Week 8) or Study Early Discontinuation 
(within 14 days after last dose)...........................................................................51
9.3.7
Follow-up ..........................................................................................................52
9.3.8
Post Study Care..................................................................................................52
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................53
10.1
Definitions...............................................................................................................53
10.1.1 Pretreatment Events ...........................................................................................53
10.1.2 AEs....................................................................................................................53
10.1.3 Additional Points to Consider for PTEs and AEs................................................53
10.1.4 SAEs..................................................................................................................55
10.1.5 Special Interest AEs...........................................................................................56
10.1.6 Severity of PTEs and AEs..................................................................................56
10.1.7 Causality of AEs ................................................................................................57
10.1.8 Relationship to Study Procedures.......................................................................57
10.1.9 Start Date...........................................................................................................57
10.1.10
Stop Date .....................................................................................................57
10.1.11
Frequency ....................................................................................................57
10.1.12
Action Concerning Study Medication...........................................................57
10.1.13
Outcome.......................................................................................................58
10.2
Procedures...............................................................................................................58
10.2.1 Collection and Reporting of AEs........................................................................58
10.2.1.1
PTE and AE Collection Period ...............................................................58
10.2.1.2
PTE and AE Reporting ...........................................................................59
10.2.2 Collection and Reporting of SAEs......................................................................59
10.2.3 Reporting of Abnormal Liver Function Tests as an SAE ....................................60
10.3
Follow-up of SAEs ..................................................................................................60
CCI


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10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....60
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................62
12.0
DATA HANDLING AND RECORDKEEPING............................................................63
12.1
eCRFs......................................................................................................................63
12.2
Record Retention .....................................................................................................63
13.0
STATISTICAL METHODS..........................................................................................65
13.1
Statistical and Analytical Plans ................................................................................65
13.1.1 Analysis Sets......................................................................................................65
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................65
13.1.3 Efficacy Analysis...............................................................................................65
13.1.4 Handling of Missing Data ..................................................................................66
13.1.5 Safety Analysis ..................................................................................................66
13.2
Interim Analysis and Criteria for Early Termination ................................................66
13.3
Determination of Sample Size..................................................................................67
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................68
14.1
Study-Site Monitoring Visits ...................................................................................68
14.2
Protocol Deviations..................................................................................................68
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................68
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................69
15.1
IRB and/or IEC Approval ........................................................................................69
15.2
Subject Information, Informed Consent, and Subject Authorization .........................70
15.3
Subject Confidentiality ............................................................................................71
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................71
15.4.1 Publication and Disclosure.................................................................................71
15.4.2 Clinical Trial Registration..................................................................................72
15.4.3 Clinical Trial Results Disclosure ........................................................................72
15.5
Insurance and Compensation for Injury....................................................................72
16.0
REFERENCES..............................................................................................................73
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications and Treatments...............................................................29
Table 8.a
Investigational Drug...........................................................................................34
Table 8.b
Sponsor-Supplied Drug......................................................................................35
Table 9.a
Clinical Laboratory Tests...................................................................................41
Table 9.b
Requirements for Subject Diary Entries Regarding Subjective Symptoms..........45


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Table 9.c
Severity of Subjective Symptoms.......................................................................45
Table 9.d
Los Angeles (LA) classification for diagnosis and grading of erosive 
esophagitis .........................................................................................................46
Table 10.a
Takeda Medically Significant AE List................................................................56
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................23
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................74
Appendix B
Responsibilities of the Investigator.....................................................................76
Appendix C
Elements of the Subject Informed Consent.........................................................78
Appendix D
Investigator Consent to Use of Personal Information..........................................81
Appendix E
Definition of Heartburn/ Regurgitation Severity.................................................82
Appendix F
Rescue Medication Guideline.............................................................................83
Appendix G
Detailed Description of Amendments to Text.....................................................84


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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: A Randomized, Double-Blind, Double-Dummy 
Phase 3 Study to Evaluate the Efficacy and Safety of Oral Once-Daily 
administration of TAK-438 20 mg compared to Lansoprazole 30 mg in 
the Treatment of Subjects with Erosive Esophagitis
IND No.: 
Not applicable
EudraCT No.:
Not applicable 
Study Number: TAK-438_303
Phase: 3
Study Design:
A phase 3, multicenter, double-blind, non-inferiority study of TAK-438 20 mg versus Lansoprazole 30 mg given once 
daily (OD) for up to 8 weeks in subjects with erosive esophagitis, with the LA classification grade A/B or C/D serving 
as the stratification factors at randomization, where all subjects with endoscopic healing of erosive esophagitis 2, 4, or 
8 weeks after the start of the study will be construed as “completed cases” who then may be invited to participate with 
further informed consent in the planned, ensuing, maintenance trial (TAK-438_305).
Primary Objectives:
To demonstrate the non-inferior efficacy of TAK-438 versus Lansoprazole in the healing of subjects with erosive 
esophagitis classified as LA classification grades A to D during the 8-week treatment.
Secondary Objectives:
To compare the efficacy of TAK-438 versus Lansoprazole in the healing of subjects with erosive esophagitis 
classified as LA classification grades A to D during the 2-week treatment.
To compare the efficacy of TAK-438 versus Lansoprazole in the healing of subjects with erosive esophagitis 
classified as LA classification grades A to D during the 4-week treatment.
To compare the safety of TAK-438 versus Lansoprazole in subjects with erosive esophagitis classified as LA 
classification grades A to D.
Additional Objectives:
To compare the difference of TAK-438 versus Lansoprazole in the subjective symptoms of erosive esophagitis and 
health-related quality of life measures.
To compare the difference of TAK-438 versus Lansoprazole in the percentage of days without rescue medication 
during the treatment phase.
Subject Population: Subjects aged ≥18 years (and at least the local age of consent) inclusive with erosive esophagitis 
who were diagnosed as LA Classification grades A to D.
Number of Subjects:
TAK-438 20 mg group: approximately 240
Lansoprazole 30 mg group: approximately 240 
Estimated total: approximately 480 at randomization 
Number of Sites:
Estimated total: Approximately 50 sites in 
multiple countries
Dose Level(s):
TAK-438 20 mg group: TAK-438 (one 20 mg tablet) + Lansoprazole
placebo (matching 30 mg capsule) given once daily after breakfast
Lansoprazole 30 mg group: TAK-438 placebo (matching 20 mg tablet)
+ Lansoprazole (one 30 mg capsule) given once daily after breakfast
Route of Administration:
Oral


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Duration of Treatment:
2, 4, or 8 weeks
Period of Evaluation:
1-28 days (Screening Phase) including
3-7 days of Observation Phase
2, 4, 6 or 8 weeks (Treatment Phase)
7-14 days (Follow-up Phase)
Main Criteria for Inclusion:
All subjects are to be evaluated for eligibility for entry in the study based on the following criteria.
Subjects who have endoscopically confirmed (Los Angeles classification grade A-D) erosive esophagitis. Subjects 
must also have provided (or when applicable their legally acceptable representative has provided) informed consent, 
are capable of understanding and complying with the study procedures and agree to use appropriate contraception.
Main Criteria for Exclusion:
Subjects who have hypersensitivity to TAK-438 or related compounds and lansoprazole, a significant history of 
central nervous system (CNS), cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, 
endocrine or hematological disease, or any significant results from physical examinations, or subjects with a liver 
function test > upper limit of normal, or clinical laboratory results as deemed by the investigator. Subjects that have 
any co-morbidities, medical or surgical history that may affect the esophagus or have an acute upper gastrointestinal
bleeding, gastric or duodenal ulcer within 30 days, with history or treatment of malignancy within 5 years are also 
excluded.
Main Criteria for Evaluation and Analyses:
Efficacy:
The primary efficacy endpoint of this study is the rate of endoscopic healing of erosive esophagitis during the 8-week 
treatment phase.
The secondary efficacy endpoints of this study are

the rate of endoscopic healing of erosive esophagitis during the 2-week treatment.

the rate of endoscopic healing of erosive esophagitis during the 4-week treatment.
Other efficacy endpoints include subjective symptoms of erosive esophagitis as recorded in subject diaries (e.g.
heartburn, gastric acid regurgitation), health-related quality of life measures and percentage of days without using 
rescue medication. 
Safety:
The safety endpoints of this study include adverse events, laboratory test values, electrocardiogram (ECG), vital signs, 
serum gastrin and pepsinogen I/II values.
Statistical Considerations:
Efficacy Analysis :
For the primary efficacy endpoint of Week 8 healing rate of erosive esophagitis, a 2-sided 95% confidence interval 
(CI) will be constructed for the difference between TAK-438 and Lansoprazole treatment groups and its lower bound 
will be compared to the non-inferiority margin of -10%.
The secondary endpoints of Week 2 and Week 4 healing rates of erosive esophagitis will be compared between 
TAK-438 and Lansoprazole treatment groups by constructing a 2-sided 95% CI for the healing rate difference.
The additional endpoints related to GERD symptoms and the use of rescue medication during treatment will be 
compared between treatment groups using Wilcoxon rank-sum tests. Analysis of Health-Related Quality of Life 
endpoints will be conducted with an Analysis of Covariance model with treatment and baseline EE grade (A/B vs 
C/D) as factors and baseline as a covariate.
Statistical inference will be performed at a 2-sided 0.05 level of significance or via 2-sided 95% CIs. 


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Safety Analysis:
Safety analysis will be performed by summarizing the incidence of adverse events, clinical laboratory tests including 
gastrin and pepsinogen I/II levels, vital signs, and ECGs. No statistical testing or inferential statistics will be 
generated.
Sample Size Justification: 
Assuming that the true Week 8 healing rate is 94.7% for both TAK-438 and Lansoprazole, and assuming that the 
dropout rate is up to 20%, a sample size of 160 subjects per group will provide 90% power to establish non-inferiority 
using a 2-sided 95% CI with a -10% non-inferiority margin. A sample size of 240 subjects per group is planned in 
order to provide more subjects with healed EE to the subsequent maintenance study TAK-438_305 and to provide 
adequate subjects for regulatory requirements in various countries.
The assumption of the 94.7% true healing rate is based on Phase 2 studies TAK-438/CCT-001 and 
TAK-390MR/CCT-001.


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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/Coordinating Investigator
Takeda Development Center Asia, Pte. Ltd. will select a Signatory Coordinating Investigator from 
the investigators who participate in the study. Selection criteria for this investigator will include 
significant knowledge of the study protocol, the study medication, their expertise in the therapeutic 
area and the conduct of clinical research as well as study participation. The Signatory Coordinating 
Investigator will be required to review and sign the clinical study report and by doing so agrees 
that it accurately describes the results of the study.


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3.3
List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BMI
Body Mass Index
BUN
blood urea nitrogen
CEC
Clinical Endpoint Committee
CFR
Code of Federal Regulations
CK/CPK
creatine phosphokinase
Cl
chlorine
Cmax
maximum observed plasma concentration
CNS
central nerve system
eCRF
electronic case report form 
CRO
contract research organization
CYP
cytochrome P450 enzyme
DNA
deoxyribonucleic acid
ECG
electrocardiogram
EE
erosive esophagitis
EDC
electronic data capture
EM
extensive metabolizers 
FDA
Food and Drug Administration
FAS
full analysis set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GGT
-glutamyl transferase
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HCV-RNA
hepatitis C virus- ribonucleic acid
HIV
human immunodeficiency virus
H. pylori
Helicobacter pylori
HRQoL
Health-Related Quality of Life
IC
informed consent
ICH
International Conference on Harmonisation
ID
identification 


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IEC
independent ethics committee
INN
International Nonproprietary Name
INR
International Normalized Ratio
IRB
institutional review board
IU
International unit(s)
IUDs
intrauterine devices
IVRS
interactive voice response system
IWRS
interactive web response system
LA classification
Los Angeles classification
LDH
lactate dehydrogenase
LLN
lower limit of normal
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
NERD
non-erosive reflux disease
NSAIDs
non-steroidal anti-inflammatory drugs 
P-CAB
potassium-competitive acid blockers
pH4 HTR
pH4 holding time ratio
PM
poor metabolizers 
PPI
Proton pump inhibitor
PPS
per-protocol analysis set
PTP
Press Through Package
QD
quaque die, every day
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
TBC
to be confirmed
TBil
total bilirubin 
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
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
Erosive esophagitis is among the gastric acid-related disorders in which gastric acid reflux to the 
esophagus leads to problems in affected individuals. In 1994, the concept of a “mucosal break,” 
defined as “‘an area of slough or an area of erythema with a discrete lined demarcation from the 
adjacent or normal looking mucosa,” was introduced in the Los Angeles classification for 
diagnosis and grading of erosive esophagitis. Erosive esophagitis is graded in severity into 
4 grades (A-D) based on the extent of mucosal breaks. Acid reflux induces prolonged, unpleasant 
subjective symptoms, such as heart burn or gastric acid reflux, in symptomatic patients with 
erosive esophagitis, often aggravating their Heath-Related Quality of Life (HRQoL). 
Due to westernization of diet in Asia, there is an increase in the patients with erosive esophagitis.
The proton pump inhibitors (PPIs), such as Lansoprazole, represent the drugs of first choice for 
erosive esophagitis, and are being widely used all over the world. 
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 reason 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 


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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 
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) (e.g., 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 2 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/duodenal ulcer healing and for the prevention of 


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recurrence of a gastric or duodenal ulcer during NSAID or aspirin administration and has 
subsequently been launched in Japan for these indications. All treatments were well-tolerated.
4.2
Rationale for the Proposed Study
In a phase 2 dose-ranging study of TAK-438 in subjects with erosive esophagitis 
(TAK-438/CCT-001), dose-response efficacy was shown for TAK-438, showing TAK-438 to be 
non-inferior to Lansoprazole at either of the doses tested (5 mg, 10 mg, 20 mg, and 40 mg), with no 
particular safety concerns identified. Furthermore, the rate of endoscopic healing of erosive 
esophagitis in subjects with more severe disease (LA classification grades C/D) was 95% or higher 
with TAK-438 at doses 20 mg or higher compared to 87% with Lansoprazole 30 mg, which led to 
the clinically recommended dose of TAK-438 for erosive esophagitis being determined as 20 mg.
In light of these considerations, it was decided that this study was to be implemented to prove the 
non-inferiority of TAK-438 20 mg to Lansoprazole 30 mg in efficacy for erosive esophagitis. This 
study will further examine the effectiveness and safety of TAK-438 in Asian subjects outside of 
Japan with erosive esophagitis. 


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective(s)
The primary objective is to demonstrate the non-inferior efficacy of TAK-438 versus 
Lansoprazole in the treatment of subjects with erosive esophagitis classified as LA classification 
grades A to D during the 8–week treatment.
5.1.2
Secondary Objectives 
To compare the efficacy of TAK-438 versus Lansoprazole in the healing of subjects with erosive 
esophagitis classified as LA classification grades A to D during the 2-week treatment.
To compare the efficacy of TAK-438 versus Lansoprazole in the healing of subjects with erosive 
esophagitis classified as LA classification grades A to D during the 4-week treatment.
To compare the safety of TAK-438 versus Lansoprazole in subjects with erosive esophagitis 
classified as LA classification grades A to D.
5.1.3
Additional Objectives 
5.2
Endpoints
5.2.1
Primary Endpoint 
The primary efficacy endpoint of this study is the rate of endoscopic healing* of erosive 
esophagitis during the 8-week treatment.
*Endoscopic healing: defined as subjects endoscopically diagnosed as LA classification grade O during the
treatment phase.
5.2.2
Secondary Endpoints 
The secondary efficacy endpoints of this study are
!
the rate of endoscopic healing of erosive esophagitis during the 2-week treatment,
!
the rate of endoscopic healing of erosive esophagitis during the 4-week treatment.
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The safety endpoints of this study include adverse events, laboratory test values, ECG, vital signs, 
serum gastrin values, and pepsinogen I/II values.
5.2.3
Additional Endpoints
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
A phase 3, multi-center, double-blind, non-inferiority study of TAK-438 20 mg versus 
Lansoprazole 30 mg given once daily for up to 8 weeks in subjects with erosive esophagitis, with 
the LA classification grade A/B or C/D serving as the stratification factors at randomization, where 
all subjects with endoscopic healing of erosive esophagitis 2, 4, or 8 weeks after the start of the 
study will be construed as “completed cases” who then may be invited to participate with further 
informed consent in the planned, ensuing, maintenance trial (TAK-438_305).
Upon randomization subjects will be assigned (at a 1:1 ratio) to receive either oral TAK-438 20 mg 
or Lansoprazole 30 mg all study medication will once daily after breakfast except on Day 1 when it 
will be administered at the study site before the subject’s visit is concluded.
This study will be conducted at a total of around 50 sites across Asia with an estimated total of 
240 subjects randomized to each treatment group totaling 480 for the study.
The study will consist of a Screening Phase of up to 28 days, including an Observation Phase of 
3-7 days prior to the randomization visit (Day 1), during which a baseline observation of EE 
symptoms will be completed, and then a Treatment Phase of up to 8 weeks. There will be 6 subject 
visits scheduled: the start of the Observation Phase (Visit 1), the start of the Treatment Phase 
(Visit 2), after 2 weeks of treatment (Visit 3), after 4 weeks of treatment (Visit 4), after 6 weeks of 
treatment (Visit 5), after 8 weeks of treatment (Visit 6), and a phone call during the Follow-up 
phase (only for those not participating in TAK-438_305 study).
Dosing will commence on Day 1 after randomization at Visit 2 (after completion of all required 
assessments scheduled on the Day 1). 
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A. 


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Figure 6.a
Schematic of Study Design
6.2
Justification for Study Design, Dose, and Endpoints
For the patient population studied
With the westernization of lifestyle and the aging of society, erosive esophagitis has been steadily 
increasing over the years. In the diagnosis of erosive esophagitis, the LA classification, first 
introduced in 1994 at the World Congress of Gastroenterology, has been widely used ever since. A 
phase 2 dose-ranging study of TAK-438 (TAK-438/CCT-001) was conducted earlier using the LA 
classification. In this trial of TAK-438 in erosive esophagitis, subjects with mucosal breaks 
diagnosed as the LA classification grades A to D were enrolled, to the exclusion of those with 
co-morbidities or a history of these conditions that could influence the efficacy evaluation of 
TAK-438.
For study design and sample size used
1. Study design
This study was designed as a randomized, double-blind, parallel-group comparison of TAK-438 
versus the PPI Lansoprazole, a first drug of choice for erosive esophagitis, as control to 
demonstrate the non-inferiority of TAK-438. 
In light of the results of a phase 2 dose-ranging study of TAK-438 (TAK-438/CCT-001) 
demonstrating a lower rate of endoscopic healing in subjects with the baseline LA classification 
grades C/D than those with grades A/B, at the start of treatment (visit 1), the present study was 
planned to stratify the subjects by baseline endoscopic findings (grades A/B or C/D) at 
randomization.


