Conditions: Duodenal Ulcer
Keywords: Drug therapy Gastrointestinal Diseases Digestive System Diseases Lansoprazole Anti-Ulcer Agents Gastrointestinal Agents Proton Pump Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 533
Healthy volunteers: no

Brief summary:
The purpose of this study is to demonstrate the non-inferior efficacy of TAK-438 versus lansoprazole in the treatment of participants with duodenal ulcer.

Detailed description:
The drug being tested in this study is called TAK-438. TAK-438 is being tested to treat people who have duodenal ulcers and also may or may not have Helicobacter pylori (HP) infection. This study will look at duodenal ulcer healing and also the elimination of HP in people who take TAK-438 versus lansoprazole. The study will enroll approximately 530 patients.

Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which remained undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* TAK-438 20 mg
* Lansoprazole 30 mg

HP+ participants will be asked to take a TAK- 438 tablet and a lansoprazole capsule twice daily in conjunction with bismuth-containing quadruple therapy for 2 weeks, followed up by a TAK-438 tablet and a lansoprazole capsule once daily for up to 4 weeks. HP negative (HP-) participants will be asked to take a TAK-438 tablet and a lansoprazole capsule once daily for up to 6 weeks.

This multi-center trial will be conducted China, Korea and Taiwan. The overall time to participate in this study is up to 10 weeks. Participants will make multiple visits plus final visit at 2 weeks or 4 weeks after last dose of study drug for a follow-up assessment.

Arms:
arm 1: H. pylori negative (HP -) participants: TAK-438 20 mg, tablets, orally, once daily (QD) and lansoprazole placebo-matching capsules, orally, QD for up to 6 weeks. H. pylori positive (HP +) participants: TAK-438 20 mg, tablets, orally, twice daily (BID) and lansoprazole placebo-matching capsules, orally, BID for first 2 weeks along with Bismuth-Containing Quadruple Therapy followed byTAK-438 20 mg, tablets, orally, QD and lansoprazole placebo-matching capsules, orally, QD for up to 4 weeks. arm 2: H. pylori negative (HP -) participants: lansoprazole 30 mg, capsules, orally, QD and TAK-438 placebo-matching tablets, orally, QD for up to 6 weeks. HP + participants: lansoprazole 30 mg, capsules, orally, BID and TAK-438 placebo-matching tablets, orally, BID for first 2 weeks along with Bismuth-Containing Quadruple Therapy followed by lansoprazole 30 mg, capsules, orally, QD and TAK-438 placebo-matching tablets, orally, BID for up to 4 weeks.

Interventions: intervention 1: TAK-438 intervention 2: Lansoprazole intervention 3: TAK-438 Placebo intervention 4: Lansoprazole Placebo intervention 5: Bismuth-Containing Quadruple Therapy
Intervention descriptions: intervention 1: TAK-438 tablets intervention 2: Lansoprazole capsules intervention 3: TAK-438 placebo-matching tablets. intervention 4: Lansoprazole placebo-matching capsules intervention 5: 1 g Amoxicillin, 500 mg clarithromycin and 600 mg bismuth potassium citrate/bismuth tripotassium dicitrate, twice daily (BID).

Protocol document:
Prot_000.pdf: 



Title: A Randomized Double-Blind, Double-Dummy, Phase 3 Study to Evaluate the Efficacy and 
Safety of Oral TAK-438 20 mg Compared to Lansoprazole 30 mg Once- or Twice-Daily in the 
Treatment of Endoscopically Confirmed Duodenal Ulcer Subjects With or Without Helicobacter 
pylori Infection
NCT Number: NCT03050359
Protocol Approve Date: 30 August 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
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.


PROTOCOL AMENDMENT
A Randomized Double-Blind, Double-Dummy, Phase 3 Study to Evaluate the Efficacy and 
Safety of Oral TAK-438 20 mg Compared to Lansoprazole 30 mg Once- or Twice-Daily in 
the Treatment of Endoscopically Confirmed Duodenal Ulcer Subjects With or Without 
Helicobacter pylori Infection
Comparison of TAK-438 (Vonoprazan) to Lansoprazole in the Treatment of Duodenal 
Ulcer Subjects With or Without Helicobacter pylori Infection
Sponsor:
Takeda Development Center Asia Pte Ltd
21 Biopolis Road, Nucleos North Tower, Level 4, Singapore 138567 
Study Number:
TAK-438_304
IND Number:
Not Applicable
EudraCT Number:
Not Applicable 
Compound:
TAK-438
Date:
30 August 2018
Amendment 
Number:
03
Amendment History
Date
Amendment Number
Amendment Type
Region
21 Nov 2012
Initial Protocol
Not applicable
Asia Pacific
27 Sep 2016
01
Substantial
Asia Pacific
21 Dec 2016
02
Substantial
Asia Pacific
30 Aug 2018
03
Substantial
Asia Pacific
Prop
eda: For non-commercial use only and subject to the applicable Terms of Use