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2. Sample size
For a description of the rationale for sample size determination, refer to Section 13.3.
For the doses of the study medications used
In a phase 2 dose-ranging study of TAK-438 in subjects with erosive esophagitis 
(TAK-438/CCT-001), TAK-438 exhibited a dose-response efficacy, when given once daily at 
doses 5 mg, 10 mg, 20 mg, and 40 mg for 8 weeks, and demonstrated its non-inferiority to 
Lansoprazole 30 mg at either of the doses examined, with no particular safety concerns identified. 
Additionally, given that the rate of endoscopic healing of erosive esophagitis in subjects with more 
severe disease (LA classification grades C/D) was 95% or higher with TAK-438 at doses 20 mg or 
higher compared to 87% with Lansoprazole 30 mg, the clinically recommended dose of TAK-438 
for erosive esophagitis was determined as 20 mg.
The dose of Lansoprazole was determined as 30 mg, which represents its therapeutic dose for 
erosive esophagitis.
For the route of administration used
In a phase 1 single-dose study of TAK-438 in healthy male volunteers conducted in Japan, which 
evaluated the influence of diet on the pharmacokinetics of TAK-438 10 mg and 40 mg, the 
AUC0-48 and the Cmax was shown to be increased by 1.32-fold (95% CI, 1.18 to 1.48) and by 
1.21-fold (95% CI, 0.951 to 1.54), respectively, with TAK-438 10 mg, and by 1.15-fold (95% CI, 
1.05 to 1.27) and by 1.08 (95% CI, 0.944 to 1.23), respectively, with TAK-438 40 mg, after meals 
compared to those seen under fasting conditions, demonstrating that the postprandial increases in 
AUC and Cmax with TAK-438 were modest. Again, pharmacological results from the same phase 1
study demonstrated that once-daily dosing of TAK-438 exhibited adequate acid-inhibitory effects 
that were sustained over a 24-hour period. It is of note here that the control agent Lansoprazole 
30 mg has been approved for erosive esophagitis as a once-daily regimen.
Based on these results, it was decided that TAK-438 would be given after breakfast as a once-daily 
regimen, as in the earlier phase 2 dose-ranging study of TAK-438 (TAK-438/CCT-001).
For the duration of treatment used
The primary endpoint of the phase 2 dose-ranging study of TAK-438 was defined as the rate of 
endoscopic healing of erosive esophagitis after 4 weeks of treatment with the study medications, 
based on the assumption that TAK-438 is expected to have a faster onset of action than the PPIs 
such as Lansoprazole. However, given that the PPIs have been approved for 8-week dosing as the 
drugs of first choice for erosive esophagitis, the primary endpoint of this study was defined as the 
rate of endoscopic healing after 8 weeks of treatment with TAK-438. Therefore, the study was 
designed to allow the subjects to complete the study at the time point at which endoscopic healing 
of erosive esophagitis has been confirmed 2, 4, or 8 weeks of treatment to move on to the 
maintenance study (TAK-438_305).


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For the Observation Phase incorporated in the study
Subjects with erosive esophagitis are not only afflicted with esophageal mucosal breaks but also 
suffer from unpleasant subjective symptoms associated with gastric acid reflux, often leading to a 
worsening of their HRQoL. Major subjective symptoms associated with acid reflux include 
heartburn and gastric acid regurgitations and relieving these symptoms as a step toward improving 
their HRQoL represents an important component of the treatment for subjects with erosive 
esophagitis.
Thus, it was decided that an observation phase would be included to establish an appropriate 
baseline for evaluation of the effect of TAK-438 on these major symptoms, i.e., heartburn and 
gastric acid regurgitations, associated with acid reflux.
For the endpoints used
1. Primary endpoint
Endoscopic healing of esophageal mucosal breaks represents the goal of treatment for erosive 
esophagitis, in which Lansoprazole 30 mg has been approved for use once daily for up to 8 weeks.
As it is the aim of this study to prove the non-inferior efficacy of TAK-438 versus Lansoprazole in 
subjects diagnosed as the LA classification grades A to D, the primary endpoint was defined as the 
rate of endoscopic healing during an 8-week treatment phase.
2. Secondary endpoints
As TAK-438 is expected to produce more sustained, potent acid-inhibitory effects and earlier 
healing of erosive esophagitis than Lansoprazole 30 mg, the above-mentioned phase 2
dose-ranging study (TAK-438/CCT-001) was conducted with the primary endpoint defined as the 
rate of endoscopic healing after 4 weeks of treatment, which demonstrated the non-inferiority of 
TAK-438 versus Lansoprazole. In the approved Japan package insert for TAK-438, it claims that 
the usual administration should be limited up to 4 weeks. However, when the effect is insufficient, 
the drug may be administered up to 8 weeks. Furthermore, it is thought likely that TAK-438 
produces endoscopic healing of erosive esophagitis as early as after 2 weeks of treatment, given its 
sustained, potent acid-inhibitory effects. Thus, the secondary endpoint of this study was defined as 
the rate of endoscopic healing of erosive esophagitis after 2 and 4 weeks of treatment with the 
study medications.
A dose-dependent elevated serum gastrin was observed in TAK-438 subjects from a completed 
Phase 2 study so to proactively address safety concerns it is appropriate to monitor serum gastrin 
level. Thus the serum gastrin and pepsinogen I/II will be collected from baseline to study 
completed.
3. Additional endpoints
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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.
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 randomization.
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 has been confirmed in an endoscopy to have erosive esophagitis, i.e. the LA 
classification grades A to D within 14 days of the start of the Day 1 (Visit 2). 
Note: The recruitment goal is to ensure that those with LA classification grade C/D will 
account for more than 30% of all subjects enrolled (144/480), with no further recruitment of 
those with grade A/B considered when they account for more than 70% (336/480) of all 
subjects.
4. The subject is aged 18 years old or older (or the local age of consent if that is older), male or 
female, at the time of signing an informed consent, and is being treated on an outpatient basis 
for erosive esophagitis, including those admitted temporarily for examination.
5. 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.
7.2
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 84 days prior to the start of the 
Observation phase.
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 is in a dependant 
relationship with a study site employee who is involved in conduct of this study (e.g., spouse, 
parent, child, sibling) or may consent under duress.
4. The subject has, in the judgment of the investigator, clinically significant abnormal 
hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening. 


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5. The subject has a history or clinical manifestations of serious CNS, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, urological, endocrine or hematological disease.
6. The subject has a history of hypersensitivity or allergies to TAK-438 (including its 
excipients*) or to proton pump inhibitors (PPIs).
*D-mannitol, crystalline cellulose, hydroxypropyl cellulose, fumaric acid, croscarmellose 
sodium, magnesium stearate, hypromellose, macrogol 6000, titanium oxide, yellow iron 
sesquioxide and iron sesquioxide.
7. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 1 year prior to the Observation Phase (Visit 1).
8. The subject is required to take excluded medications 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. The subject has participated in another clinical study within the past 30 days from Visit 1.
11. The subject has co-morbidities that could affect the esophagus (eosinophilic esophagitis, 
esophageal varices, scleroderma, viral or fungal infection, esophageal strictures), a history of 
radiotherapy or cryotherapy for the esophagus; those with corrosive or physiochemical injury 
(with the possible inclusion in the study of those with Schatzki’s ring or Barrett’s esophagus).
12. The subject has a history of surgical procedures that may affect the esophagus (eg, 
fundoplication and mechanical dilatation for esophageal strictures excluding Schatzki’s ring) 
or a history of gastric or duodenal surgery excluding endoscopic removal of benign polyps.
13. The subject developed acute upper gastrointestinal bleeding, gastric ulcer (a mucosal defect 
with white coating) or duodenal ulcer (a mucosal defect with white coating), within 30 days 
before the start of the Observation Phase (Visit 1) (with the possible inclusion of those with 
gastric or duodenal erosion). The subjects requiring NSAIDs or aspirin treatment along with 
the concomitant PPI therapy to prevent GI bleeding should not be enrolled.
14. The subject has Zollinger-Ellison syndrome or gastric acid hypersecretion or a history of 
gastric acid hypersecretion.
15. The subject is scheduled for surgery that requires hospitalization or requires surgical treatment 
during his/her participation in the study.
16. The subject has a history of malignancy or was treated for malignancy within 5 years before 
the start of the Observation Phase (Visit 1) (the subject may be included in the study if he/she 
has cured cutaneous basal cell carcinoma or cervical carcinoma in situ). 
17. The subject has acquired immunodeficiency syndrome (AIDS) or hepatitis, including hepatitis
virus carriers: HBs-antigen positive or HCV-antibody-positive (the subject may be included in 
the study if he/she is HCV-antigen or HCV-RNA-negative).


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18. Laboratory tests performed at the start of the Early Observation Phase (visit 1) revealed any of 
the following abnormalities in the subject:
a) Creatinine levels: > 2 mg/dL (>177 µmol/L).
b) ALT, AST or total bilirubin levels: > the upper limit of normal (ULN).
19. Subject is active in the Screening Period after the closure of enrollment identified by the 
Sponsor or the number of subjects randomized with LA classification A/B or C/D have 
reached the required sample size.
7.3
Excluded Medications and Treatments
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
Table 7.a
Excluded Medications and Treatments
From 84 days 
prior to 
treatment to 
completion of 
the study
From 30 days 
prior to 
treatment 
through study 
completion
From 14 days 
prior to the 
screening 
endoscopy 
procedure 
through study 
completion
From 14 days 
prior to 
13C/14C Urea
Breath test
From 7 days 
prior to the 
start of the 
Observation 
Period 
through study 
completion
From start of the 
Observation Period to 
completion of the 
study
Other 
investigational 
drugs or drugs 
administered 
due to 
participation in 
another clinical 
trial
H. pylori
eradication 
therapy (ie, PPI 
+ 2 antibiotics)
PPIs (interfere 
with gastric 
acid secretion)
Metronidazole, 
Bismuth 
preparations, 
Ecabet sodium 
hydrate 
(interfere with 
13C/14C Urea 
breath test)
H2 antagonists 
(interfere with 
gastric acid 
secretion)
Other agents affecting 
digestive organs 
including: muscarinic 
M3 receptor antagonists, 
prokinetics, 
anticholinergic agents, 
prostaglandins, 
anti-gastrin agents or 
mucosal-protective 
agents.
Hormonal 
contraceptives
Atazanavir sulfates; 
Rilpivirine 
hydrochloride 
(contraindicated with 
TAK-438)
Antibiotics($) 
(interfere with 
13C or 14C Urea 
Breath test (a)
Surgical procedures that 
could affect gastric acid 
secretion (e.g. upper 
gastrointestinal surgery, 
vagotomy) or for 
treatment of EE 
(fundoplication)
Bisphosphonates (b)
Footnotes are on the following page.


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(a) Prohibited period is 4 weeks prior to the 13C or 14C Urea breath test or local 13C or 14C Urea breath test kits package 
insert requirement.
(b) Except subjects that were using these agents before signing the informed consent form at the screening visit and the 
dose and administration will not be changed during the study. Switching between once-daily and weekly regimens is 
allowed for drugs containing the same active ingredients. Also allowed are compliant subjects on a stable dose (in 
accordance with the package insert) at the time of signing consent that has no GI inflammation or history of such.
7.4
Diet, Fluid, Activity Control 
The principal investigator, the co-investigators, and the study collaborators are to explain, and give 
instructions on, the following before the start of the study or during the study, as well as to check to 
see if the subjects keep to the instructions at the time of their scheduled visits.

Every subject should keep to the scheduled visits, seek medical consultation, and undergo 
predetermined laboratory.

The subject should ensure that all study medications are swallowed with approximately 240 ml 
water soon after breakfast according to the administration, dose and dosing schedule. Subjects 
should be instructed according to section 8.1.3.1 (Missed Doses) and 9.2 (Compliance). 
Details of any missed or forgotten doses should be reported to the Investigator or designee at 
the subsequent study visit.

The subject should store all medications in a cool, dry, safe place which is out of reach at 
children and to bring all study supplies (empty / used / unused drug packets and diaries alike) 
to each study visit.

The subject should record his/her night time (during sleep) subjective symptoms and the 
previous daytimes subjective symptoms in his/her subject diary upon rising in the morning on 
a daily basis. The subject should also record the use of rescue medication since the start of the 
Observation Period as well as his/her study medication compliance status during the Treatment 
Phase. 

Subjects will be required to fast for at least 10 hours before each visit, where fasting blood 
draw will be taken and/or endoscopy will be performed, after the Informed Consent is signed.
Fasting status means no food or nutritional drinks. Water is allowed. Any medication that 
needs to be taken with food, and study medications, should be held until after the fasting blood 
draw has been taken and/or endoscopy has been performed. Medication that does not need to 
be taken with food should be continued. Investigator must instruct the subject accordingly 
prior to visits in which serum gastrin and pepsinogen I/II levels will be measured and 
endoscopy will be performed.

After the start of treatment with the study medication in the Treatment Phase, the subject 
should present to the clinic in the morning as scheduled during the Treatment Phase.

If on any day between study visits the subject failed to eat breakfast he/she should take the 
study medication at about the same time as he/she usually does.

When the subject is to be treated by physicians other than the study investigators taking other 
medications, such as over-the-counter drugs, beyond those prescribed, he/she should consult 


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the study investigator or designee beforehand. When the subject was treated by a physician 
other than the investigator or when he/she took other medications such as over-the-counter 
drugs beyond those prescribed, he/she should report on the treatment received or the 
medications taken at the next study visit.

The subject should report on all subjective or objective symptoms experienced with regard to 
their details, day of onset, severity, outcome, and day of outcome at every visit. In case of 
emergency, such as occurrence of a serious AE, the subject or his/her family should contact the 
principal investigator as soon as possible.

The subject should use contraception without fail. (A female subject of childbearing potential 
from signing of informed consent throughout the duration of the study and 1 month after the 
final dose of the study medication.). Pregnancy in a female subject, if found, should be 
reported immediately.

The subject should not donate blood during the study, and should report on any such donation 
immediately.

The subject should refrain from excessive drinking and eating, an extreme diet change 
(eg, change to an extremely high-fat diet) or excessive exercise throughout the study.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study should be 
recorded in the case report form (eCRF) using the following categories. For screen failure subjects, 
refer to Section 9.1.13.
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 times of upper limit of normal (ULN).
2. Major protocol deviation. The discovery post-randomization 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.


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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 or lack of efficacy 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. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject. 
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF, for example: 
non-compliance.
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 
addition, efforts should be made to perform all procedures scheduled for the Early Termination 
Visit. Discontinued or withdrawn subjects will not be replaced.


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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 (20 mg tablets and matching placebo 
tablets) and Lansoprazole (30 mg capsules and matching placebo capsules) defined below. Study 
medication will be packaged in a blinded fashion.
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. The code name is TAK-438. The International Nonproprietary Name (INN) is 
vonoprazan. TAK-438 20 mg and matching placebo investigational drug is manufactured by 
Takeda Pharmaceutical Company, Osaka, Japan and will be supplied as pale red, film-coated 
tablets.
The chemical name of Lansoprazole (AG-1749) is:
(RS)-2-({[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridylmethyl]sulfinyl} benzimidazole. 
Lansoprazole 30 mg will have a dual supply chain. The Lansoprazole 30 mg for the study 
conducted in China is manufactured locally by Tianjin Takeda, Tianjin China. Lansoprazole 
30 mg for all other countries and matching placebo for Lansoprazole 30 mg is manufactured by 
Takeda Pharmaceutical Company, Osaka, Japan. All Lansoprazole 30 mg and matching placebo 
will be supplied as a white colored capsule.
TAK-438 and Lansoprazole investigational drug will be foil/foil blistered packaged into 20-day 
(2 weeks plus 6 extra days) child-resistant blister cards. Each blister card will include 20 TAK-438 
20 mg or placebo tablets and 20 Lansoprazole 30 mg or placebo capsules.
Each blister card will be labeled in a blinded fashion with a single panel or multi language booklet 
label appropriate to the countries in which it will be used. The labels will include pertinent study 
information and country-specific regulatory caution statement. 
An Interactive Web Response System (IWRS) program will be used to manage inventory, assist 
the site in dispensing the proper investigational drug to the subjects, record accountability and 
support the return to sponsor or designee of these investigational drugs after study completion.


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Table 8.a
Investigational Drug
Study medication 
form
Description
Manufacturer and Location
TAK-438 20 mg tablet
Pale red film-coated tablet scored on 
both sides
Takeda Pharmaceutical Company Ltd, Japan
TAK-438 20 mg 
matching placebo 
tablet
Pale red film-coated tablet scored on 
both sides
Takeda Pharmaceutical Company Ltd, Japan
Lansoprazole 30 mg 
capsule
White capsule 
Tianjin Takeda Pharmaceuticals Co., Ltd, China(for 
the study in China) / Takeda Pharmaceutical 
Company Limited, Osaka, Japan (for the study in 
countries except for China) 
Lansoprazole 30 mg 
matching placebo 
capsule
White capsule 
Takeda Pharmaceutical Company Ltd, Japan
The TAK-438 tablets, the Lansoprazole and each matching placebo are difficult to distinguish
from their appearance.
8.1.1.2
Ancillary Materials
Daily subject diaries will be dispensed to all subjects entering the study.
8.1.1.3
Sponsor-Supplied Drug
All drugs referenced in Section 8.1.1.1 of this protocol will be supplied by the sponsor.
8.1.1.4
Rescue Medication
During the study period including the screening period, those over-the-counter medication such as 
Gelusil (main ingredients are aluminum hydroxide, magnesium hydroxide and simethicone) or 
other bicarbonate based medication if available in the participating countries can be used as the 
rescue medication if the symptoms caused by acid reflux could not be tolerated by the subjects. 
The administration of rescue medication shall be in accordance to the package insert approved in 
the corresponding countries. Subjects shall be instructed to refrain from using rescue medication. 
Subjects shall contact the investigators if they would like to take the rescue medication at a dose 
higher than the approved ones in the local insert package.
The use of rescue medication shall be recorded in the subject daily diary. 
For detailed rescue medication administration guideline at each country, please refer to the 
Appendix F.


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8.1.2
Storage
TAK-438, Lansoprazole and each matching placebo investigational drug 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 sponsor-supplied drugs 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 meets all the inclusion criteria and none of the exclusion criteria will be 
randomly assigned to receive either once daily TAK-438 or Lansoprazole after breakfast via the 
IWRS. 
Blinding will be achieved using double-dummy, therefore at each dosing time-point subjects will 
take 1 tablet and 1 capsule, one will be active and the other will be placebos. All subjects will 
self-administer the study medications at approximately the same time each morning after 
breakfast.
Subjects will receive study drug for 2-8 weeks of treatment, thereafter those who that do not 
continue on to the TAK-438-305 study, will move into the follow-up phase 7-14 days after the last 
dose (with a phone call follow-up completed within 7-14 days after the last dose).
The subject will take the first dose of study medication at Visit 2 after completion of all 
assessments but before leaving the clinic. At all subsequent study visits during the Treatment 
Phase the subject should be instructed to present to the clinic for study visit without taking the 
study medication. The daily dose of the study medication on those days will be taken by the subject 
after completion of assessments.
Table 8.b describes the dose and tablet/capsule count that will be provided to each group.
Table 8.b
Sponsor-Supplied Drug
Treatment 
Group
Dose
Treatment Description
Active
Placebo
A
20 mg TAK-438 QD
One 20 mg TAK-438 tablet
One placebo for 30 mg Lansoprazole 
capsule
B
30 mg Lansoprazole 
QD
One 30 mg Lansoprazole 
capsule
One placebo for 20 mg TAK-438 tablet


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8.1.3.1
Missed Doses
Subjects should be instructed that all doses of study medication (TAK-438 or Lansoprazole) 
should be taken on time. Subjects should also be instructed that if any dose is missed inadvertently 
it is acceptable for that dose to be taken within 12 hours of the time that it was due. If longer than 
12 hours have passed since the dose was due, it should not be taken but noted instead in the 
subject’s diary that the dose was missed.
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 in the subject should treat the subject symptomatically. 
8.2
Investigational drug Assignment and Dispensing Procedures
The investigator or investigator’s designee will access the IWRS at Visit 1 after the subject 
provides informed consent in order to obtain a subject number. When study eligibility is confirmed 
(ie, at Visit 2), the investigator or the investigator’s designee will utilize the IWRS to randomize 
the subject into the study. During this contact, the investigator or designee will provide the 
necessary subject-identifying information, including the subject number assigned at screening. 
The Med ID number of the investigational drug to be dispensed will then be provided by the 
IWRS. 
If sponsor-supplied drug (TAK-438 20 mg tablet or matching placebo tablet, Lansoprazole 30 mg 
capsule or matching placebo capsule) is lost or damaged, the site can request a replacement from 
IWRS. (Refer to IWRS manual provided separately.) The Med ID number will be entered onto the 
eCRF at each dispensing visit.
At subsequent drug-dispensing visits, the investigator or designee will again contact the IWRS to 
request additional investigational drug for a subject. 
The IWRS will provide 1 Med ID number for dispensing to subjects for a 2 week visit and 2 Med 
ID numbers for a 4 week visit.


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8.3
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule 
prior to the start of the study. All randomization information will be stored in a secured area, 
accessible only by authorized personnel.
Subjects will be assigned in a 1:1 ratio to TAK-438 and Lansoprazole treatment groups. Subject 
randomization will be stratified by baseline endoscopic findings (LA classification grades A/B vs
C/D).
8.4
Investigational Drug Blind Maintenance 
The investigational drug blind will be maintained using the IWRS.
8.5
Unblinding Procedure 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. In the 
event of a medical emergency, if possible, the medical monitor should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding.
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by 
accessing the IWRS.
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF.
If any site personnel are unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study. 
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the approved protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug, TAK-438 20 mg, Lansoprazole 30 mg, or their matching 
placebo, the investigator must maintain records of all sponsor-supplied drug delivery to the site, 
site inventory, dispensation and use by each subject, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the 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 recording in IWRS. 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.