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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 investigators per individual country 
requirements 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
Asian Regional 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)
Property of Takeda: For non-comme
to the applicable Terms of Use
ntry
ntry
be carrie
e carr
or assign
assig
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nal Con
al Co
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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 
Property of Takeda: For non-commer
 to the applic
o
cable Terms of Use
dance
dance
wing:
wing:
lidated
lidate
ta privac
priva
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 03 Summary of Changes
This document describes the changes in reference to the protocol incorporating Amendment 
No. 03. The primary reason for this amendment is to reduce the sample sizes of the overall 
population and Chinese subpopulation due to reduction in the dropout rate and change in the 
proportion of the Chinese subpopulation.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
For specific descriptions of text changes and where the changes are located, see Appendix E.
Changes in Amendment 03
1. Removal of reference to Study TAK-438_115 as part of rationale for study design.
2. Subjects with no ulcer healing at Week 6 could be treated with another course of PPI or other 
anti-acid secretory agents or antibiotics, at the discretion of the investigator.
3. Exclusion criterion 10 concerning subjects participating in another clinical study within 
30 days of Visit 1, is deleted. 
4. Exclusion criterion 12 is deleted to allow subjects with ulcer size >2 cm in any diameter and 
those with >3 separate duodenal ulcers to enter the study. 
5. A footnote is added to Table 9.b to clarify that subjects with negative hepatitis C virus antibody 
test results may be randomized before hepatitis C-viral load-RNA test results are available.
6. Procedure for retesting of abnormal liver function tests, and a clarification concerning elevated 
serum gastrin and pepsinogen I and II levels, which are physiological responses to increased 
gastric pH and the suppression of gastric acid secretion.
7. The liver function test at Visit 3 is clarified as a fasting clinical laboratory test.
8. The sample sizes for the overall study population and the Chinese subpopulation have been 
recalculated on the basis of an estimated dropout rate of 10% (previously 20%), resulting in 
sample size re-estimation.
9. H pylori eradication data from this study (TAK-438_304) will be pooled with data from 
TAK-438_302. 
10. Study-specific endoscopy may be waived at the investigator’s discretion if endoscopy with 
associated images has been performed within 14 days before Day 1.
11. Time of dosing of TAK-438 amended to after breakfast or dinner (previously after breakfast 
only).
12. Clarification of follow-up guidance on excluded medications and treatments in Table 7.a, 
amended for proton pump inhibitors, histamine H2 receptor antagonists, insulin, antidiabetic 
agents, and antibiotics.
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13. Provision has been made for the use of premedication for endoscopy to be provided at 
investigator’s discretion.
14. Formulation of bismuth for use in Korean sites is specified in relevant sections of the protocol.
15. Provision for serum gastrin follow-up for all subjects.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Coordinating Investigator.........................................................................................15
3.3
List of Abbreviations ...............................................................................................16
3.4
Corporate Identification...........................................................................................17
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.2
Rationale for the Proposed Study.............................................................................20
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................22
5.1
Objectives................................................................................................................22
5.1.1
Primary Objective ..............................................................................................22
5.1.2
Secondary Objectives.........................................................................................22
5.2
Endpoints.................................................................................................................22
5.2.1
Primary Endpoint...............................................................................................22
5.2.2
Secondary Endpoints..........................................................................................22
5.2.3
Additional Endpoints .........................................................................................22
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................24
6.1
Study Design ...........................................................................................................24
6.2
Justification for Study Design, Dose, and Endpoints ................................................25
6.3
Premature Termination or Suspension of Study or Investigational Site.....................28
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................28
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........28
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Sites ..................................................................28
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............29
7.1
Inclusion Criteria .....................................................................................................29
7.2
Exclusion Criteria ....................................................................................................29
7.3
Excluded Medications and Treatments.....................................................................31
7.4
Diet, Fluid, Activity Control ....................................................................................33
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7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................34
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................35
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................36
8.1
Study Drug and Materials ........................................................................................36
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................36
8.1.2
Storage...............................................................................................................37
8.1.3
Dose and Regimen .............................................................................................38
8.1.4
Overdose............................................................................................................39
8.2
Study Drug Assignment and Dispensing Procedures ................................................40
8.3
Randomization Code Creation and Storage..............................................................40
8.4
Investigational Drug Blind Maintenance ..................................................................40
8.5
Unblinding Procedure..............................................................................................40
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................41
9.0
STUDY PLAN ..............................................................................................................43
9.1
Study Procedures.....................................................................................................43
9.1.1
Informed Consent Procedure..............................................................................43
9.1.2
Demographics, Medical History, and Medication History Procedure..................43
9.1.3
Physical Examination Procedure ........................................................................44
9.1.4
Weight, Height and BMI....................................................................................45
9.1.5
Vital Sign Procedure..........................................................................................45
9.1.6
Documentation of Concomitant Medications......................................................45
9.1.7
Documentation of Concurrent Medical Conditions.............................................45
9.1.8
Procedures for Clinical Laboratory Samples.......................................................45
9.1.9
Contraception and Pregnancy Avoidance Procedure...........................................47
9.1.10 Pregnancy ..........................................................................................................48
9.1.11 ECG Procedure..................................................................................................48
9.1.12 Documentation of Screen Failure .......................................................................49
9.1.13 Documentation of Randomization......................................................................49
9.1.14 Endoscopy .........................................................................................................49
9.1.15 Gastrointestinal Symptoms of Duodenal Ulcer and Quality of Life.....................50
9.2
Monitoring Subject Treatment Compliance..............................................................51
9.3
Schedule of Observations and Procedures................................................................51
9.3.1
Visit 1 (Screening) .............................................................................................51
9.3.2
Visit 2 (includes Randomization) .......................................................................52
9.3.3
Treatment Period – Visit 3 .................................................................................52
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9.3.4
Treatment Period – Visit 4 .................................................................................53
9.3.5
End of Treatment Period – Visit 5......................................................................54
9.3.6
Early Termination..............................................................................................54
9.3.7
Follow-up Period – Visits F-1 and F-2 ...............................................................55
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................56
10.1
Definitions...............................................................................................................56
10.1.1 Pretreatment Events ...........................................................................................56
10.1.2 AEs....................................................................................................................56
10.1.3 Additional Points to Consider for PTEs and AEs................................................56
10.1.4 SAEs..................................................................................................................58
10.1.5 Special Interest AEs...........................................................................................59
10.1.6 Severity of PTEs and AEs..................................................................................59
10.1.7 Causality of AEs ................................................................................................59
10.1.8 Relationship to Study Procedures.......................................................................60
10.1.9 Start Date...........................................................................................................60
10.1.10
Stop Date .....................................................................................................60
10.1.11
Frequency ....................................................................................................60
10.1.12
Action Concerning Study Drug(s) ................................................................60
10.1.13
Outcome.......................................................................................................60
10.2
Procedures...............................................................................................................61
10.2.1 Collection and Reporting of AEs........................................................................61
10.2.2 Collection and Reporting of SAEs......................................................................62
10.2.3 Reporting of Abnormal LFTs as SAEs (Medically Significant Event) ................62
10.3
Follow-up of SAEs ..................................................................................................63
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....63
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................64
12.0
DATA HANDLING AND RECORDKEEPING............................................................65
12.1
CRFs .......................................................................................................................65
12.2
Record Retention .....................................................................................................65
13.0
STATISTICAL METHODS..........................................................................................67
13.1
Statistical and Analytical Plans ................................................................................67
13.1.1 Analysis Sets......................................................................................................67
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................67
13.1.3 Efficacy Analysis...............................................................................................67
13.1.4 Safety Analysis ..................................................................................................70
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13.2
Interim Analysis and Criteria for Early Termination ................................................70
13.3
Determination of Sample Size..................................................................................70
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................72
14.1
Study-Site Monitoring Visits ...................................................................................72
14.2
Protocol Deviations..................................................................................................72
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................72
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................73
15.1
IRB and/or IEC Approval ........................................................................................73
15.2
Subject Information, Informed Consent, and Subject Authorization .........................73
15.3
Subject Confidentiality ............................................................................................75
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................75
15.4.1 Publication and Disclosure.................................................................................75
15.4.2 Clinical Trial Registration..................................................................................75
15.4.3 Clinical Trial Results Disclosure ........................................................................76
15.5
Insurance and Compensation for Injury....................................................................76
16.0
REFERENCES..............................................................................................................77
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications and Treatments...............................................................32
Table 8.a
TAK-438 and Lansoprazole Properties...............................................................37
Table 8.b
Dose Regimen of Sponsor-Supplied Drugs.........................................................39
Table 9.a
Characteristics of Current Duodenal Ulcers........................................................43
Table 9.b
Clinical Laboratory Tests...................................................................................46
Table 10.a
Takeda Medically Significant AE List................................................................59
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................25
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................78
Appendix B
Responsibilities of the Investigator.....................................................................81
Appendix C
Elements of the Subject Informed Consent.........................................................83
Appendix D
Investigator Consent to Use of Personal Information..........................................86
Appendix E
Detailed Description of Amendments to Text.....................................................87
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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 TAK-438 20 mg 
Compared to Lansoprazole 30 mg Once- or Twice-Daily in the Treatment 
of Endoscopically confirmed Duodenal Ulcer Subjects with or without 
Helicobacter pylori infection
IND No.:
Not applicable
EudraCT No.: 
Not applicable
Study Number: TAK-438_304
Phase: 3
Study Design:
This is a phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group, noninferiority study of 
TAK-438 versus lansoprazole in subjects who have endoscopic evidence of duodenal ulcer with or without 
Helicobacter pylori (H pylori) infection. Randomization will be stratified by H pylori infection status.
Subjects whose eligibility is confirmed during the 28-day screening period will complete Visit 2/ Day 1 procedures 
performed as listed in Appendix A to ensure continued eligibility. Dosing will begin after randomization on Day 1 and 
continue for up to 6 weeks. Study drug administration will depend on the H pylori infection status of the subject, and 
include quadruple therapy for the first 2 weeks in H pylori infected (HP+) subjects. 
Treatment Period – Dose and Regimen:

HP+ subjects will take TAK-438 20 mg or lansoprazole 30 mg (blinded with matching placebo) twice daily 
(BID) in conjunction with bismuth-containing quadruple therapy for 2 weeks (amoxicillin 1 g BID, 
clarithromycin 500 mg BID, and bismuth potassium citrate/bismuth tripotassium dicitrate 600 mg 
[equivalent to 220 mg bismuth], BID). After 2 weeks of eradication therapy, subjects will be required to take 
only TAK-438 or lansoprazole once daily (QD) for up to 4 weeks (ie, up to a total of 6 weeks treatment). The 
subjects will remain in the same treatment arm throughout the study duration.

Non-H pylori infected (HP-) subjects will take TAK-438 20 mg or lansoprazole 30 mg (blinded with 
matching placebo) QD for up to 6 weeks. 
For all subjects, ulcer healing rates will be assessed by endoscopy at Weeks 4 and 6 of treatment. With or without 
endoscopic evidence of duodenal ulcer healing, the treatment duration of the study is no more than 6 weeks. 
Subjects (HP+ or HP-) with endoscopic healing of duodenal ulcer(s) at Week 4 or Week 6 will discontinue treatment 
at that time, and subjects without ulcer healing by Week 6 of treatment period will discontinue treatment at Week 6. 
All subjects will participate in a gastrin recovery and safety follow-up.
Follow-up Period:
The subjects to be followed up will include both HP+ and HP- subjects, with or without confirmed ulcer healing 
during the treatment period.
The monitoring of the recovery of serum gastrin-17 level and pepsinogen I/II ratio in the follow-up period will be for 
a maximum of 4 weeks. The follow-up period ends when the recovery of serum gastrin-17 level and pepsinogen I/II 
ratio is confirmed or at the end of the 4-week follow-up period.
All HP+ subjects will provide a follow-up 13C-UBT at the F-2 visit to ascertain HP eradication status.
For subjects with no ulcer healing at Week 6 of treatment, the investigator may follow local clinical practice and these 
subjects may be treated with another course of PPI or other anti-acid secretory agents or antibiotics, during the safety 
follow-up period
Primary Objective:
To demonstrate the noninferior efficacy of TAK-438 versus lansoprazole in the treatment of subjects with duodenal 
ulcer.
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Secondary Objectives:
To demonstrate the noninferiority of H pylori eradication with TAK-438 versus lansoprazole.
To compare the safety of TAK-438 versus lansoprazole in subjects with duodenal ulcer.
Subject Population: Male and nonpregnant, nonlactating female subjects at least 18 years of age (or the minimum 
legal age of consent, if that is >18 years), with duodenal ulcer(s).
Number of Subjects:
Per treatment group: 265
TAK-438 group: approximately 265 randomized
Lansoprazole group: approximately 265 randomized
Estimated total: 530 randomized subjects
Number of Sites:
Estimated total: approximately 60 in Asia
Dose Levels:
TAK-438 group:
HP+ subjects
(Day 1 to Day 14): TAK-438 20 mg + lansoprazole placebo BID for 
2 weeks, given in conjunction with bismuth-containing quadruple 
therapy (amoxicillin 1 g BID, clarithromycin 500 mg BID, and 