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The investigator must maintain 100% accountability for all sponsor-supplied drugs 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 (or Med ID or job number) 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 sponsor-supplied drugs TAK-438 20 mg,
Lansoprazole 30 mg and their matching placebo 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 and number, description of sponsor-supplied drugs, expiry or retest 
date, date and amount dispensed including initials of the person dispensing the drug, and the date 
and amount returned to the site by the subject, including the initials of the person receiving the 
sponsor-supplied drug. The log should include all required information as a separate entry for each 
subject to whom sponsor-supplied drug is dispensed.
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. The investigator will retain a 
copy of the documentation regarding clinical study material accountability, return, and/or 
destruction, and originals 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, sponsor or its designee will prepare additional 
labels, certificates of analyses, 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.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, race as described by the 
subject, smoking status, history of use alcohol and history of caffeine-containing drinks, history of 
H. pylori eradication therapy (e.g., triple therapy with PPI + amoxycillin + clarithromycin) and 
date of completion of such therapy (within the past 1 year/more than 1 year) of the subject at 
Observation Phase. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.7). Medical history will include the following:

Erosive esophagitis.

Other upper gastrointestinal diseases including gastric ulcer, duodenal ulcer, erosive 
esophagitis, non-erosive gastroesophageal reflux disease or procedures.
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 90 days prior to signing of the informed 
consent form. Medication history will include the following:

PPIs.

Histamine H2 receptor antagonists.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the pretreatment assessment immediately prior to the 
start of investigational drug) will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; 
(6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 


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(10) lymph nodes; and (11) other. All subsequent physical examinations should assess clinically 
significant changes from the baseline examination.
9.1.4
Weight, Height and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. BMI is calculated by sponsor or its designee using metric units with the formula provided 
below. 
BMI = weight (kg)/height (m)2
9.1.5
Vital Sign Procedure
Vital signs will include body temperature (oral, tympanic or infra-axillary measurement), sitting 
blood pressure (5 minutes), and pulse (bpm). Vital signs will be assessed at all time points 
specified in the Trial Schedule (Appendix A).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw.
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.
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 
(ECG), or physical examination abnormalities noted at screening/baseline examination. The 
condition (ie, diagnosis) should be described.
9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Except for 
Hepatitis B and C analysis, all other samples will be analyzed at the designated central laboratory.
The maximum volume of blood to be collected at any single visit for central laboratory analysis is 
approximately 3.5-19.5 mL (Visit1, Visit 2, Visit 3, Visit 4, Visit 5 or Visit 6/Early 
Discontinuation). Additionally, the volume of blood to be collected for Hepatitis B and C tests at 
the Screening visit is up to 10 mL. The approximate total volume of blood to be collected for the 
study is 43 ml to 83 mL depending on the time point of completing the study. Details of these 
procedures and required safety monitoring will be given in the central laboratory manual.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cells
ALT(*)
Protein (qualitative)
White blood cells
ALP
Urine sugar (qualitative)
Hemoglobin
AST(*)
Hematocrit
GGT
Gastrin(*)
Pepsinogen I/II(*) ($)
Platelets
Total bilirubin(*)
Hepatitis B and C Analysis(#)
White blood cell fractions 
(neutrophils, eosinophils, basophils, 
monocytes, lymphocytes)
Direct bilirubin(*)
LDH
CK (CPK)
Albumin
Total protein
Creatinine
BUN
Uric acid
Total cholesterol
Triglycerides(*)
Glucose(*)
Potassium
Sodium
Magnesium
Calcium
Inorganic phosphorus
Chloride
Serum iron
Vitamin B12
HBsAg
HCV-antibody
HCV-antigen(+) 
HCV-RNA(+)
Other: 
Serum
Urine
Female subjects if menopause is suspected only
Follicle-stimulating hormone (FSH)
Female subjects of child-bearing potential only
hCG (for pregnancy)
(*)To be measured under fasting conditions.
($) This includes pepsinogen I, pepsinogen II and pepsinogen I/II ratio.
(#) To be measured either at the central laboratory or the local laboratory depending on the site capability.
(+) HCV-antigen and HCV-RNA are optional.
The central laboratory will perform laboratory tests for hematology, serum chemistries, and
urinalysis. The HBV and HCV tests can be done either at the local laboratory or the central 
laboratory depending on the site capability. The results of the central 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) to monitor 
recovery should be performed within a maximum of 7 days and preferably within 48-72 hours after 


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the abnormality was found. 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.
Given the possibility that the use of TAK-438 or Lansoprazole may be associated with increases in 
serum gastrin and pepsinogen I/II levels, the subjects will be examined for gastrin and pepsinogen 
I/II levels to investigate the magnitude of these increases during the Treatment Phase.
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) where applicable*:
Intrauterine devices (IUDs):

Cap (plus spermicidal cream or jelly) PLUS 
male condom.

Diaphragm (plus spermicidal cream or jelly) 
PLUS male condom.

Copper T.
*Barrier methods is only applicable in countries where spermicide is commercially available
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 
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.


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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, Lansoprazole and matching placebo) should be immediately 
discontinued. 
If the pregnancy occurs during administration of active study medication, eg, after Visit 2 or within 
4 weeks 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.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not to be followed. 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 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The time that 
the ECG was performed will be recorded. The following parameters will be recorded on the eCRF 
from the subject’s ECG trace: heart rate, RR interval, PR interval, QT interval, and QRS 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.
9.1.12 Determination of H. pylori infection status using breath test
To obtain information on H. pylori infection that reportedly could affect the onset of erosive 
esophagitis, H.pylori infection status will be measured. To establish H. pylori infection status a 
13-C urea breath test or 14C urea breath test will be performed. Exhaled air samples will be taken in 
accordance with instructions for use of locally available testing kits for H. pylori infection status 
determination.
9.1.13 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 IWRS should be contacted as a notification of screen failure.


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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>.
!
Major protocol deviation.
!
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.
9.1.14 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance/randomization into the treatment phase.
If the subject is found to be not eligible for randomization/treatment phase, the investigator should 
record the primary reason for failure on the applicable eCRF.
If the subject is found to be eligible the subject will be randomized to either TAK-438 20 mg or 
Lansoprazole 30 mg using the IWRS. Instructions on accessing and using the IWRS will be 
provided in a separate manual. Blinded details of subject treatment allocation (Med ID numbers) 
provided via the IWRS should be documented in the subject’s medical record and/or eCRF.
9.1.15
CCI
CCI


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Table 9.c
Severity of Subjective Symptoms
9.1.16 Endoscopy
Endoscopy should be performed while subjects are fasted and according to the usual practice of the 
institution (ie, in regards to pre-medications or concomitant therapies as long as they are not 
prohibited in Section 7.3 of this protocol). 
During endoscopy the Investigator, or designee, should ensure that the gastric and esophageal 
mucosa is observed for a sufficient duration that the subject’s eligibility is confirmed and/or ensure 
that accurate classification of the grade of any erosive esophagitis, Barrett’s mucosa or esophageal 
hiatal hernia observed can be made. Digital images of the current esophageal erosions should be 
captured and stored at the investigational site and they should be available in the event of a future 
medical or data query, audit or inspection.
The subject’s lesion (erosive esophagitis) should be classified based on the LA classification 
(Table 9.d).
CCI
CCI
CCI


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Table 9.d
Los Angeles (LA) classification for diagnosis and grading of erosive 
esophagitis
Mucosal break meaning: area with white coating or erythema clearly distinguished from the
surrounding mucosa
Grade
Description
Grade O
No mucosal breaks
Grade A
One or more mucosal breaks no longer than 5 mm, none of which extends between the tops of the 
mucosal folds
Grade B
One or more mucosal breaks more than 5 mm long, none of which extends between the tops of 
two mucosal folds
Grade C
Mucosal breaks that extend between the tops of two or more mucosal folds, but which involve 
less than 75% of esophageal circumference
Grade D
Mucosal breaks which involve at least 75% of esophageal circumference
Classification of Barrett’s mucosa should be in accordance with the following criteria:

At Visit 1 (within 14 days of Visit 2 [Day 1]): present (3 cm or greater), present (less than 3 
cm), absent, unknown.

Other time points for endoscopy: increased, unchanged, reduced, disappeared, unknown.
Classification of esophageal hiatal hernia should be in accordance with the following criteria:

At Visit 1 (within 14 days of Visit 2 [Day 1]): present (2 cm or greater), present (less than 2 
cm), absent, unknown.
The investigator (or designee) will record the results of endoscopy (including results of the LA 
classification and other gradings) performed promptly in the subject’s medical record. For LA 
Grade O, the investigator is allowed to record the result as “No mucosal breaks” and/or Grade O in 
the subject’s medical record. This is to reflect clinical practice in recording ‘No mucosal breaks’ in 
medical records, as Grade O is not routinely used.
To ensure the accuracy of the EE evaluation according to LA grading, a 2nd review process of the 
endoscopy images will be established at each site. The 1st reviewer i.e. the endoscopist should take 
sufficient images or videotape the process at each endoscopic examination. The 2nd reviewer will 
evaluate the EE LA grading according to the endoscopic images. 

Preferably, the principal investigator performs as the 2nd reviewer and conducts the 2nd 
review in a timely manner after the endoscopy is performed by the 1st reviewer who is a 
sub-investigator in this study.

In cases where the principal investigator is the 1st reviewer, a sub-investigator at the same site 
can be delegated as the 2nd reviewer and conducts the 2nd review in a timely manner.

Only investigators (either principal investigators or sub-investigators) can be delegated as the 
2nd reviewer. 


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If the LA grading by the two reviewers are consistent, this result becomes the final report. If not, 
the two reviewers will discuss their findings and reach a consensus which will then become the 
final report
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study medication containers to each dispensing site visit. 
Investigators or designee should perform subject treatment compliance checks by reviewing the 
subject’s diary and returned medications.
If a subject is persistently noncompliant with the study medication (TAK-438 20 mg, 
Lansoprazole 30 mg and matching placeboes) (e.g. at more than 2 consecutive compliance checks 
to have taken less than 75% or more than 133% of the study medication), it may be appropriate to 
withdraw the subject from the study. 
At each applicable study visit it should be documented in the subject’s medical record that study 
medication was dispensed or collected, or checked for compliance. All subjects should be 
reinstructed about the dosing requirement during study contacts. The authorized study personnel 
conducting the re-education must document the process in the subject source records.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Visit 1: Screening Phase (Day -28 to Day-1)
All subjects will be assessed for the following from the informed consent before the start of the 
study medication for the Treatment Phase (Visit 2). All subjects will be examined for eligibility for 
entry in the study in accordance with the primary inclusion and exclusion criteria as per 
Sections 7.1 and 7.2. See Section 9.1.13 for procedures for documenting screening or 
randomization failures.
Informed consent could be obtained from the subjects within 28 days before the start of the 
Treatment Phase (Visit 2). And once the ICF is signed, registration in IWRS and collection of 
PTE/AE shall be started. Endoscopy, Hepatitis B and C tests, and ECG shall be performed within 
14 days prior to randomization visit. However, all the other procedures for eligibility check must 
be completed within Observation Phase which is 3 to 7 days before randomization day (Visit 2) 
in order to obtain a baseline data for the subject including the EE symptoms recorded in patient 
diaries.
If fasting is not the routine clinical practice of the site, the procedures requiring fasting will be 
performed at another visit.
Procedures to be completed at Visit 1 include:

Informed consent obtained.

Access IWRS to obtain subject number.


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
EQ-5D-5L questionnaire. In order to avoid subject’s bias, this shall be completed by the 
subjects as the first priority of all procedures after the subject provides Informed Consent and 
are registered in the IWRS. 

Eligibility assessment (review Inclusion/exclusion criteria).

Demographics, vital signs, medical and medication history and concurrent medical conditions.

Concomitant medication assessment.

Height and weight. BMI will be calculated during data analysis.

Physical examination.

ECG procedure.

Fasting clinical laboratory examination (urinalysis, hematology, serum chemistry excluding
gastrin & pepsinogen I/II).

Urine pregnancy test (in females of childbearing potential only).

FSH (when menopause is suspected).

Hepatitis B and C analysis at the local laboratory or the central laboratory depending on the site 
capability.

Guidance on the avoidance of pregnancy and ova donation.

Endoscopy.

Instructions on how to make entries in the subject diary, provision of the diary, and 
commencement of diary entry.

Pretreatment events assessment.

Prescribe rescue medication.

Dispense Medical Emergency Card.
9.3.2
Visit 2: Treatment Phase (Randomization, Day1)
Randomization will take place on Day 1. The following procedures will be performed and 
documented during Study Randomization:

EQ-5D-5L questionnaire. In order to avoid subject’s bias, this shall be completed by the 
subjects as the first priority of all procedures at this visit.

Eligibility assessment (review Inclusion/exclusion criteria).

Physical examination.

Vital signs.

Urine pregnancy test (in females of childbearing potential only).


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
13C or 14C Urea Breath test for H. pylori.

Fasting clinical laboratory examination (Serum gastrin, pepsinogen I, II and I/II ratio).

Concomitant medications assessment.

Collect daily subject diary since Visit 1 and review.

Adverse Event/ Pretreatment Event assessment.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IWRS system, as described in Section 
8.2. For eligible subjects the following should be completed:

Randomization via IWRS.

Dispense study medication (first daily dose to be taken after completion of scheduled study 
assessments and before subject leaves the study site) and instruct the subject on correct 
self-administration for subsequent daily doses as described in Section 6.1. 

Dispense new diary and re-instruct on completion and compliance if needed.

Prescribe rescue medication if needed.

Guidance on the avoidance of pregnancy and ova donation.
For ineligible subjects, the procedure for documenting Screening failures is provided in 
Section 9.1.13.
9.3.3
Visit 3: Treatment Phase (Day 15 / Week 2)
Procedures to be completed at Visit 3 include:

EQ-5D-5L questionnaire. In order to avoid subject’s bias, this shall be completed by the 
subjects as the first priority of all procedures at this visit.

Physical examination.

Vital signs.

Fasting clinical laboratory tests (hematology, chemistry including gastrin & pepsinogen I/II, 
urinalysis).

Urine pregnancy test (in females of childbearing potential only).

ECG procedure (to be performed in those in whom endoscopic healing has been confirmed 
during visits involving endoscopy).

Endoscopy.

Review treatment compliance, re-instruct the subject if appropriate.

Collect subject diary since visit 2 and review, dispense new diary and re-instruct the subject if 
appropriate.


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
Guidance on the avoidance of pregnancy and ova donation.

Adverse Event assessment.

Concomitant medications assessment.

Register the subject study completion in the IWRS if endoscopic healing of erosive esophagitis 
has been confirmed after 2 weeks of treatment. 

Initiate informed consent process for TAK-438_305 (only if endoscopic healing is confirmed 
and if the TAK-438_305 study has not been completed). 

Collect the study drugs dispensed at the last visit including the used packages and dispense 
additional Treatment Phase drug via the IWRS (only if endoscopic healing of erosive 
esophagitis has not been confirmed after 2 weeks of treatment).

Prescribe rescue medication if needed.
9.3.4
Visit 4: Treatment Phase (Day 29 / Week 4)
Procedures to be completed at Visit 4 include:

EQ-5D-5L questionnaire. In order to avoid subject’s bias, this shall be completed by the 
subjects as the first priority of all procedures at this visit.

Physical examination.

Vital signs.

Fasting clinical laboratory tests (hematology, chemistry including gastrin & pepsinogen I/II, 
urinalysis).

Urine pregnancy test (in females of childbearing potential only).

Endoscopy.

ECG procedure (to be performed in those in whom endoscopic healing has been confirmed 
during visits involving endoscopy).

Guidance on the avoidance of pregnancy and ova donation.

Review treatment compliance, re-instruct the subject if necessary and dispense investigational 
drugs.

Collect completed diary since Visit 3, review completion compliance, and dispense new daily 
diary.

Adverse Event assessment.

Concomitant medications assessment.

Register the subject study completion in the IWRS if endoscopic healing of erosive esophagitis 
has been confirmed after 4 weeks of treatment. 


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
Initiate informed consent process for TAK-438_305 (only if endoscopic healing is confirmed 
and if the TAK-438_305 study has not been completed). 

Collect the study drugs dispensed at the last visit including the used packages and dispense 
additional Treatment Phase drug via the IWRS (only if endoscopic healing of erosive 
esophagitis has not been confirmed after 4 weeks of treatment).

Prescribe rescue medication if needed.
9.3.5
Visit 5: Treatment Phase (Day 43 / Week 6)
Procedures to be completed at Visit 5 include:

Fasting liver function tests: ALT, AST, total bilirubin and direct bilirubin.

Guidance on the avoidance of pregnancy and ova donation.

Adverse Event assessment.

Concomitant medications assessment.
9.3.6
Visit 6: End of Treatment (Day 57 / Week 8) or Study Early Discontinuation (within 
14 days after last dose)
The Final Visit will be performed on Visit 6 (Day 57), or at the Study early discontinuation visit. 
The following procedures will be performed and documented:

EQ-5D-5L questionnaire. In order to avoid subject’s bias, this shall be completed by the 
subjects as the first priority of all procedures at this visit.

Physical examination.

Vital signs.

Collect completed diary since visit 4, review completion compliance.

Fasting clinical laboratory tests (hematology, chemistry including gastrin & pepsinogen I/II, 
urinalysis).

ECG procedure.

Urine pregnancy test (in females of childbearing potential only).

Endoscopy.

Review treatment compliance.

Adverse Event assessment.

Concomitant medications assessment.

Guidance on the avoidance of pregnancy and ova donation.


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
Initiate informed consent process for TAK-438_305 (only endoscopic healing is confirmed 
and if the TAK-438_305 study has not been completed).

Register the subject study discontinuation or completion via IWRS.

Collect the study drugs dispensed at the last visit including the used packages.
For all randomized subjects, the investigator must complete the End of Study eCRF page.
9.3.7
Follow-up
The study site staff will follow up with a phone call (only for subjects that do not continue on to the 
TAK-438_305 study) between 7 and 14 days after the last dose of study medication. Any new AEs 
will be recorded in the eCRFs and subject’s medical record. Follow-up will begin the first day after 
the Final Visit/Early Termination and will continue until 14 days post treatment. 
9.3.8
Post Study Care
The study medication will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies as required.


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10.0
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 (i.e. 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 (e.g. 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 (e.g. 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 (e.g. “worsening 
of…”).

If a subject has a pre-existing episodic condition (e.g. 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 (e.g. “worsening of…”).

If a subject has a degenerative concurrent condition (e.g. 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 (e.g. “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 
(e.g. “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 (e.g. “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 (e.g. 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.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The principal investigator must make the distinction between exacerbation of 
pre-existing illness and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
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
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizures
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
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 Adverse Event (serious or non-serious) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication by 
the investigator 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 
AEs of Special Interest.
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.


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10.1.7 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Yes:
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 can be 
argued, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
No:
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 Yes 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 No.
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/serious 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/serious PTE (e.g. 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.

Dose Increased – the dose was increased due to the particular AE.

Dose Reduced – the dose was reduced due to the particular AE.


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
Dose Interrupt–d - The study medication was temporarily interrupted (discontinued) 
(including voluntary drug interruption by the subject) due to the particular AE, and resumed at 
a later date.
10.1.13
Outcome 

Recovered/Resolved – Subject returned to first assessment status with respect to the 
AE/serious 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/serious 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 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/serious PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/serious PTE but was left 
with permanent/significant impairment (e.g. recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/serious PTEs which are considered as the cause of death.

Unknown – the course of the AE/serious 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 Visit 2) 
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 (Visit 2). Routine collection of AEs will continue until the Final Visit or Early 
Termination. A follow-up phone call will be made to each subject 7 to 14 days following the last 
dose of study drug to collect any AEs that may have occurred. The stop date of the AE/serious PTE 
is the date at which the subject recovered, the event resolved but with sequelae or the subject died.


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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.

Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (yes or no) (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.
Subject diary and questionnaire will not be used as a primary means to collect AEs. However, 
should the investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the patient for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied.
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:


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
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 1.1.
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 as an SAE
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).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator 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 


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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
eCRFs 
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 Clinical Study Site Agreement 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 unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. 
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment.
This review will assess the accuracy and completeness of the study database.
13.1.1 Analysis Sets
Analysis of efficacy variables will be conducted in the Full Analysis Set defined as all randomized 
subjects who receive at least 1 dose of study medication and have at least 1 post-baseline 
endoscopy, and will be based on the randomized treatment. The primary efficacy endpoint and the 
secondary efficacy endpoints will also be analyzed in the Per Protocol Set; subject evaluability 
criteria for the Per Protocol Set will be specified in the SAP. Analysis of safety variables will be 
conducted in the Safety Analysis Set defined as all subjects who take at least 1 dose of study 
medication and will be based on the treatment received. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Baseline and demographic information will be listed and summarized by treatment group and 
overall. For continuous variables, the summary will consist of descriptive statistics (number of 
subjects, mean, and standard deviation, minimum, median, and maximum). For categorical 
variables, the summary will consist of number and percentage of subjects in each category. 
13.1.3 Efficacy Analysis
The following analyses will be provided using the Full Analysis Set.
For the primary efficacy endpoint of Week 8 healing rate of erosive esophagitis, a 2-sided 95% 
confidence interval (CI) will be constructed for the difference between TAK-438 and 
Lansoprazole treatment groups. If the lower bound of this CI is ≥-10%, non-inferiority for 
TAK-438 relative to Lansoprazole will be declared. Week 8 healing rate of erosive esophagitis 
will also be analyzed in subgroups defined by baseline LA classification grades A/B vs C/D.
The secondary endpoints of the Week 2 healing rate of erosive esophagitis and the Week 4 healing 
rate of erosive esophagitis will be compared between TAK-438 and Lansoprazole treatment 
groups by constructing a 2-sided 95% CI for the healing rate difference.
The additional endpoints related to GERD symptoms during treatment will be compared between 
treatment groups using Wilcoxon rank-sum tests, with treatment effects presented using 
Hodges-Lehmann estimator and 95% Moses CI. Analysis of HRQoL endpoints will be conducted 
with an Analysis of Covariance model with treatment and baseline EE grade (A/B vs C/D) as 
factors and baseline as a covariate.


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Another additional endpoint of percentage of days without rescue medication during the treatment 
phase will be compared between treatment groups using Wilcoxon rank-sum test.
Statistical inference will be performed at a 2-sided 0.05 level of significance or via 2-sided 95% 
CIs. Adjustment for multiplicity will be performed for the primary and secondary efficacy 
endpoints in the following fashion: The primary endpoint of Week 8 healing rate will be first tested 
for non-inferiority; if non-inferiority with regard to the primary endpoint is established, then the 
secondary endpoint of Week 2 healing rate will be tested for superiority.
13.1.4 Handling of Missing Data
For the primary efficacy endpoint of Week 8 healing rate of erosive esophagitis, FAS subjects 
assessed as LA classification of Grade O based on the endoscopy data obtained on Day 2 or after 
(where Day 1 is the date of first dose of study medication) will be considered as healed subjects. 
Other FAS subjects will be considered as ‘not healed’. Missing data will not occur in the analysis 
of the primary endpoint.
For the secondary endpoint of Week 2 healing rate of erosive esophagitis, FAS subjects who have 
no endoscopy data during Day 2 to Day 21 will be excluded from the analysis. FAS subjects 
assessed as LA classification of Grade O based on the endoscopy data obtained between Day 2 and 
Day 21 will be considered as healed subjects. Other FAS subjects will be considered as ‘not 
healed’.
For the secondary endpoint of Week 4 healing rate of erosive esophagitis, FAS subjects who have 
no endoscopy data during Day 2 to Day 42 will be excluded from the analysis. FAS subjects 
assessed as LA classification of Grade O based on the endoscopy data obtained between Day 2 and 
Day 42 will be considered as healed subjects. Other FAS subjects will be considered as ‘not 
healed’.
Further details will be described in the Statistical Analysis Plan.
13.1.5 Safety Analysis
Safety analysis will be performed using the safety analysis set. 
The number and percentage of subjects with treatment-emergent adverse events will be 
summarized by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class and
Preferred Term overall, by severity, and by relationship to study drug for each treatment group. 
Separate summaries will also be generated for treatment-related adverse events overall and by 
severity. Change from baseline in clinical laboratory tests (including serum gastrin and pepsinogen 
I/II), vital signs and quantitative ECG variables will be summarized by treatment group. For 
qualitative ECG assessments, post-baseline results will be tabulated against baseline. Subjects 
with markedly abnormal values for laboratory tests, vital signs, and ECG parameters will be 
tabulated. No statistical testing or inferential statistics will be generated.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.


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13.3
Determination of Sample Size
Assuming that the true Week 8 healing rate is 94.7% for both TAK-438 and Lansoprazole, and 
assuming that the dropout rate is up to 20%, a sample size of 160 subjects per group will provide 
90% power to establish non-inferiority using a 2-sided 95% CI with a -10% non-inferiority 
margin. A sample size of 240 subjects per group is planned in order to provide more subjects with 
healed EE to the subsequent maintenance study TAK-438_305 and to provide adequate subjects 
for regulatory requirements in various countries.
The assumption of the 94.7% true healing rate is based on Phase 2 studies TAK-438/CCT-001 and 
TAK-390MR/CCT-001.
In a randomized, double-blind study in US (M87-092), the difference in Week 8 EE healing rate 
between lansoprazole 30 mg and placebo groups was 42.9% with a lower limit of 27.8% for the 
2-sided 95% confidence interval. Based on this study, the non-inferiority margin is specified as 
-10%.


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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.
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 (i.e. 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 state and federal/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 (i.e. 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 (e.g. 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 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 (e.g. 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 (i.e. subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During 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 Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site 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. Takeda contact information, along with 
investigator’s city, state (for US investigators), country, and recruiting status will be registered and 
available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of this clinical trial, 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 Clinical Study Site 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. Jones, R., Horbach, S., Sander, P., & Ryden-Bergsten, T. (2003). Heartburn in patients with 
gastro-oesophageal reflux disease in Germany and Sweden: a study on patients’ burden of 
disease. [Research Support, Non-U.S. Gov’t]. Pharmacoeconomics, 21(15), 1091-1102.
3. Mahadeva, S., Wee, H., L., Goh, K., & Thumboo, J. (2009). The EQ-5D (Euroqol) is a valid 
generic instrument for measuring quality of life in patients with dyspepsia. BMC 
Gastroenterology, 9. Doi: http://dx.doi.org/10.1186/1471-230X-9-20.
4. 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 
Phase
Treatment Phase
Follow-up 
Phase
Timing
At start of 
Signing ICF
At start 
of study 
drug
After 2 
weeks
After 4 
weeks
After 6 
weeks
After 8 
weeks
Study Day:
Days –28 to 
–1 
(Observation 
Period: Day 
-7 to -3)
Day 1*
(e)
Week 2
(Day 15) 
(e)
Week 4
(Day 29) 
(e)
Week 6
(Day 43)
Week 8
(Day 
57) (e)
At study 
early 
discontinuati
on
Follow-U
p phone 
call (k)
Visit Windows (Days)
±3 
±3 
±3
±3 
Within 14 
days after the 
last dose
7 – 14 
days after 
the last 
dose
Visit Number
1
2
3
4
5
6
Informed consent
X
X(j)
X(j)
X(j)
Inclusion/exclusion criteria
X(a)
X
Demographics/medical history
X(a)
Medication history
X(a)
Physical examination
X(a)
X
X
X
X
X
Vital signs
X(a)
X
X
X
X
X
Weight, height and BMI
X(a)
Concomitant medications
X(a)
X
Concurrent medical conditions
X(a)
Clinical laboratory tests (b)
X (a)
X
X
X
X
Liver function test (p)
X
Serum gastrin/ pepsinogen I/II 
levels
X
X
X
X
X
H. pylori breath test
X
Guidance on avoidance of 
pregnancy and ova donation
X(a)
X
X
X
X
X
X
FSH 
X(c)
Urine pregnancy test (hCG) (d)
X(a)
X
X
X
X
X
Electrocardiogram (ECG)
X (f)
X (h)
X (h)
X
X
Hepatitis B and C tests
X (f, n)
Dispense / collect / review 
Daily diary (symptom 
collection and rescue 
medication use), and complete 
EQ-5D-5L questionnaire (m)
X(a)
X
X
X
X
X
Dispense the Medical 
Emergency Card
X
Endoscopy
X (f)
X (l)
X (l)
X (l)
X
Prescribe rescue medication (o)
X
X
X
X
Obtain subject number via 
IWRS
X
Randomization via accessing 
IWRS
X(g)
X(l)
X(l)
X(l)
Dispense investigational drug
via IWRS
X (g)
X (i)
X(i)
Collect the drug dispensed
X
X
X
X
Review study medication 
compliance 
X
X
X
X
Footnotes are on last table page.


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Appendix A
Schedule of Study Procedures (continued)
Screening 
Phase
Treatment Phase
Follow-up 
Phase
Timing
At start of 
Signing ICF
At start 
of study 
drug
After 2 
weeks
After 4 
weeks
After 6 
weeks
After 8 
weeks
Study Day:
Days –28 to 
–1 
(Observation 
Period: Day 
-7 to -3)
Day 1*
(e)
Week 2
(Day 15) 
(e)
Week 4
(Day 29) 
(e)
Week 6
(Day 43)
Week 8
(Day 
57) (e)
At study 
early 
discontinuati
on
Follow-U
p phone 
call (k)
Visit Windows (Days)
±3 
±3 
±3
±3 
Within 14 
days after the 
last dose
7 – 14 
days after 
the last 
dose
Visit Number
1
2
3
4
5
6
Access IWRS for study 
discontinuation or completion 
if applicable
X
X
X
X
AE/PTE assessment
Follow-up phone call (k)
X
* The day of first investigational drug administration for Treatment period is Day 1. The day before first 
investigational drug administration for Treatment period is Day -1.
(a) The visit window for those annotated procedures is 3 to 7 days prior to the start of the study treatment. During this 
period, the baseline observation of EE symptoms recorded in the patient diary will be completed. 
(b) Hematology, serum chemistry, and urinalysis.
(c) Only if menopause is suspected.
(d) Urine HCG test to be performed only in female subjects of childbearing potential.
(e) During the treatment phase, the subject should be instructed to present to the clinic without taking the study 
medication when instructed (ie, Investigator must instruct the subject accordingly prior to visits in which serum gastrin 
and pepsinogen I/II levels will be measured, endoscopy will be performed). The daily dose of the study medication 
will be taken by the subject after completion of assessments on the day of study visits. 
(f) The visit window for assessment of Hepatitis B and C, and endoscopy is defined as Day -14 to Day -1. However, 
any reliable, documented results available from an endoscopy performed in a routine clinical setting within 14 days 
prior to randomization (Day 1) (before signing of informed consent) will be accepted instead, given the invasive 
nature of the procedure. Additionally, reliable, documented results available from an ECG performed in a routine 
clinical setting, and tests for Hepatitis B and C, within 14 days prior to randomization (Day 1) (before signing of 
informed consent) will be accepted.
(g) The first dose of the study medication will be taken by the subject after completion of scheduled study assessments
and before subject leaves the study site. Access the IWRS for the randomization before start administration.
(h) To be performed in those in whom endoscopic healing has been confirmed during visits involving endoscopy.
(i) To be performed in those in whom endoscopic healing has not been confirmed.
(j) If appropriate initiate consent process for TAK-438_305 study.
(k) Only for subjects that do not continue on to the TAK-438_305 study.
(l) At the time point where endoscopic healing of erosive esophagitis has been confirmed after 2, 4, or 8 weeks of 
treatment, the subject will complete the study, and may be eligible for randomization of the long-term EE maintenance 
study (TAK-438_305) after signing of further informed consent.
(m) EQ-5D-5L questionnaire shall be the first priority in all procedures (except signing the ICF) at each visit.
(n) Hepatitis B and C analysis in accordance with Section 9.1.8 Table 9.a will be conducted at the local laboratory or 
central laboratory depending on the site capability. 
(o) Rescue medication is prescribed by the investigators at the start of the Screening visit and, if needed, at the 
subsequent visits.
(p) Liver function tests include ALT, AST, total bilirubin and direct bilirubin.


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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 the probability for random 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. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. 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.
15. 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.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. 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.
19. 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 


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participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. 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.
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 
performed throughout the study for all female subjects of childbearing potential. If a subject is 


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found to be pregnant during study, study medication will be discontinued and the investigator 
will offer the subject the choice to receive unblinded treatment information.
25. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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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
Definition of Heartburn/ Regurgitation Severity 
Definitions of Heartburn/Regurgitation Severity 
None 
No symptoms
Mild 
Occasional symptoms, can be ignored, does not influence daily routine
Moderate 
Symptoms cannot be ignored and/ or occasionally influence daily routine
Severe
Symptoms present most of the day and/ or regularly influence daily routine


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Appendix F
Rescue Medication Guideline 
A guideline of commonly used medications which may be used as rescue medications in each of 
the 4 countries is presented in the table below. The local insert package will be distributed to sites 
once sites are activated. If the listed rescue medications are not available, please contact 
Quintiles/Takeda Medical Advisor for confirmation of available brand. During the rescue 
medication administration, please note:
1. Subjects should be instructed to take rescue medication only after consultation with the 
investigator;
2. The administration of rescue medication shall be in accordance to the local package insert;
3. For aluminum based medications, an interval of at least 2 hours must be maintained between 
administration of study medication (TAK-438 or lansoprazole) and rescue medication;
4. When rescue medication has been taken for more than 7 consecutive days, or more than 25% of 
the days in whole study period, investigator should discuss with CRO/sponsor and decide 
whether to withdraw the subject.
Country/Region
Brand Name
Constituents
China
Hydrotalcite Chewable Tablets
Hydrotalcite 0.5g
Hydrotalcite Talcid
Hydrotalcite 0.5g
Gaviscon Tablets
Aluminium hydroxide 0.05g, Magnesium trisilicate 0.0125g, 
Alginic acid 0.25g
Malaysia
Gelusil
Al(OH)3 250 mg, Mg trisilicate 500 mg
Eno
Anhydrous citric acid, Na bicarbonate, Na carbonate
Gaviscon
Na alginate 250mg, Na bicarbonate 133.5mg, Ca carbonate 
80mg.
Noriflux 
Na alginate, Na bicarbonate, Ca carbonate
Korea 
Amphojel tab
Aluminum hydroxide 
Almagel suspension/tab
Almagate 
Gelfos
Aluminum phosphate colloidal 12.38g /20g 
Lamina-G sol
Sodium alginate 5g/100 ml
Taiwan
Gowell Tablets “WECAM”
Aluminum Dihydroxyal (50.000 mg), Metamagnesium 
aluminum silicate(450.000 mg)
Alginos oral suspension
Alginate Sodium 50mg, Sodium Bicarbonate 26.7mg, 
Calcium Carbonate 16mg
NACID
Aluminum Magnesium Carbonate Hydroxide Tetrahydrate 
Synthetic 500mg


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Appendix G
Detailed Description of Amendments to Text 
Page 2, Section 1.1 Contacts
Existing Text
Issue
Asia Pacific Contact
Serious adverse event pregnancy and special 
interest adverse event reporting
Medical Monitor
(medical advice on protocol, compound, and 
medical management of subjects)
Responsible Medical Officer 
(carries overall responsibility for the conduct of the 
study)
PPD


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Revised Text
Issue
Asia Pacific Contact
Serious adverse event pregnancy and special 
interest adverse event reporting
Medical Monitor
(medical advice on protocol, compound, and 
medical management of subjects)
Responsible Medical Officer 
(carries overall responsibility for the conduct of the 
study)
Rationale for Amendment
To prevent repetitious amendments for staff changes at Quintiles, a generic reference contact has 
been used. The Responsible Medical Officer has been changed.
Page 3, Section 1.2 Approvals
Existing Text
Revised Text
Rationale for Amendment
The Responsible Medical Officer has been changed. The list of approvers has been updated to 
reflect company procedure.
PPD
PPD
PPD


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Page 12, Study Summary: Main Exclusion Criteria
Existing Text
Subjects who have hypersensitivity to TAK-438 or related compounds, a significant history of 
central nervous system (CNS), cardiovascular, pulmonary, hepatic, renal, metabolic, 
gastrointestinal, urological, endocrine or hematological disease, or any significant results from 
physical examinations, or clinical laboratory results as deemed by the investigator. Subjects that 
have any co-morbidities, medical or surgical history that may affect the esophagus or have an 
acute upper gastrointestinal bleeding, gastric or duodenal ulcer within 30 days, with history or 
treatment of malignancy within 5 years are also excluded.
Revised Text
Subjects who have hypersensitivity to TAK-438 or related compounds and lansoprazole, a 
significant history of central nervous system (CNS), cardiovascular, pulmonary, hepatic, renal, 
metabolic, gastrointestinal, urological, endocrine or hematological disease, or any significant 
results from physical examinations, or subjects with a liver function test > upper limit of 
normal, or clinical laboratory results as deemed by the investigator. Subjects that have any 
co-morbidities, medical or surgical history that may affect the esophagus or have an acute upper 
gastrointestinal bleeding, gastric or duodenal ulcer within 30 days, with history or treatment of 
malignancy within 5 years are also excluded.
Rationale for Amendment
An exclusion criterion for subjects with a hypersensitivity to lansoprazole, administered during the 
study, has been added to the Study Summary and to Section 7.4 (Exclusion Criteria), and the 
exclusion of subjects with an LFT > ULN has been added to the Study Summary to align with the 
current text in Section 7.4.
Page 18, Page Section 4.1 Background
Added Text
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/duodenal ulcer 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. All 
treatments were well-tolerated.
Rationale for Amendment
To provide further knowledge and data on TAK-438, a summary of phase 3 clinical data has been 
added to the Background section.


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Page 27, Section 7.1 Inclusion Criteria
Existing Text
3. The subject has been confirmed in an endoscopy to have erosive esophagitis, i.e. the LA 
classification grades A to D within 7 days of the start of the Day 1 (Visit 2).
Revised Text
3. The subject has been confirmed in an endoscopy to have erosive esophagitis, i.e. the LA 
classification grades A to D within 14 days of the start of the Day 1 (Visit 2).
Rationale for Amendment
The window period before randomization for endoscopic confirmation of erosive esophagitis has 
been extended to 14 days to reduce screen and prescreen failure.
Page 46, Section 9.1.16 Endoscopy
Existing Text
Classification of Barrett’s mucosa should be in accordance with the following criteria:

At Visit 1: present (3 cm or greater), present (less than 3 cm), absent, unknown.

Other time points for endoscopy: increased, unchanged, reduced, disappeared, unknown.
Classification of esophageal hiatal hernia should be in accordance with the following criteria:

At Visit 1: present (2 cm or greater), present (less than 2 cm), absent, unknown.
The investigator (or designee) will record the results of endoscopy (including results of the LA 
classification and other gradings) performed promptly in the subject’s medical record.
Revised Text
Classification of Barrett’s mucosa should be in accordance with the following criteria:

At Visit 1 (within 14 days of Visit 2 [Day 1]): present (3 cm or greater), present (less than 3 
cm), absent, unknown.

Other time points for endoscopy: increased, unchanged, reduced, disappeared, unknown.
Classification of esophageal hiatal hernia should be in accordance with the following criteria:

At Visit 1 (within 14 days of Visit 2 [Day 1]): present (2 cm or greater), present (less than 2 
cm), absent, unknown.
The investigator (or designee) will record the results of endoscopy (including results of the LA 
classification and other gradings) performed promptly in the subject’s medical record. For LA 
Grade O, the investigator is allowed to record the result as “No mucosal breaks” and/or 
Grade O in the subject’s medical record. This is to reflect clinical practice in recording ‘No 
mucosal breaks’ in medical records, as Grade O is not routinely used.


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Rationale for Amendment
Wording has been added to qualify when endoscopy should be performed during the Screening 
period (Visit 1). Additionally, text has been added to reflect clinical practice in recording ‘No 
mucosal breaks’ in medical records, as Grade O is not routinely used.
Page 47, Section 9.3.1 (Screening Phase)
Existing Text
Informed consent could be obtained from the subjects within 28 days before the start of the 
Treatment Phase (Visit 2). And once the ICF is signed, registration in IWRS and collection of 
PTE/AE shall be started. However, all the other procedures for eligibility check must be completed 
within Observation Phase which is 3 to 7 days before randomization day (Visit 2) in order to 
obtain a baseline data for the subject including the EE symptoms recorded in patient diaries.
Revised Text
Informed consent could be obtained from the subjects within 28 days before the start of the 
Treatment Phase (Visit 2). And once the ICF is signed, registration in IWRS and collection of 
PTE/AE shall be started. Endoscopy, Hepatitis B and C tests, and ECG shall be performed 
within 14 days prior to randomization visit. However, all the other procedures for eligibility 
check must be completed within Observation Phase which is 3 to 7 days before randomization 
day (Visit 2) in order to obtain a baseline data for the subject including the EE symptoms recorded 
in patient diaries.
Added Text

Dispense Medical Emergency Card.
Rationale for Amendment
The window period before randomization for endoscopic confirmation of erosive esophagitis has 
been extended to 14 days to reduce screen and prescreen failure. As ECG, and tests for Hepatitis B 
and C, is performed at the time of endoscopy, this window period has been extended to 14 days, 
too.
The procedure: Dispense the Medical Emergency Card, in the Screening Visit, has been added to 
address an audit finding. Many investigators were not clear when the card shall be dispensed to the 
patients.
Page 75, Appendix A Schedule of Study Procedures
Existing Text
FSH 
X(a)
(f) The visit window for assessment of ECG, Hepatitis B and C, and endoscopy is defined as Day -7 to Day -1. 
However, any reliable, documented results available from an endoscopy performed in a routine clinical setting within 
7 days prior to randomization (Day 1) (before signing of informed consent) will be accepted instead, given the 
invasive nature of the procedure.


TAK-438
Study No. TAK-438_303
Page 89 of 89
Protocol (Incorporating Amendment No. 05)
01 September 2016
CONFIDENTIAL
Added and Revised Text
FSH 
X(c)
Dispense the Medical 
Emergency Card
X
(f) The visit window for assessment of Hepatitis B and C, and endoscopy is defined as Day -14 to Day -1. However, 
any reliable, documented results available from an endoscopy performed in a routine clinical setting within 14 days 
prior to randomization (Day 1) (before signing of informed consent) will be accepted instead, given the invasive 
nature of the procedure. Additionally, reliable, documented results available from an ECG performed in a 
routine clinical setting, and tests for Hepatitis B and C, within 14 days prior to randomization (Day 1) (before 
signing of informed consent) will be accepted.
Rationale for Amendment
The window period before randomization for endoscopic confirmation of erosive esophagitis has 
been extended to 14 days to reduce screen and prescreen failure. As ECG, and the tests for 
Hepatitis B and C, is performed at the time of endoscopy, this window period has been extended to 
14 days, too. Footnote for FSH assessment has been corrected.


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PPD

SAP_000.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: A Randomized, Double-Blind, Double-Dummy Phase 3 Study to Evaluate the 
Efficacy and Safety of Oral Once-Daily administration of TAK-438 20 mg compared to 
Lansoprazole 30 mg in the Treatment of Subjects with Erosive Esophagitis
NCT Number: NCT02388724
SAP Approve Date: 23 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.


TAK-438_303 Statistical Analysis Plan Version 2
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TAKEDA DEVELOPMENT CENTER
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-438_303
A Randomized, Double-Blind, Double-Dummy Phase 3 Study to Evaluate the Efficacy and 
Safety of Oral Once-Daily administration of TAK-438 20 mg compared to Lansoprazole 30 mg 
in the Treatment of Subjects with Erosive Esophagitis
PHASE 3
Version: 2
Date: 23 August 2017
Prepared by:
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.
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1.0
APPROVAL SIGNATURES
Electronic signatures can be found on the last page of this document.
Study Title:
A Randomized, Double-Blind, Double-Dummy Phase 3 Study to Evaluate 
the Efficacy and Safety of Oral Once-Daily administration of TAK-438 20 
mg compared to Lansoprazole 30 mg in the Treatment of Subjects with 
Erosive Esophagitis
TDC Approvals:
Date
Date
Date
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2.0
TABLE OF CONTENTS
1.0
APPROVAL SIGNATURES.......................................................................................................2
2.0
TABLE OF CONTENTS ............................................................................................................3
3.0
LIST OF ABBREVIATIONS.......................................................................................................6
4.0
OBJECTIVES............................................................................................................................7
4.1.
PRIMARY OBJECTIVES .................................................................................................................7
4.2.
SECONDARY OBJECTIVES.............................................................................................................7
4.3.
ADDITIONAL OBJECTIVES .............................................................................................................7
4.4.
STUDY DESIGN............................................................................................................................7
5.0
ANALYSIS ENDPOINTS...........................................................................................................9
Primary Endpoint.......................................................................................................................9
Secondary Endpoints.................................................................................................................9
Additional Endpoints..................................................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.....................................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION ................................................................. 11
7.1
GENERAL CONSIDERATIONS .......................................................................................................11
7.1.1
DEFINITIONS..............................................................................................................................11
7.1.2
ANALYSIS SETS.........................................................................................................................11
7.1.3
HANDLING OF RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS ......................................12
7.1.3.1
RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 2-WEEK TREATMENT .........12
7.1.3.2
RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 4-WEEK TREATMENT .........12
7.1.3.3
RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 8-WEEK TREATMENT .........12
7.1.4
HANDLING OF DATA WHEN CALCULATING PROPORTION OF DAYS WITHOUT SUBJECTIVE SYMPTOMS 
ACCORDING TO SUBJECT DIARY ................................................................................................. 12
7.1.5
HANDLING OF DATA WHEN CALCULATING MEAN SEVERITY ACCORDING TO SUBJECT DIARY ............13
7.1.6
HANDLING OF PARTIALLY SUSTAINED RESOLUTION ACCORDING TO SUBJECT DIARY .......................14
7.1.7
HANDLING OF SUSTAINED RESOLUTION ACCORDING TO SUBJECT DIARY........................................14
7.1.8
HRQOL (EQ-5D-5L).................................................................................................................15
7.1.9
HANDLING OF DATA WHEN CALCULATING PROPORTION OF DAYS WITHOUT RESCUE MEDICATION.... 15
7.1.10
HANDLING OF OTHER ENDPOINTS ...............................................................................................16
7.2
STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS...............................17
7.2.1
DISPOSITION OF SUBJECTS.........................................................................................................17
7.2.1.1
STUDY INFORMATION .................................................................................................................17
7.2.1.2
SCREEN FAILURES.....................................................................................................................17
7.2.1.3
SUBJECT ELIGIBILITY.................................................................................................................17


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7.2.1.4
NUMBER OF SUBJECTS RANDOMIZED BY COUNTRY, SITE, AND TREATMENT GROUP.........................18
7.2.1.5
DISPOSITION OF SUBJECTS.........................................................................................................18
7.2.1.6
PROTOCOL DEVIATIONS AND ANALYSIS SETS...............................................................................18
Protocol Deviations..................................................................................................................18
Analysis Sets...........................................................................................................................19
7.2.2
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...........................................................19
7.2.2.1
SUMMARY OF DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS.......................................19
7.2.2.2
MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS ........................................................20
7.2.2.3
MEDICATION HISTORY AND CONCOMITANT MEDICATIONS ..............................................................21
7.2.3
TREATMENT COMPLIANCE ..........................................................................................................21
7.2.3.1
STUDY DRUG EXPOSURE AND COMPLIANCE.................................................................................21
7.3
EFFICACY ANALYSIS..................................................................................................................22
7.3.1
PRIMARY EFFICACY ENDPOINT.................................................................................................... 22
7.3.1.1
PRIMARY ANALYSIS ...................................................................................................................22
7.3.1.2
SECONDARY ANALYSIS ..............................................................................................................22
7.3.2
SECONDARY EFFICACY ENDPOINTS.............................................................................................22
7.3.2.1
RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 2-WEEK TREATMENT..........22
7.3.2.2
RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 4-WEEK TREATMENT..........23
7.3.2.3
SENSITIVITY ANALYSIS...............................................................................................................23
7.3.3
ADDITIONAL EFFICACY ENDPOINTS .............................................................................................23
7.3.3.1
GASTROINTESTINAL SYMPTOMS BASED ON SUBJECT DIARY..........................................................23
Heartburn Symptoms...............................................................................................................23
Gastric Acid Regurgitation .......................................................................................................25
7.3.3.2
HRQOL (EQ-5D-5L).................................................................................................................25
EQ-5D-5L Index Value.............................................................................................................25
EQ VAS Score.........................................................................................................................26
7.3.3.3
PROPORTION OF DAYS WITHOUT RESCUE MEDICATIONS...............................................................26
7.3.3.4
BARRETT'S MUCOSA .................................................................................................................26
7.3.4
STATISTICAL/ANALYTICAL ISSUES...............................................................................................27
7.3.4.1
ADJUSTMENTS FOR COVARIATES ................................................................................................27
7.3.4.2
HANDLING OF DROPOUTS OR MISSING DATA................................................................................27
7.3.4.3
INTERIM ANALYSES AND DATA MONITORING ................................................................................27
7.3.4.4
MULTICENTER STUDIES..............................................................................................................27
7.3.4.5
MULTIPLE COMPARISON/MULTIPLICITY ........................................................................................27
7.3.4.6
USE OF AN "EFFICACY SUBSET" OF SUBJECTS ............................................................................28


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7.3.4.7
ACTIVE-CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE OR NON-INFERIORITY......................28
7.3.4.8
SUBGROUP ANALYSIS................................................................................................................28
7.4
SAFETY ANALYSIS.....................................................................................................................29
7.4.1
TREATMENT-EMERGENT ADVERSE EVENTS..................................................................................29
7.4.1.1
OVERVIEW OF TREATMENT-EMERGENT ADVERSE EVENTS.............................................................29
7.4.1.2
DISPLAYS OF TREATMENT-EMERGENT ADVERSE EVENTS..............................................................30
7.4.2
PRETREATMENT EVENTS............................................................................................................31
7.4.2.1
DISPLAYS OF PRETREATMENT EVENTS ........................................................................................31
7.4.3
LABORATORY AND OTHER SAFETY DATA.....................................................................................32
7.4.3.1
LABORATORY TEST RESULTS ..................................................................................................... 32
Hematology and Serum Chemistry...........................................................................................32
Urinalysis
..............................................................................................................................33
Serum Gastrin, Pepsinogen I/II ................................................................................................33
7.4.4
VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY......................34
Vital Signs ..............................................................................................................................34
12-lead ECG............................................................................................................................34
7.4.5
SUBGROUP ANALYSIS FOR CHINA ...............................................................................................35
7.4.6
SUBGROUP ANALYSIS FOR KOREA..............................................................................................35
7.4.7
SUBGROUP ANALYSIS FOR TAIWAN.............................................................................................35
7.4.8
SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT................................................................... 36
7.4.9
CHANGES IN THE STATISTICAL ANALYSIS PLAN............................................................................37
8.0
REFERENCES........................................................................................................................47
9.0
APPENDIX..............................................................................................................................48
9.1
CRITERIA FOR MARKEDLY ABNORMAL VALUES ............................................................................48
9.1.1
HEMATOLOGY, SERUM CHEMISTRY, URINALYSIS, VITAL SIGNS, AND 12-LEAD ECG (EXCEPT UPPER 
MAV CRITERIA OF QTCF INTERVAL) ...........................................................................................48
9.1.2
12-LEAD ECG (UPPER MAV CRITERIA OF QTCF INTERVAL)..........................................................49
9.2
CRITERIA FOR ELEVATED LIVER ENZYME.....................................................................................50


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BMI
body mass index
BUN
blood urea nitrogen
CMH
Cochran-Mantel-Haenszel
CPK
creatine phosphokinase
ECG
electrocardiogram
EQ-5D-5L
the 5-level version of the EuroQOL five dimensions questionnaire
FAS
full analysis set
GGT
-glutamyl transferase
H. pylori
Helicobacter pylori
HRQoL
Health-Related Quality of Life
LA classification
Los Angeles classification
LDH
lactate dehydrogenase
LLN
lower limit of normal
LS means
least square means
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
PPS
per protocol set
QOL
quality-of-life
QTcF
QT interval corrected by Fridericia's method
SAP
statistical analysis plan
Tbili
total bilirubin
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WHO Drug
World Health Organization Drug Dictionary
WMWodds
Wilcoxon-Mann-Whitney odds


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4.0
OBJECTIVES
4.1.
PRIMARY OBJECTIVES
The primary objective is to demonstrate the non-inferior efficacy of TAK-438 versus Lansoprazole in the treatment 
of subjects with erosive esophagitis classified as LA classification grades A to D during the 8-week treatment.
4.2.
SECONDARY OBJECTIVES
To compare the efficacy of TAK-438 versus Lansoprazole in the healing of subjects with erosive esophagitis 
classified as LA classification grades A to D during the 2-week treatment.
To compare the efficacy of TAK-438 versus Lansoprazole in the healing of subjects with erosive esophagitis 
classified as LA classification grades A to D during the 4-week treatment.
To compare the safety of TAK-438 versus Lansoprazole in subjects with erosive esophagitis classified as LA 
classification grades A to D.
4.3.
ADDITIONAL OBJECTIVES
4.4.
STUDY DESIGN
A phase III, multi-center, double-blind, non-inferiority study of TAK-438 20 mg versus Lansoprazole 30 mg given 
once daily for up to 8 weeks in subjects with erosive esophagitis, with the LA classification grade A/B or C/D 
serving as the stratification factors at randomization, where all subjects with endoscopic healing of erosive 
esophagitis 2, 4, or 8 weeks after the start of the study will be construed as “completed cases” who then may be 
invited to participate with further informed consent in the planned, ensuing, maintenance trial (TAK-438_305).
Upon randomization subjects will be assigned (at a 1:1 ratio) to receive either oral TAK-438 20 mg or Lansoprazole 
30 mg all study medication will once daily after breakfast except on Day 1 when it will be administered at the study 
site before the subject’s visit is concluded. 
This study will be conducted at a total of around 50 sites across Asia with an estimated total of 240 subjects 
randomized to each treatment group totaling 480 for the study.
The study will consist of a Screening Phase of up to 28 days, including an Observation Phase of 3-7 days prior to the 
randomization visit (Day 1), during which a baseline observation of EE symptoms will be completed, and then a 
Treatment Phase of up to 8 weeks. There will be 6 subject visits scheduled: the start of the Observation Phase (Visit 
1), the start of the Treatment Phase (Visit 2), after 2 weeks of treatment (Visit 3), after 4 weeks of treatment (Visit 
4), after 6 weeks of treatment (Visit 5), after 8 weeks of treatment (Visit 6), and a phone call during the Follow-up 
phase (only for those not participating in TAK-438_305 study).
Dosing will commence on Day 1 after randomization at Visit 2 (after completion of all required assessments 
scheduled on the Day 1).
CCI


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Figure 4.a Schematic of Study Design


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5.0
ANALYSIS ENDPOINTS
Primary Endpoint
The primary efficacy endpoint of this study is the rate of endoscopic healing* of erosive esophagitis during the 8-
week treatment.
*Endoscopic healing: defined as subjects endoscopically diagnosed as LA classification grade O during the 
treatment phase
Secondary Endpoints
The secondary efficacy endpoints of this study are
∀
the rate of endoscopic healing of erosive esophagitis during the 2-week treatment,
∀
the rate of endoscopic healing of erosive esophagitis during the 4-week treatment.
The safety endpoints of this study include adverse events, laboratory test values, ECG, vital signs, serum gastrin 
values, and pepsinogen I/II values.
Additional Endpoints
CCI


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6.0
DETERMINATION OF SAMPLE SIZE
Assuming that the true Week 8 healing rate is 94.7% for both TAK-438 and Lansoprazole, and assuming that the 
dropout rate is up to 20%, a sample size of 160 subjects per group will provide 90% power to establish non-
inferiority using a 2-sided 95% CI with a -10% non-inferiority margin. A sample size of 240 subjects per group is 
planned in order to provide more subjects with healed EE to the subsequent maintenance study TAK-438_305 and to 
provide adequate subjects for regulatory requirements in various countries. 
The assumption of the 94.7% true healing rate is based on Phase 2 studies TAK-438/CCT-001 and TAK-
390MR/CCT-001. 
In a randomized, double-blind study in US (M87-092), the difference in Week 8 EE healing rate between 
lansoprazole 30 mg and placebo groups was 42.9% with a lower limit of 27.8% for the 2-sided 95% confidence 
interval. Based on this study, the non-inferiority margin is specified as -10%. 


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1 GENERAL CONSIDERATIONS
7.1.1 DEFINITIONS
The following definitions and calculation formulas will be used.
- TEAE: An adverse event 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.
- Descriptive statistics: number of subjects, mean, standard deviation, maximum, minimum, and quartiles
- 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, e.g., the 
day prior to Study Day 1 is Day -1 and the day after Study Day 1 is Day 2.
- Follow-up Day: The day after the last dose of the study medication will be defined as Follow-up Day 1. Other 
follow-up days are defined relative to Follow-up Day 1.
- Duration of exposure to study medication (days): date of last dose of study medication - date of first dose of
study medication + 1
- Study drug compliance (%): (number of days the subject answered "Yes" in the subject diary to the question 
"Study medication taken?") / duration of exposure to study medication * 100 (rounded to 1 decimal place)
- Age (years): The following only applies to subjects from countries other than Korea. If the date informed 
consent obtained or the date of birth is missing, then age will be missing. If the month and the day of the date 
informed consent obtained is before the month and the day of the date of birth, then age will be calculated as 
follows: the year of the date informed consent obtained - the year of the date of birth - 1. For all others, age will 
be calculated as follows:  the year of the date informed consent obtained - the year of the date of birth.
- BMI (kg/m2): weight (kg) / (height (m))2 (rounded to 1 decimal place)
- Pepsinogen I/II Ratio: Pepsinogen I (μg/L) / Pepsinogen II (μg/L) (rounded to 1 decimal place)
- QTcF interval (msec): QT interval (msec) / (RR interval (sec))0.33 (rounded to the nearest whole number)
- Confidence interval for one sample proportion: Exact (Clopper-Pearson) confidence interval will be used.
- Confidence interval for two sample proportion difference: Wald confidence interval will be used.
- Significant TEAE: Any TEAE (not including serious TEAEs) that led to an intervention, including withdrawal 
of drug treatment, dose increase, dose reduction or significant additional concomitant therapy.
7.1.2 ANALYSIS SETS
Analysis of efficacy variables will be conducted in the full analysis set defined as all randomized subjects who 
receive at least 1 dose of study medication and have at least 1 post-baseline endoscopy, and will be based on the 
randomized treatment.
The primary efficacy endpoint and the secondary efficacy endpoints will also be analyzed in the per protocol set
defined as all FAS subjects who did not have any of the major protocol deviations listed below. Analyses will be 
based on the randomized treatment.
- Subjects who did not meet inclusion criteria #3


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- Subjects who met exclusion criteria #8, #11, #12, #13, or #14
- Subjects with study medication compliance of less than 70%
- Subjects who have been unblinded prior to database lock
- Subjects who have violated the rules specified in section 7.3 of the protocol
Analysis of safety variables will be conducted in the safety analysis set defined as all subjects who take at least 1 
dose of study medication and will be based on the treatment received.
7.1.3 HANDLING OF RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS
7.1.3.1
RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 2-WEEK
TREATMENT
A subject who is diagnosed as LA classification grade O from endoscopy tests performed between Study Day 2 and 
Study Day 21 will be considered as a healed subject. Subjects who do not have any endoscopy data during this 
period will be treated as missing. Subjects who do not meet this requirement will be considered as 'not healed'. 
Healing rate will be calculated from the healed and not healed subjects, however, any subjects diagnosed as LA 
classification grade O from endoscopy tests performed before the study medication administration will be excluded 
from the analysis. 
7.1.3.2
RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 4-WEEK
TREATMENT
A subject who is diagnosed as LA classification grade O from endoscopy tests performed between Study Day 2 and 
Study Day 42 will be considered as a healed subject. Subjects who do not have any endoscopy data during this 
period will be treated as missing. Subjects who do not meet this requirement will be considered as 'not healed'. 
Healing rate will be calculated from the healed and not healed subjects, however, any subjects diagnosed as LA
classification grade O from endoscopy tests performed before the study medication administration will be excluded 
from the analysis.
7.1.3.3
RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 8-WEEK
TREATMENT
A subject who is diagnosed as LA classification grade O from any of the endoscopy tests performed after Study Day 
2 will be considered as a healed subject. Subjects who do not meet this requirement will be considered as 'not 
healed'. Healing rate will be calculated from the healed and not healed subjects, however, any subjects diagnosed as 
LA classification grade O from endoscopy tests performed before the study medication administration will be 
excluded from the analysis.
7.1.4 HANDLING OF DATA WHEN CALCULATING PROPORTION OF DAYS WITHOUT 
SUBJECTIVE SYMPTOMS ACCORDING TO SUBJECT DIARY
Each subjective symptom of erosive esophagitis as recorded in subject diaries (i.e., heartburn, gastric acid 
regurgitation) will be handled as below.
For each subject, the proportion of days without subjective symptoms will be calculated as follows at each visit. If 
the denominator of the following formula is missing, then the calculated result should also be missing.


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Proportion of days without subjective symptoms (%) = (number of days where "None" is recorded as the 
severity of symptom for the visit) / (number of days the severity of symptom is recorded) * 100 (rounded to 1 
decimal place)
(Note: Severity recorded as "Not Completed" will be treated as missing.)
The following visits will be used.
Visit
Time Interval (days)
Study Day
Follow-up Day
Baseline
Day -6 – Day 1
Week 1
Day 2 – Day 8
up to and including Follow-up Day 1
Week 2
Day 9 – Day 15
up to and including Follow-up Day 1
Week 4
Day 16 – Day 29
up to and including Follow-up Day 1
Week 8
Day 30 – Day 57
up to and including Follow-up Day 1
Treatment Phase
on and after Day 2
up to and including Follow-up Day 1
7.1.5 HANDLING OF DATA WHEN CALCULATING MEAN SEVERITY ACCORDING TO SUBJECT 
DIARY
Each subjective symptom of erosive esophagitis as recorded in subject diaries (i.e., heartburn, gastric acid 
regurgitation) will be handled as below.
Severity will be scored as follows. None: 0, Mild: 1, Moderate: 2, Severe: 3.
For each subject, the mean severity will be calculated as follows at each visit. If the denominator is missing, then the 
calculated result should also be missing.
Mean severity = (total score of the severity recorded for the visit) / (number of days the severity of symptom is 
recorded) (rounded to 2 decimal places)
(Note: Severity recorded as "Not Completed" will be treated as missing.)
The following visits will be used.
Visit
Time Interval (days)
Study Day
Follow-up Day
Baseline
Day -6 – Day 1
Week 1
Day 2 – Day 8
up to and including Follow-up Day 1
Week 2
Day 9 – Day 15
up to and including Follow-up Day 1
Week 4
Day 16 – Day 29
up to and including Follow-up Day 1
Week 8
Day 30 – Day 57
up to and including Follow-up Day 1
Treatment Phase
on and after Day 2
up to and including Follow-up Day 1


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7.1.6 HANDLING OF PARTIALLY SUSTAINED RESOLUTION ACCORDING TO SUBJECT DIARY
Analysis will be performed on data obtained from Day 2 to the day after the last dose of the study medication 
(treatment phase). If there are no records concerning subjective symptoms in the subject diary during the treatment 
phase, then the subject will be excluded from the analysis. Severity recorded as "Not Completed" will be treated as 
missing.
An event will have occurred if "None" is recorded as the severity of the subjective symptom for seven days in a row 
or more. The event date will be defined as the first day of the 7-day period of the first event confirmed. A subject 
will be censored if there are records concerning subjective symptoms in the subject diary during the treatment phase 
but an event has not occurred. The censoring date will be defined as below.
If the entries concerning subjective symptoms in the subject diary do not continue for seven days in a row, then 
Day 2 will be the censoring date.
If there are records concerning subjective symptoms in the subject diary for at least seven days in a row, then 
six days before the last day of the last 7-day period will be the censoring date.
7.1.7 HANDLING OF SUSTAINED RESOLUTION ACCORDING TO SUBJECT DIARY
Analysis will be performed on data obtained from Day 2 to the day after the last dose of the study medication 
(treatment phase). If there are no records concerning subjective symptoms in the subject diary during the treatment 
phase, then the subject will be excluded from the analysis. Severity recorded as "Not Completed" will be treated as 
missing.
An event will have occurred if "None" is recorded as the severity of the subjective symptom for seven days in a row 
or more until the day after the last dose of study medication. The event date will be defined as the first day of the 7-
day period when the event is confirmed. A subject will be censored if there are records concerning subjective 
symptoms in the subject diary during the treatment phase but an event has not occurred. The censoring date will be 
defined as below.
If there are no records in the subject diary concerning subjective symptoms on Day 8 or after, then Day 2 will 
be the censoring date.
If there is an entry in the subject diary concerning subjective symptoms on Day 8 or after, then six days before 
the last entry will be the censoring date.


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7.1.8 HRQOL (EQ-5D-5L)
All evaluable data (i.e., non-missing) obtained in the corresponding time interval will be used in evaluating the EQ-
5D-5L index value and EQ VAS score. If more than one observation lies within the same visit window, the 
observation with the closest Study Day to the scheduled Study Day will be used. If there are two observations 
equidistant to the scheduled Study Day, the later observation will be used.
The EQ-5D-5L index values will be calculated from the EQ-5D-5L descriptive system scores based on the EQ-5D-
5L Crosswalk value sets. If any of the questions are not answered, the EQ-5D-5L index value of the day will be 
treated as missing.
Visit
Scheduled Study Day
(days) 
Time Interval (days) 
Study Day
Follow-up Day
Baseline 
Study Day:
1
-28 – 1 
Week 2
Study Day:
15
2 – 21
up to and including Follow-up Day 14
Week 4
Study Day:
29
22 – 42
up to and including Follow-up Day 14
Week 8
Study Day:
57
43 – 71
up to and including Follow-up Day 14
7.1.9 HANDLING OF DATA WHEN CALCULATING PROPORTION OF DAYS WITHOUT RESCUE 
MEDICATION
For each subject, the proportion of days without rescue medication will be calculated as follows at each visit. If the 
denominator is missing, then the calculated result should also be missing.
Proportion of days without rescue medication (%) = (number of days in the visit where the subject answered 
"No" in the subject diary to the question "Any antacid taken?") / (number of days in the visit where the 
question "Any antacid taken?" was answered in the subject diary) * 100 (rounded to 1 decimal place)
(Note: Records entered as "Not Completed" will be treated as missing.)
The following visits will be used.
Visit
Time Interval (days)
Study Day
Follow-up Day
Week 2
Day 2 – Day 15
up to and including Follow-up Day 1
Week 4
Day 16 – Day 29
up to and including Follow-up Day 1
Week 8
Day 30 – Day 57
up to and including Follow-up Day 1
One Month to the 
Day of Last Dose
27 days before the last dose –
day of last dose
Treatment Phase
on Day 2 or after
up to and including Follow-up Day 1


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7.1.10 HANDLING OF OTHER ENDPOINTS
For each visit, all evaluable observation (i.e., non-missing) obtained in the corresponding time interval will be used. 
If more than one observation lies within the same visit window, the observation with the closest Study Day to the 
scheduled Study Day will be used. If there are two observations equidistant to the scheduled Study Day, the later 
observation will be used. If there are two observations with the same Study Day, the earlier observation will be used.
Weight, BMI, 13-C or 14C breath test (H. pylori infection status), Endoscopy (esophageal hiatal hernia)
Visit
Scheduled Study Day
(days) 
Time Interval (days) 
Study Day
Follow-up Day
Baseline 
Study Day:
1
-28 – 1 
Endoscopy (Barrett's mucosa), Clinical laboratory tests (other than ALT, AST, total bilirubin, and direct 
bilirubin), Gastrin, Pepsinogen I/II, Vital signs, 12-lead ECG
Visit
Scheduled Study Day
(days) 
Time Interval (days) 
Study Day
Follow-up Day
Baseline 
Study Day:
1
-28 – 1 
Week 2
Study Day:
15
2 – 21
up to and including 
Follow-up Day 14
Week 4
Study Day:
29
22 – 42
up to and including 
Follow-up Day 14
Week 8
Study Day:
57
43 – 71
up to and including 
Follow-up Day 14
Clinical laboratory tests (ALT, AST, total bilirubin, and direct bilirubin)
Visit
Scheduled Study Day
(days) 
Time Interval (days) 
Study Day
Follow-up Day
Baseline 
Study Day:
1
-28 – 1 
Week 2
Study Day:
15
2 – 21
up to and including 
Follow-up Day 14
Week 4
Study Day:
29
22 – 35
up to and including 
Follow-up Day 14
Week 6
Study Day:
43
36 – 49
up to and including 
Follow-up Day 14
Week 8
Study Day:
57
50 – 71
up to and including 
Follow-up Day 14


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7.2 STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS
7.2.1 DISPOSITION OF SUBJECTS
7.2.1.1
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.
7.2.1.2
SCREEN FAILURES
Analysis Set:
All Subjects Who Were Not Randomized
Analysis Variables:
Age (years) 
[Min<= - <65, 65<= - <75, 75<= - <=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.
7.2.1.3
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, 
Major Protocol Deviation, 
Lost to Follow-Up, 
Voluntary Withdrawal, 
Study Termination, 
Did Not Meet Entrance Criteria, 
Other]
Analytical Methods:
(1) Eligibility for Randomization
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.


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7.2.1.4
NUMBER OF SUBJECTS RANDOMIZED BY COUNTRY, SITE, AND TREATMENT GROUP
Analysis Set:
Randomized Set
Analysis Variables:
Randomization Status
[Yes]
Stratum:
Country
[China, Malaysia, South Korea, Taiwan]
Site
[Site numbers will be used as categories]
Analytical Methods:
(1) Number of Subjects Randomized by Country, Site, and Treatment Group
Frequency distribution will be provided for each stratum by treatment group and overall.
7.2.1.5
DISPOSITION OF SUBJECTS
Analysis Set:
Randomized Set
Analysis Variables:
Study Drug Administration Status
[No]
Reason for Not Being Treated
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to Follow-Up, 
Voluntary Withdrawal, Study Termination, 
Pregnancy, Lack of Efficacy, Other]
Study Drug Completion Status
[Completed Study Drug, 
Prematurely Discontinued Study Drug]
Reason for Discontinuation of Study Drug
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to Follow-Up, 
Voluntary Withdrawal, Study Termination, 
Pregnancy, Lack of Efficacy, Other]
Analytical Methods:
(1) Disposition of Subjects
Frequency distributions will be provided for each treatment group 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.
7.2.1.6
PROTOCOL DEVIATIONS AND ANALYSIS SETS
Protocol Deviations
Analysis Set:
Randomized Set
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 treatment group and overall for each deviation 
category. A subject who has several deviations will be counted once in each appropriate 


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category. A subject who has several deviations that can be classified into the same 
category will be counted only once.
Analysis Sets
Analysis Set:
Randomized Set
Analysis Variables:
Analysis Sets
Full Analysis Set
Per Protocol Set
Safety Analysis Set
[Included]
[Included]
[Included]
Analytical Methods:
(1) Analysis Sets
Frequency distributions will be provided by treatment group and overall.
7.2.2 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
7.2.2.1
SUMMARY OF DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Analysis Set:
Randomized Set
Analysis Variables:
Country
[China, Malaysia, South Korea, Taiwan]
Age (years)
[Min<= - <65, 65<= - <75, 75<= - <=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<= - <18.5, 18.5<= - <25.0, 
25.0<= - <=Max]
Smoking Classification
[The Subject Has Never Smoked, 
The Subject Is a Current Smoker, 
The Subject Is an Ex-smoker]
Consumption of Alcohol
[Drink Everyday, 
Drink a Couple of Days Per Week,
Drink a Couple of Days Per Month, 
Never Drink]
Consumption of Caffeine
[Yes, No]


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History of H.pylori Eradication Therapy [Yes (End of Treatment: Within the Past 1 Year), 
Yes (End of Treatment: More than 1 Year), No]
H. pylori Infection Status
[Positive, Negative]
LA Classification (Baseline)
[Grade O, Grade A, Grade B, Grade C, Grade D]
[Grade O, Grade A/B, Grade C/D]
Barrett's Mucosa (Baseline)
[Present (3 cm or Greater), 
Present (Less than 3 cm), Absent, Unknown]
Esophageal Hiatal Hernia (Baseline)
[Present (2 cm or Greater), 
Present (Less than 2 cm), Absent, Unknown]
Diary for Gastrointestinal Symptoms
Mean Severity of Heartburn 
Symptoms (Baseline)
[0.00, 0.00< - <=1.00, 1.00< - <=2.00, 
2.00< - <=3.00]
Mean Severity of Gastric Acid 
Regurgitation (Baseline)
[0.00, 0.00< - <=1.00, 1.00< - <=2.00, 
2.00< - <=3.00]
HRQoL (EQ-5D-5L)
EQ-5D-5L Index Value (Baseline)
EQ VAS Score (Baseline)
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 treatment group and overall.
7.2.2.2
MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS
Analysis Set:
Safety Analysis Set
Analysis Variables:
Medical History
Concurrent Medical Conditions
Analytical Methods:
(1) Medical History by System Organ Class and Preferred Term
(2) Concurrent Medical Conditions by System Organ Class and Preferred Term
Frequency distributions will be provided for each treatment group. MedDRA dictionary 
will be used for coding. Summaries will be provided using SOC and PT, where SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency. 
A subject with multiple occurrences of medical history or concurrent medical condition
within a SOC will be counted only once in that SOC. A subject with multiple 
occurrences of medical history or concurrent medical condition within a PT will be 
counted only once in that PT.


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7.2.2.3
MEDICATION HISTORY AND CONCOMITANT MEDICATIONS
Analysis Set:
Safety Analysis Set
Analysis Variables:
Medication History
Concomitant Medications
Analytical Methods:
(1) Medication History by Preferred Medication Name
(2) Concomitant Medications That Started Prior to and Were Ongoing at Baseline as 
well as Those That Started After Baseline by Preferred Medication Name
Frequency distributions will be provided for each treatment group. WHO Drug 
dictionary will be used for coding. Summaries will be provided using preferred 
medication names and sorted in decreasing frequency based on the number of reports. 
A subject who has been administered several medications with the same preferred 
medication name will be counted only once for that preferred medication name.
7.2.3 TREATMENT COMPLIANCE
7.2.3.1
STUDY DRUG EXPOSURE AND COMPLIANCE
Analysis Set:
Safety Analysis Set
Analysis Variables:
Duration of Exposure to Study Drug (days) [1<= - <=14, 15<= - <=28, 29<= - <=56, 
57<= - <=Max]
Study Drug Compliance (%)
[Min<= - <50.0, 50.0<= - <70.0, 
70.0<= - <90.0, 90.0<= - <=Max]
Analytical Methods:
(1) Study Drug Exposure and Compliance
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided by treatment group and overall.


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7.3 EFFICACY ANALYSIS
The full analysis set will be the main analysis set used. The per protocol set will be used for analyses performed 
secondarily on the primary efficacy endpoint and secondary efficacy endpoints in order to examine the robustness of 
the results.
7.3.1 PRIMARY EFFICACY ENDPOINT
7.3.1.1
PRIMARY ANALYSIS
Analysis Set:
Full Analysis Set
Analysis Variable:
Rate of Endoscopic Healing of Erosive Esophagitis During the 8-week Treatment (%)
Analytical Methods:
(1) Rate of Endoscopic Healing of Erosive Esophagitis During the 8-week Treatment
Frequency distributions will be provided by treatment group along with rates and the 
two-sided 95% confidence intervals.
The differences in the rates between the TAK-438 group and the Lansoprazole group (the
TAK-438 group – the Lansoprazole group) and the two-sided 95% confidence intervals 
using the Wald method will be provided. If the lower bound of this 95% confidence 
intervals is ≥-10%, non-inferiority for TAK-438 relative to Lansoprazole will be 
declared.
7.3.1.2
SECONDARY ANALYSIS
Analysis Set:
Per Protocol Set
Analysis Variable:
Rate of Endoscopic Healing of Erosive Esophagitis During the 8-week Treatment (%)
Analytical Methods:
(1) Sensitivity Analysis
To check the robustness of the results, the same analyses as those in section 7.3.1.1 will 
be performed using the per protocol set.
7.3.2 SECONDARY EFFICACY ENDPOINTS
7.3.2.1
RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 2-WEEK 
TREATMENT
Analysis Set:
Full Analysis Set
Analysis Variable:
Rate of Endoscopic Healing of Erosive Esophagitis During the 2-week Treatment (%)
Analytical Methods:
(1) Rate of Endoscopic Healing of Erosive Esophagitis During the 2-week Treatment
Frequency distributions will be provided by treatment group along with rates and the 
two-sided 95% confidence intervals. Also, the differences in the rates between the TAK-
438 group and the Lansoprazole group (the TAK-438 group – the Lansoprazole group) 
and the two-sided 95% confidence intervals will be provided. Details concerning 
interpretation are described in section 7.3.4.5.


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7.3.2.2
RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 4-WEEK 
TREATMENT
Analysis Set:
Full Analysis Set
Analysis Variable:
Rate of Endoscopic Healing of Erosive Esophagitis During the 4-week Treatment (%)
Analytical Methods:
(1) Rate of Endoscopic Healing of Erosive Esophagitis During the 4-week Treatment
Frequency distributions will be provided by treatment group along with rates and the 
two-sided 95% confidence intervals. Also, the differences in the rates between the TAK-
438 group and the Lansoprazole group (the TAK-438 group – the Lansoprazole group) 
and the two-sided 95% confidence intervals will be provided. Details concerning 
interpretation are described in section 7.3.4.5.
7.3.2.3
SENSITIVITY ANALYSIS
Analysis Set:
Per Protocol Set
Analysis Variable:
Rate of Endoscopic Healing of Erosive Esophagitis During the 2-week Treatment (%)
Rate of Endoscopic Healing of Erosive Esophagitis During the 4-week Treatment (%)
Analytical Methods:
(1) Sensitivity Analysis
To check the robustness of the results, the same analyses as section 7.3.2.1 and 7.3.2.2
will be performed using the per protocol set.
7.3.3 ADDITIONAL EFFICACY ENDPOINTS
7.3.3.1
 
 
CCI
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CCI


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7.3.3.2
CCI
CCI
CCI


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7.3.3.3
PROPORTION OF DAYS WITHOUT RESCUE MEDICATIONS
Analysis Set:
Full Analysis Set
Analysis Variables:
Proportion of Days Without Rescue Medications (%)
Visit:
Week 2, Week 4, Week 8, One Month to the Day of Last Dose, Treatment Phase
Analytical Methods:
(1) Proportion of Days Without Rescue Medications
Descriptive statistics will be provided for each visit by treatment group. The difference in 
the medians between the TAK-438 group and the Lansoprazole group (the TAK-438
group – the Lansoprazole group) and the two-sided 95% confidence intervals will be 
provided for each visit using the Hodges-Lehmann estimator. Wilcoxon rank-sum tests 
will be used to test for treatment differences at each visit. WMWodds of the TAK-438
group to the Lansoprazole group and the two-sided 95% confidence intervals will also be 
provided for each visit based on Wilcoxon-Mann-Whitney test statistics.
7.3.3.4
BARRETT'S MUCOSA
Analysis Set:
Full Analysis Set
Analysis Variables:
Barrett's Mucosa (Change)
[Increased, Unchanged, Reduced, Disappeared, Unknown]
Subgroups:
Barrett's Mucosa (Baseline)
[Present (3 cm or Greater), Present (Less than 3 cm), Absent, 
Unknown]
Visit:
Week 2, Week 4, Week 8
Analytical Methods:
(1) Frequency distribution of Barrett's Mucosa (Change) by Baseline Barrett's Mucosa
Frequency distribution will be provided for each subgroup and visit by treatment group.
CCI


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7.3.4 STATISTICAL/ANALYTICAL ISSUES
7.3.4.1
ADJUSTMENTS FOR COVARIATES
Analysis Set:
Full Analysis Set
Analysis Variable:
Rate of Endoscopic Healing of Erosive Esophagitis During the 8-week Treatment (%)
Rate of Endoscopic Healing of Erosive Esophagitis During the 2-week Treatment (%)
Rate of Endoscopic Healing of Erosive Esophagitis During the 4-week Treatment (%)
Stratified Variable:
LA Classification (Baseline)
[Grade A/B, Grade C/D]
Analytical Methods:
(1) CMH Test for the Rate of Endoscopic Healing of Erosive Esophagitis During the 8-
week Treatment (%)
(2) CMH Test for the Rate of Endoscopic Healing of Erosive Esophagitis During the 2-
week Treatment (%)
(3) CMH Test for the Rate of Endoscopic Healing of Erosive Esophagitis During the 4-
week Treatment (%)
A CMH test with baseline LA Classification as a stratification factor will be used to 
compare the above analysis variable between the TAK-438 group and the Lansoprazole
group for treatment differences. Mantel-Haenszel estimate of risk difference between the
TAK-438 group and the Lansoprazole group (the TAK-438 group – the Lansoprazole
group) and the two-sided 95% confidence interval using the Wald method will also be 
provided.
7.3.4.2
HANDLING OF DROPOUTS OR MISSING DATA
For the primary endpoint "rate of endoscopic healing of erosive esophagitis during the 8-week treatment" and the 
secondary efficacy endpoints "rate of endoscopic healing of erosive esophagitis during the 2-week treatment" and 
"rate of endoscopic healing of erosive esophagitis during the 4-week treatment", missing data will be handled 
according to section 7.1.3.
Values below the lower limit of quantification will be treated as zero when calculating the descriptive statistics. 
Values above the upper limit of quantification will be treated as the upper limit values when calculating the 
descriptive statistics.
7.3.4.3
INTERIM ANALYSES AND DATA MONITORING
No interim analysis is planned in this study.
7.3.4.4
MULTICENTER STUDIES
Treatment-by-center interaction will not be explored in this study.
7.3.4.5
MULTIPLE COMPARISON/MULTIPLICITY
Adjustment for multiplicity will be performed for the primary efficacy endpoint "The Rate of Endoscopic Healing of 
Erosive Esophagitis during the 8-week Treatment" and the secondary efficacy endpoints "The Rate of Endoscopic 
Healing of Erosive Esophagitis during the 2-week Treatment" and "The Rate of Endoscopic Healing of Erosive 
Esophagitis During the 4-week Treatment" in the following fashion. The following procedure is based on the closed 
testing principle and the analysis will be conducted using the full analysis set.
-
The primary endpoint "The Rate of Endoscopic Healing of Erosive Esophagitis during the 8-week Treatment" 
will be tested for non-inferiority between the TAK-438 group and the Lansoprazole group. If the lower bound 


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of the 95% confidence interval of the treatment difference (the TAK-438 group – the Lansoprazole group) is 
≥-10%, non-inferiority for TAK-438 relative to Lansoprazole will be declared.
-
If the previous test is successful, the secondary endpoint "The Rate of Endoscopic Healing of Erosive 
Esophagitis during the 2-week Treatment" will be tested for superiority between the TAK-438 group and the 
Lansoprazole group. The lower bound of the 95% confidence interval of the treatment difference (the TAK-438 
group – the Lansoprazole group) will be compared to 0%.
-
If the previous test is successful, the primary endpoint "The Rate of Endoscopic Healing of Erosive Esophagitis 
during the 8-week Treatment" will be tested for superiority between the TAK-438 group and the Lansoprazole 
group.
-
If the previous test is successful, the secondary endpoint "The Rate of Endoscopic Healing of Erosive 
Esophagitis during the 4-week Treatment" will be tested for superiority between the TAK-438 group and the 
Lansoprazole group. 
7.3.4.6
USE OF AN "EFFICACY SUBSET" OF SUBJECTS
In addition to analyses on the primary and secondary efficacy endpoints using the full analysis set, sensitivity 
analyses will also be performed using the per protocol set to examine the robustness of the results.
7.3.4.7
ACTIVE-CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE OR NON-INFERIORITY
For the primary efficacy endpoint, non-inferiority for TAK-438 relative to Lansoprazole will be confirmed in the 
full analysis set using a non-inferiority margin of 10% as described in section 7.3.1.1 "Primary Analysis".
7.3.4.8
SUBGROUP ANALYSIS
Analysis Set:
Full Analysis Set
Analysis Variable:
Rate of Endoscopic Healing of Erosive Esophagitis During the 8-week Treatment (%)
Rate of Endoscopic Healing of Erosive Esophagitis During the 2-week Treatment (%)
Rate of Endoscopic Healing of Erosive Esophagitis During the 4-week Treatment (%)
Subgroups:
Age (years)
[Min<= - <65, 65<= - <75, 75<= - <=Max]
Gender
[Male, Female]
H. pylori Infection Status
[Positive, Negative]
LA Classification (Baseline)
[Grade A/B, Grade C/D]
Barrett's Mucosa (Baseline)
[Present, Absent]
Version of Informed Consent Form 
[Protocol Amendment No.3 or Later]
Analytical Methods:
(1) Subgroup Analysis for the Rate of Endoscopic Healing of Erosive Esophagitis 
During the 8-week Treatment (%)
(2) Subgroup Analysis for the Rate of Endoscopic Healing of Erosive Esophagitis 
During the 2-week Treatment (%)
(3) Subgroup Analysis for the Rate of Endoscopic Healing of Erosive Esophagitis 
During the 4-week Treatment (%)
The same analyses as those in section 7.3.2.2 will be performed for each of the above
subgroups.


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7.4 SAFETY ANALYSIS
7.4.1 TREATMENT-EMERGENT ADVERSE EVENTS
7.4.1.1
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 treatment group.
(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) Treatment-Emergent Adverse Events Corresponding to Liver Function Test 
Abnormalities (number of events, number and percentage of subjects)
11) Significant Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)
TEAEs will be counted according to the rules below.
Number of subjects
・
Summaries for 2), 5) and 7)
A subject with occurrences of TEAE in both categories (i.e., Related and Not Related) 
will be counted once in the Related category.
・
Summary for 3)
A subject with multiple occurrences of TEAE will be counted once for the TEAE with 
the maximum intensity.


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・
Summaries other than 2), 3), 5) and 7)
A subject with multiple occurrences of TEAE will be counted only once.
Number of events
For each summary, the total number of events will be calculated.
7.4.1.2
DISPLAYS OF TREATMENT-EMERGENT ADVERSE EVENTS
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Intensity
[Mild, Moderate, Severe]
Time of Onset (day)
[1<= - <=14, 15<= - <=28, 29<= - <=56, 57<= - <=Max]
Analytical Methods: The following summaries will be provided using frequency distribution for each treatment 
group.
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) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Over Time
(12) Most Frequent Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(13) Treatment-Emergent Adverse Events Corresponding to Liver Function Test 
Abnormalities by System Organ Class and Preferred Term


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(14) Drug-Related Treatment-Emergent Adverse Events Corresponding to Liver 
Function Test Abnormalities by System Organ Class and Preferred Term
(15) Significant Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(16) Drug-Related Significant Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term
(17) Most Frequent Non Serious 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), (6) and (11)
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.
・
Summary table for (11)
A subject with a TEAE that occurs in more than one interval is counted in all the 
intervals that the TEAE occurs. For each time interval, a subject with multiple 
occurrences of TEAE within a SOC or a PT will be counted only once in that SOC or PT.
When calculating percentages for each time interval, the number of subjects at risk (i.e., 
subjects who either have an exposure or have an occurrence of TEAE, during or after the 
corresponding time interval) will be used as the denominator. The number of subjects 
whose onset of any one of the TEAEs is within the time interval will be used as the 
numerator.
・
Summary table for (12)
Most frequent TEAEs refer to PTs whose percentages are at least 2% in any one of the 
treatment groups.
・
Summary table for (17)
Most frequent non-serious TEAEs refer to PTs that are not serious whose percentages are 
at least 5% in any one of the treatment groups. If there are no PTs whose percentages 
exceed 5%, the threshold is lowered to 2%. When counting the number of "Subjects With 
Any TEAEs", subjects with at least one of these most frequent non-serious TEAEs will 
be counted.
7.4.2 PRETREATMENT EVENTS
7.4.2.1
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 


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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.
7.4.3 LABORATORY AND OTHER SAFETY DATA
7.4.3.1
LABORATORY TEST RESULTS
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 Fractions (Neutrophils (%), Eosinophils (%), Basophils (%), 
Monocytes (%), Lymphocytes (%)) 
Serum Chemistry
ALT (U/L)
ALP (U/L)
AST (U/L)
GGT (U/L)
Total Bilirubin (μmol/L)
Direct Bilirubin (μmol/L)
LDH (U/L)
CK (CPK) (U/L)
Albumin (g/L)
Total Protein (g/L)
Creatinine (μmol/L)
BUN (mmol/L)
Uric Acid (mmol/L)
Total Cholesterol (mmol/L)
Triglycerides (mmol/L)
Glucose (mmol/L)
Potassium (mmol/L)
Sodium (mmol/L)
Magnesium (mmol/L)
Calcium (mmol/L)
Inorganic Phosphorus (mmol/L)
Chloride (mmol/L)
Serum Iron (μmol/L)
Vitamin B12 (pmol/L)
Visit:
ALT, AST, Total Bilirubin, and Direct Bilirubin:
Baseline, Week 2, Week 4, Week 6, Week 8
Variables other than ALT, AST, Total Bilirubin, and Direct Bilirubin:
Baseline, Week 2, Week 4, Week 8
Analytical Methods: For each variable, summaries (1) and (2) will be provided by treatment group.
For applicable variables, summaries (3) and (4) will be provided by treatment group.
(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.


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(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 
Parameters
Overall frequency distributions of MAV during treatment phase will be provided. If a 
laboratory parameter has both lower and upper MAV criteria, analysis will be performed 
for each. Further details are given in Appendix.
(4) Number and Percentage of Subjects with Elevated Liver Enzyme Laboratory 
Parameters
Overall frequency distributions of elevated hepatic parameters during treatment phase will 
be provided. Further details are given in Appendix.
Urinalysis
Analysis Set:
Safety Analysis Set
Analysis Variables : Protein
[Neg, Trace, 30 mg/dL, 100 mg/dL, 300 mg/dL, >=2000 mg/dL]
Sugar
[Neg, 100 mg/dL, 250 mg/dL, 500 mg/dL, 1000 mg/dL, >=2000 mg/dL]
Visit:
Baseline, Week 2, Week 4, Week 8
Analytical Methods: The following summaries will be provided for each treatment group.
(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.
Serum Gastrin, Pepsinogen I/II
Analysis Set:
Safety Analysis Set
Analysis Variables : Serum Gastrin (pmol/L)
Pepsinogen I (μg/L)
Pepsinogen II (μg/L)
Pepsinogen I/II Ratio
Visit:
Baseline, Week 2, Week 4, Week 8
Analytical Methods: The following summaries will be provided for each treatment group.
(1) Summary of Serum Gastrin and Pepsinogen I/II Results
For each visit, descriptive statistics for observed values and changes from baseline (each 
post-baseline visit - baseline) will be provided.


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7.4.4 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY
Vital Signs
Analysis Set:
Safety Analysis Set
Analysis Variables: Body Temperature (C)
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Pulse (bpm)
Visit:
Baseline, Week 2, Week 4, Week 8
Analytical Methods: For each variable, summaries (1) and (2) will be provided by treatment group.
(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.
12-lead ECG
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)
Interpretation
["Within Normal Limits",
"Abnormal, Not Clinically Significant",
"Abnormal, Clinically Significant"]
Visit:
Baseline, Week 2, Week 4, Week 8
Analytical Methods: For each variable other than interpretations, summary (1) will be provided by treatment group.
For applicable variables, summary (2) will be provided by treatment group.
For interpretation, summary (3) will be provided by treatment group.
(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 


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ECG laboratory 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.
7.4.5 SUBGROUP ANALYSIS FOR CHINA
Analysis Population: Subjects in China
Analytical Methods: The same analyses as those in section 7.2 to 7.4.4 will be conducted for the subjects in China.
7.4.6 SUBGROUP ANALYSIS FOR KOREA
Analysis Population: Subjects in Korea
Subjects in Countries other than Korea
Analytical Methods: (1) The same analyses as those in the following sections will be conducted for the subjects in 
Korea.
・
Section 7.2.1.5, 7.2.2.1, 7.2.3.1
・
Section 7.3.1.1, 7.3.2.1, 7.3.2.2, 7.3.3.1 ("Heartburn Symptom" (Analysis Variables (1), 
(2), (3), (5), (8)), "Gastric Acid Regurgitation" (Analysis Variables (1), (2), (3), (5), (8))), 
7.3.3.4, 7.3.4.8
・
Section 7.4.1.1, 7.4.1.2 ((1), (4) – (17)), 7.4.3, 7.4.4
(2) The same analyses as those in the following sections will be conducted for the subjects in 
countries other than Korea.
・
Section 7.2.1.5, 7.2.2.1, 7.2.3.1
・
Section 7.3.1.1, 7.3.2.1, 7.3.2.2, 7.3.3.1 ("Heartburn Symptom" (Analysis Variables (1), 
(2), (3), (5), (8)), "Gastric Acid Regurgitation" (Analysis Variables (1), (2), (3), (5), (8))), 
7.3.3.4, 7.3.4.8
・
Section 7.4.1.1, 7.4.1.2 ((1), (4) – (17)), 7.4.3, 7.4.4
7.4.7 SUBGROUP ANALYSIS FOR TAIWAN
Analysis Population: Subjects in Taiwan
Subjects in Countries other than Taiwan
Analytical Methods: (1) The same analyses as those in the following sections will be conducted for the subjects in 
Taiwan.
・
Section 7.2.1.5, 7.2.2.1, 7.2.3.1
・
Section 7.3.1.1, 7.3.2.1, 7.3.2.2, 7.3.3.1 ("Heartburn Symptom" (Analysis Variables (1), 
(2), (3), (5), (8)), "Gastric Acid Regurgitation" (Analysis Variables (1), (2), (3), (5), (8))), 
7.3.3.4, 7.3.4.8
・
Section 7.4.1.1, 7.4.1.2 ((1), (4) – (17)), 7.4.3, 7.4.4


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(2) The same analyses as those in the following sections will be conducted for the subjects in 
countries other than Taiwan.
・
Section 7.2.1.5, 7.2.2.1, 7.2.3.1
・
Section 7.3.1.1, 7.3.2.1, 7.3.2.2, 7.3.3.1 ("Heartburn Symptom" (Analysis Variables (1), 
(2), (3), (5), (8)), "Gastric Acid Regurgitation" (Analysis Variables (1), (2), (3), (5), (8))), 
7.3.3.4, 7.3.4.8
・
Section 7.4.1.1, 7.4.1.2 ((1), (4) – (17)), 7.4.3, 7.4.4
7.4.8 SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT
・
Significance level: 5% (two-sided test)
・
Confidence coefficient: 95% (two-sided)
No statistical testing will be performed if there are less than 5 subjects.


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7.4.9 CHANGES IN THE STATISTICAL ANALYSIS PLAN
The changes from the original SAP (Version: 1, Date: 01 September 2015) to the amended SAP were described 
below with a rationale for changes provided.
Page 1, TITLE PAGE
Existing Text
Revised Text
Rationale for Amendment
The department and position of the responsible person have been changed.
Page 2, Section 1.0 APPROVAL SIGNATURES
Existing Text
Revised Text
Rationale for Amendment
The Responsible persons have been changed.
Page 7, Section 4.4. STUDY DESIGN
Existing Text
The study will consist of a Screening Phase of up to 28 days including an Observation Phase of 3-7 days prior to the 
randomization visit (Day 1), during which a baseline observation of EE symptoms will be completed, and then a 
Treatment Phase of up to 8 weeks. There will be 5 subject visits scheduled: the start of the Observation Phase (Visit 
1), the start of the Treatment Phase (Visit 2), after 2 weeks of treatment (Visit 3), after 4 weeks of treatment (Visit 
4), after 8 weeks of treatment (Visit 5), and a phone call during the Follow-up phase (only for those not participate
in TAK-438_305 study).
PPD
PPD
PPD
PPD


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Revised Text
The study will consist of a Screening Phase of up to 28 days, including an Observation Phase of 3-7 days prior to the 
randomization visit (Day 1), during which a baseline observation of EE symptoms will be completed, and then a 
Treatment Phase of up to 8 weeks. There will be 6 subject visits scheduled: the start of the Observation Phase (Visit 
1), the start of the Treatment Phase (Visit 2), after 2 weeks of treatment (Visit 3), after 4 weeks of treatment (Visit 
4), after 6 weeks of treatment (Visit 5), after 8 weeks of treatment (Visit 6), and a phone call during the Follow-up 
phase (only for those not participating in TAK-438_305 study).
Rationale for Amendment
Visit 5 (6 weeks of treatment) has been added in the protocol.
Page 11, Section 7.1.1 DEFINITIONS
Added Text
A TEAE whose relationship to study drug is missing will be considered drug-related. A TEAE whose intensity is 
missing will be considered severe.
Rationale for Amendment
The handling rules for missing data for TEAE have been added.
Page 11, Section 7.1.1 DEFINITIONS
Added Text
Pepsinogen I/II Ratio: Pepsinogen I (μg/L) / Pepsinogen II (μg/L) (rounded to 1 decimal place)
Rationale for Amendment
The calculation formula for the above variable has been added with the number of decimal places.
Page 11, Section 7.1.1 DEFINITIONS
Added Text
Significant TEAE: Any TEAE (not including serious TEAEs) that led to an intervention, including withdrawal of 
drug treatment, dose increase, dose reduction or significant additional concomitant therapy.
Rationale for Amendment
The significant TEAE should be analyzed and the definition of this type of TEAE has been added.
Page 13, Section 7.1.5 HANDLING OF DATA WHEN CALCULATING MEAN SEVERITY ACCORDING 
TO SUBJECT DIARY
Existing Text
Mean severity = (total score of the severity recorded for the visit) / (number of days the severity of symptom is 
recorded) * 100 (rounded to 2 decimal places)


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Revised Text
Mean severity = (total score of the severity recorded for the visit) / (number of days the severity of symptom is 
recorded) (rounded to 2 decimal places)
Rationale for Amendment
The expression "* 100" has been deleted because of clerical error.
Page 15, Section 7.1.9 HANDLING OF DATA WHEN CALCULATING PROPORTION OF DAYS 
WITHOUT RESCUE MEDICATION
Existing Text
One month to the 
Day of Last Dose
27 days before the last dose –
day of last dose
up to and including Follow-up Day 1
Revised Text
One Month to the 
Day of Last Dose
27 days before the last dose –
day of last dose
Rationale for Amendment
The expression "m" has been replaced with "M". The condition "up to and including Follow-up Day 1" was not a 
clerical error, but the condition was not necessary because there was the condition "27 days before the last dose -
day of last dose".
Page 16, Section 7.1.10 HANDLING OF OTHER ENDPOINTS
Added Text
If there are two observations with the same Study Day, the earlier observation will be used.
Rationale for Amendment
The handling rules of multiple observations with the same Study Day have been added.
Page 16, Section 7.1.10 HANDLING OF OTHER ENDPOINTS
Existing Text
Endoscopy (Barrett's mucosa), Clinical laboratory tests, Gastrin, Pepsinogen I/II, Vital signs, 12-lead ECG
Revised Text
Endoscopy (Barrett's mucosa), Clinical laboratory tests (other than ALT, AST, total bilirubin, and direct bilirubin), 
Gastrin, Pepsinogen I/II, Vital signs, 12-lead ECG
(omitted)


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Clinical laboratory tests (ALT, AST, total bilirubin, and direct bilirubin)
Visit
Scheduled Study Day
(days) 
Time Interval (days) 
Study Day
Follow-up Day
Baseline 
Study Day:
1
-28 – 1 
Week 2
Study Day:
15
2 – 21
up to and including Follow-up Day 14
Week 4
Study Day:
29
22 – 35
up to and including Follow-up Day 14
Week 6
Study Day:
43
36 – 49
up to and including Follow-up Day 14
Week 8
Study Day:
57
50 – 71
up to and including Follow-up Day 14
Rationale for Amendment
Visit 5 (6 weeks of treatment) has been added in the protocol for evaluating liver function tests (ALT, AST, total 
bilirubin, and direct bilirubin).
Page 18, Section 7.2.1.5 DISPOSITION OF SUBJECTS
Added Text
(2) Flow Chart of Subject Distribution
Flow chart will be provided.
Rationale for Amendment
The analysis for providing a flow chart has been added.
Page 22, Section 7.3.2.1 RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 
2-WEEK TREATMENT
Existing Text
The primary efficacy endpoint will be first tested for non-inferiority. If non-inferiority with regard to the primary 
efficacy endpoint is established, then the secondary efficacy endpoint "The Rate of Endoscopic Healing of Erosive 
Esophagitis during the 2-week Treatment" will be tested for superiority.
Revised Text
Details concerning interpretation are described in section 7.3.4.5.
Rationale for Amendment
The details concerning interpretation has been moved to section 7.3.4.5. 
Page 23, Section 7.3.2.2 RATE OF ENDOSCOPIC HEALING OF EROSIVE ESOPHAGITIS DURING THE 
4-WEEK TREATMENT
Added Text
Details concerning interpretation are described in section 7.3.4.5.


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Rationale for Amendment
The interpretation for the test of "The Rate of Endoscopic Healing of Erosive Esophagitis During the 4-week 
Treatment" has been added to section 7.3.4.5 to be clarified.
Page 26, Section 7.3.3.4 BARRETT'S MUCOSA
Existing Text
Present (3 cm or greater)
Revised Text
Present (3 cm or Greater)
Rationale for Amendment
The expression "greater" has been replaced with "Greater" because of clerical error.
Page 27, Section 7.3.4.2 HANDLING OF DROPOUTS OR MISSING DATA
Added Text
Values below the lower limit of quantification will be treated as zero when calculating the descriptive statistics. 
Values above the upper limit of quantification will be treated as the upper limit values when calculating the 
descriptive statistics.
Rationale for Amendment
The handling rules of values below the lower or upper limit values for calculating the descriptive statistics have been 
added.
Page 27, Section 7.3.4.5 MULTIPLE COMPARISON/MULTIPLICITY
Existing Text
Adjustment for multiplicity will be performed for the primary efficacy endpoint "The Rate of Endoscopic Healing of 
Erosive Esophagitis during the 8-week Treatment" and the secondary efficacy endpoint "The Rate of Endoscopic 
Healing of Erosive Esophagitis during the 2-week Treatment" in the following fashion. The primary endpoint will be 
first tested for non-inferiority. If non-inferiority with regard to the primary endpoint is established, then the 
secondary endpoint will be tested for superiority. This procedure is based on the closed testing principle and the 
analysis will be conducted using the full analysis set.
Revised Text
Adjustment for multiplicity will be performed for the primary efficacy endpoint "The Rate of Endoscopic Healing of 
Erosive Esophagitis during the 8-week Treatment" and the secondary efficacy endpoints "The Rate of Endoscopic 
Healing of Erosive Esophagitis during the 2-week Treatment" and "The Rate of Endoscopic Healing of Erosive 
Esophagitis During the 4-week Treatment" in the following fashion. The following procedure is based on the closed 
testing principle and the analysis will be conducted using the full analysis set.
-
The primary endpoint "The Rate of Endoscopic Healing of Erosive Esophagitis during the 8-week Treatment" 
will be tested for non-inferiority between the TAK-438 group and the Lansoprazole group. If the lower bound 
of the 95% confidence interval of the treatment difference (the TAK-438 group – the Lansoprazole group) is 
≥-10%, non-inferiority for TAK-438 relative to Lansoprazole will be declared.


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-
If the previous test is successful, the secondary endpoint "The Rate of Endoscopic Healing of Erosive 
Esophagitis during the 2-week Treatment" will be tested for superiority between the TAK-438 group and the 
Lansoprazole group. The lower bound of the 95% confidence interval of the treatment difference (the TAK-438 
group – the Lansoprazole group) will be compared to 0%.
-
If the previous test is successful, the primary endpoint "The Rate of Endoscopic Healing of Erosive Esophagitis 
during the 8-week Treatment" will be tested for superiority between the TAK-438 group and the Lansoprazole 
group.
-
If the previous test is successful, the secondary endpoint "The Rate of Endoscopic Healing of Erosive 
Esophagitis during the 4-week Treatment" will be tested for superiority between the TAK-438 group and the 
Lansoprazole group.
Rationale for Amendment
The interpretation for the superiority tests of "The Rate of Endoscopic Healing of Erosive Esophagitis During the 8-
week Treatment" and "The Rate of Endoscopic Healing of Erosive Esophagitis During the 4-week Treatment" has 
been explicitly added to the procedure already defined in the protocol. The revised procedure is still based on the 
closed testing principle and maintains maintain a Type 1 error rate at 5%.
Page 29, Section 7.4.1.1 OVERVIEW OF TREATMENT-EMERGENT ADVERSE EVENTS
Added Text
5) Relationship to Study Drug of Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
(number of events, number and percentage of subjects)
11) Significant Treatment-Emergent Adverse Events (number of events, number and percentage of subjects)
Rationale for Amendment
The analyses for these types of TEAEs has been added.
Page 30, Section 7.4.1.2 DISPLAYS OF TREATMENT-EMERGENT ADVERSE EVENTS
Existing Text
System Organ Class
Revised Text
SOC
Rationale for Amendment
The expression "System Organ Class" has been replaced with "SOC" for expression consistency.
Page 30, Section 7.4.1.2 DISPLAYS OF TREATMENT-EMERGENT ADVERSE EVENTS
Added Text
(8) Drug-Related Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by System Organ 
Class and Preferred Term
(10) Serious Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred Term


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(15) Significant Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
(16) Drug-Related Significant Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
(17) Most Frequent Non Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
Summary table for (17)
Most frequent non-serious TEAEs refer to PTs that are not serious whose percentages are at least 5% in any one of 
the treatment groups. If there are no PTs whose percentages exceed 5%, the threshold is lowered to 2%. When 
counting the number of "Subjects With Any TEAEs", subjects with at least one of these most frequent non-serious 
TEAEs will be counted.
Rationale for Amendment
The analyses for these types of TEAEs has been added.
Page 32, Section 7.4.3.1 LABORATORY TEST RESULTS (Hematology and Serum Chemistry)
Existing Text
Visit: Baseline, Week 2, Week 4, Week 8
Revised Text
Visit: ALT, AST, Total Bilirubin, and Direct Bilirubin:
Baseline, Week 2, Week 4, Week 6, Week 8
Variables other than ALT, AST, Total Bilirubin, and Direct Bilirubin:
Baseline, Week 2, Week 4, Week 8
Rationale for Amendment
Week 6 has been added in the protocol for evaluating liver function tests (ALT, AST, total bilirubin, and direct 
bilirubin).
Page 33, Section 7.4.3.1 LABORATORY TEST RESULTS (Serum Gastrin, Pepsinogen I/II)
Existing Text
Pepsinogen I (mcg/L), Pepsinogen II (mcg/L)
Revised Text
Pepsinogen I (μg/L), Pepsinogen II (μg/L)
Rationale for Amendment
The expression "mcg" has been replaced with "μg" for using more suitable expression.


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Page 34, Section 7.4.4 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED 
TO SAFETY (Vital Signs)
Existing Text
Body Temperature (°C)
Revised Text
Body Temperature (C)
Rationale for Amendment
The expression "°C" has been replaced with "C" for using more suitable expression.
Page 34, Section 7.4.4 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED 
TO SAFETY (12-lead ECG)
Existing Text
Visit: Baseline, Week 2, Week 8
Revised Text
Visit: Baseline, Week 2, Week 4, Week 8
Rationale for Amendment
Week 4 has been added because of clerical error.
Page 34, Section 7.4.4 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED 
TO SAFETY (12-lead ECG)
Existing Text
12-lead ECG interpretations (3 places)
Revised Text
interpretations (3 places)
Rationale for Amendment
The expression "12-lead ECG" has been deleted for expression consistency with TFLs.
Page 35, Section 7.4.6 SUBGROUP ANALYSIS FOR KOREA
Existing Text
・
Section 7.3.1.1, 7.3.2.1, 7.3.2.2, 7.3.3.1 ("Heartburn Symptom" (Analysis Variables (1), (2), (5), (8)), 
"Gastric Acid Regurgitation" (Analysis Variables (1), (2), (5), (8))), 7.3.4.8
・
Section 7.4.1.1, 7.4.1.2 ((1), (4) – (12)), 7.4.3.1 ("Hematology and Serum Chemistry" (3) and "Serum Gastrin, 
Pepsinogen I/II (1)"), 7.4.4 ("Vital Signs" (2) and "12-lead ECG " (2))     (2 places)
Revised Text
・
Section 7.3.1.1, 7.3.2.1, 7.3.2.2, 7.3.3.1 ("Heartburn Symptom" (Analysis Variables (1), (2), (3), (5), (8)), 
"Gastric Acid Regurgitation" (Analysis Variables (1), (2), (3), (5), (8))), 7.3.3.4, 7.3.4.8


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・
Section 7.4.1.1, 7.4.1.2 ((1), (4) – (17)), 7.4.3, 7.4.4     (2 places)
Rationale for Amendment
The analyses for the underlined part have been added.
Page 35
Added Text
7.4.7 SUBGROUP ANALYSIS FOR TAIWAN
Analysis Population: Subjects in Taiwan
Subjects in Countries other than Taiwan
Analytical Methods: (1) The same analyses as those in the following sections will be conducted for the subjects in 
Taiwan.
・
Section 7.2.1.5, 7.2.2.1, 7,2,3,1
・
Section 7.3.1.1, 7.3.2.1, 7.3.2.2, 7.3.3.1 ("Heartburn Symptom" (Analysis Variables (1), 
(2), (3), (5), (8)), "Gastric Acid Regurgitation" (Analysis Variables (1), (2), (3), (5), (8))), 
7.3.3.4, 7.3.4.8
・
Section 7.4.1.1, 7.4.1.2 ((1), (4) – (17)), 7.4.3, 7.4.4
(2) The same analyses as those in the following sections will be conducted for the subjects in 
countries other than Taiwan.
・
Section 7.2.1.5, 7.2.2.1, 7,2,3,1
・
Section 7.3.1.1, 7.3.2.1, 7.3.2.2, 7.3.3.1 ("Heartburn Symptom" (Analysis Variables (1), 
(2), (3), (5), (8)), "Gastric Acid Regurgitation" (Analysis Variables (1), (2), (3), (5), (8))), 
7.3.3.4, 7.3.4.8
・
Section 7.4.1.1, 7.4.1.2 ((1), (4) – (17)), 7.4.3, 7.4.4
Rationale for Amendment
The analyses for the underlined part have been added.
Page 47, Section 8.0 REFERENCES
Added Text
Luo N, et. al. (2017) "Estimating an EQ-5D-5L Value Set for China", Value in Health, Volume 20(4): 662-669.
Rationale for Amendment
The above reference has been added.
Page 49, Section 9.1.1 HEMATOLOGY, SERUM CHEMISTRY, URINALYSIS, VITAL SIGNS, AND 12-
LEAD ECG (EXCEPT UPPER MAV CRITERIA OF QTCF INTERVAL) (Vital Signs)
Existing Text
Body Temperature (°C)
Revised Text
Body Temperature (C)


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Rationale for Amendment
The expression "°C" has been replaced with "C" for using more suitable expression.


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8.0
REFERENCES
・
DeLong ER, et. al. (1988) "Comparing the areas under two or more correlated receiver operating characteristic 
curves: a nonparametric approach", Biometrics, Volume 44(3): 837-45.
・
Divine G, et al. (2013) "A review of analysis and sample size calculation considerations for Wilcoxon tests", 
Anesth Analg, Volume 117(3): 699-710.
・
Lehmann EL, et. al. (1975) "Nonparametrics: statistical methods based on ranks", Springer.
・
Mason SJ, et. al. (2002) "Areas beneath the relative operating characteristics (ROC) and relative operating 
levels (ROL) curves: Statistical significance and interpretation", Quarterly Journal of the Royal Meteorological 
Society (128): 2145-2166.
・
O'Brien RG, et. al. (2006) "Exploiting the link between the Wilcoxon-Mann-Whitney test and a simple odds 
statistic", Proceedings of the Thirty-First Annual SAS Users Group International Conference.
・
Luo N, et. al. (2017) "Estimating an EQ-5D-5L Value Set for China", Value in Health, Volume 20(4): 662-669.


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9.0
APPENDIX
9.1CRITERIA FOR MARKEDLY ABNORMAL VALUES
9.1.1 HEMATOLOGY, SERUM CHEMISTRY, URINALYSIS, VITAL SIGNS, AND 12-LEAD ECG
(EXCEPT UPPER MAV CRITERIA OF QTCF INTERVAL)
For each parameter, all evaluable data (i.e., non-missing data) obtained up to Follow-up Day 14 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
Serum Chemistry
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
ALT (U/L)
-
>3×ULN
ALP (U/L)
-
>3×ULN
AST (U/L)
-
>3×ULN
GGT (U/L)
-
>3×ULN
Total Bilirubin (μmol/L)
-
>34.2
Direct Bilirubin (μmol/L)
-
>2×ULN
CK (CPK) (U/L)
-
>5×ULN
Albumin (g/L)
<25
-
Total Protein (g/L)
<0.8×LLN
>1.2×ULN
Creatinine (μmol/L)
-
>177
BUN (mmol/L)
-
>10.7


TAK-438_303 Statistical Analysis Plan Version 2
CROSS-REGIONAL TEMPLATE
Template Number:
C-TMPL-DO-801
Page:
49 of 51
Version Number:
1.0
Effective Date:
02 Apr 2014
This version replaces:
TMPL-104
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Printed or downloaded documents must be verified against the effective version.
CONFIDENTIAL INFORMATION
Do not distribute outside of Takeda without a confidentiality agreement.
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Uric Acid (mmol/L)
-
>0.773
Total Cholesterol (mmol/L)
-
>7.72
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
Inorganic Phosphorus (mmol/L)
<0.52
>2.00
Chloride (mmol/L)
<75
>126
Vitamin B12 (pmol/L)
<92
-
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
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 (i.e., non-missing data) obtained up to Follow-up Day 14 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.


TAK-438_303 Statistical Analysis Plan Version 2
CROSS-REGIONAL TEMPLATE
Template Number:
C-TMPL-DO-801
Page:
50 of 51
Version Number:
1.0
Effective Date:
02 Apr 2014
This version replaces:
TMPL-104
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Printed or downloaded documents must be verified against the effective version.
CONFIDENTIAL INFORMATION
Do not distribute outside of Takeda without a confidentiality agreement.
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
9.2  CRITERIA FOR ELEVATED LIVER ENZYME
All evaluable data (i.e., non-missing data) obtained up to Follow-up Day 14 will be used to determine whether each 
criteria for elevated liver enzyme in the table below is met or not. If there is more than one parameter that need to be 
considered for a criteria, parameter measurements taken on the same day will be used. For each criteria and subject, 
classifications will be made according to the conditions i) to iii) provided below.
i)
A subject who met criteria (a) at least once after baseline will be considered to have met the criteria for 
elevated liver enzyme.
ii)
If condition i) is not met but if criteria (b) is met at least once after baseline, then the subject will be considered 
to have not met the criteria for elevated liver enzyme.
iii)
If neither i) nor ii) is met, then the subject will be excluded from the analysis for the criteria for elevated liver 
enzyme.
Label
Criteria for Elevated Liver Enzyme
(a) Elevated
(b) Not Elevated
ALT > 3xULN
ALT is greater than 3 times the ULN
ALT is non-missing and less than or equal 
to 3 times the ULN
ALT > 5xULN
ALT is greater than 5 times the ULN
ALT is non-missing and less than or equal 
to 5 times the ULN
ALT > 8xULN 
ALT is greater than 8 times the ULN
ALT is non-missing and less than or equal 
to 8 times the ULN
ALT > 3xULN 
with Tbili > 2xULN
ALT is greater than 3 times the ULN and 
the total bilirubin is greater than twice the 
ULN
Either ALT is non-missing and less than 
or equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN
AST > 3xULN 
AST is greater than 3 times the ULN
AST is non-missing and less than or equal 
to 3 times the ULN
AST > 5xULN 
AST is greater than 5 times the ULN
AST is non-missing and less than or equal 
to 5 times the ULN
AST > 8xULN 
AST is greater than 8 times the ULN
AST is non-missing and less than or equal 
to 8 times the ULN
AST > 3xULN 
with Tbili > 2xULN
AST is greater than 3 times the ULN and 
the total bilirubin is greater than twice the 
ULN
Either AST is non-missing and less than 
or equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN
ALT or AST > 3xULN
Either ALT or AST is greater than 3 times 
the ULN
Both ALT and AST are non-missing and 
less than or equal to 3 times the ULN
ALT or AST > 5xULN 
Either ALT or AST is greater than 5 times 
the ULN
Both ALT and AST are non-missing and 
less than or equal to 5 times the ULN


TAK-438_303 Statistical Analysis Plan Version 2
CROSS-REGIONAL TEMPLATE
Template Number:
C-TMPL-DO-801
Page:
51 of 51
Version Number:
1.0
Effective Date:
02 Apr 2014
This version replaces:
TMPL-104
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Printed or downloaded documents must be verified against the effective version.
CONFIDENTIAL INFORMATION
Do not distribute outside of Takeda without a confidentiality agreement.
Label
Criteria for Elevated Liver Enzyme
(a) Elevated
(b) Not Elevated
ALT or AST > 8xULN 
Either ALT or AST is greater than 8 times 
the ULN
Both ALT and AST are non-missing and 
less than or equal to 8 times the ULN
ALT or AST > 3xULN 
with Tbili > 2xULN
Either ALT or AST is greater than 3 times 
the ULN and the total bilirubin is greater 
than twice the ULN
If any of the following conditions is met:
- Both ALT and AST are non-missing and 
less than or equal to 3 times the ULN.
- Total bilirubin is non-missing and less 
than or equal to twice the ULN.
ALT and AST > 3xULN 
Both ALT and AST are greater than 3 
times the ULN
Either ALT is non-missing and less than 
or equal to 3 times the ULN, or AST is 
non-missing and less than or equal to 3 
times the ULN
ALT and AST > 5xULN 
Both ALT and AST are greater than 5 
times the ULN
Either ALT is non-missing and less than 
or equal to 5 times the ULN, or AST is 
non-missing and less than or equal to 5 
times the ULN
ALT and AST > 8xULN
Both ALT and AST are greater than 8 
times the ULN
Either ALT is non-missing and less than 
or equal to 8 times the ULN, or AST is 
non-missing and less than or equal to 8 
times the ULN
ALT and AST > 3xULN 
with Tbili > 2xULN
Both ALT and AST are greater than 3 
times the ULN and the total bilirubin is 
greater than twice the ULN
If any of the following conditions is met:
- ALT is non-missing and less than or 
equal to 3 times the ULN
- AST is non-missing and less than or 
equal to 3 times the ULN
- Total bilirubin is non-missing and less 
than or equal to twice the ULN
ALP > 3xULN 
ALP is greater than 3 times the ULN
ALP is non-missing and less than or equal 
to 3 times the ULN
ALP > 3xULN 
with ALT > 3xULN 
Both ALP and ALT are greater than 3 
time the ULN
Either ALP is non-missing and less than 
or equal to 3 times the ULN, or ALT is 
non-missing and less than or equal to 3 
times the ULN
ALP > 3xULN 
with AST > 3xULN
Both ALP and AST are greater than 3 
times the ULN
Either ALP is non-missing and less than 
or equal to 3 times the ULN, or AST is 
non-missing and less than or equal to 3 
times the ULN


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