bismuth potassium citrate/bismuth tripotassium dicitrate 600 mg BID) 
for 2 weeks
(Day 15 to Day 42): TAK-438 20 mg + lansoprazole placebo QD for up 
to 4 weeks
HP- subjects
(Day 1 to Day 42): TAK-438 20 mg + lansoprazole placebo QD for up 
to 6 treatment weeks
Lansoprazole group:
HP+ subjects
(Day 1 to Day 14): lansoprazole 30 mg + TAK-438 placebo BID for 
2 weeks given in conjunction with bismuth-containing quadruple 
therapy (amoxicillin 1 g BID, clarithromycin 500 mg BID, and 
bismuth potassium citrate/bismuth tripotassium dicitrate 600 mg BID) 
for 2 weeks
(Day 15 to Day 42): lansoprazole 30 mg + TAK-438 placebo QD for up 
to 4 weeks
HP- subjects
(Day 1 to Day 42): lansoprazole 30 mg + TAK-438 placebo QD for up 
to 6 treatment weeks
Route of Administration:
Oral
Duration of Treatment:
Up to 6 weeks
Period of Evaluation:
Up to 14 weeks
Screening: up to 4 weeks
Treatment period: up to 6 weeks
Follow-up period: up to 4 weeks
Main Criteria for Inclusion:
Subjects with endoscopic evidence of one or more active duodenal ulcer(s) (ie, mucosal defects with white coating 
[including cases associated with blood coagula]) measuring 5 mm or larger in longest diameter within 14 days prior to 
randomization, who have provided (or when applicable their legally acceptable representative has provided) informed 
consent, who are capable of understanding and complying with the study procedures and who agree to use appropriate 
contraception.
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Main Criteria for Exclusion:
Subjects who have hypersensitivity to TAK-438, or related compounds or to proton pump inhibitors (PPIs), 
clarithromycin, amoxicillin, bismuth or lansoprazole; or who have a significant history of CNS, cardiovascular, 
pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, endocrine or hematological disease; or subjects with 
a liver function test > upper limit of normal; or who have any significant results from physical examinations, or 
clinical laboratory results as deemed by the investigator. Subjects that have received HP eradication therapy 30 days 
prior to visit 2 or endoscopic therapy within 30 days prior to visit 1 or also have active gastric ulcer(s) are also 
excluded. 
Main Criteria for Evaluation and Analyses:
1.
Primary Endpoint:

The primary endpoint for this study is the percentage of subjects with endoscopically confirmed healing* of 
duodenal ulcer(s) at Week 4 or 6*.
*Rate of endoscopic healing: defined as the proportion of subjects in whom the disappearance of all white coats 
associated with duodenal ulcers has been endoscopically confirmed.
2.
Secondary Endpoints: 

Percentage of HP+ subjects with successful H pylori eradication after 4 or 6 weeks of treatment, as 
determined by 13C-UBT at F-2.

Percentage of subjects with endoscopic healing of duodenal ulcer at Week 4.

Percentage of subjects with posttreatment resolution of gastrointestinal symptoms associated with duodenal 
ulcer (epigastric pain [postprandial, fasting, nocturnal], abdominal bloating, nausea/vomiting, heartburn, lack 
of appetite) at Weeks 2 through 6.
3.
Additional Endpoints: 
Other efficacy endpoints include:

Quality of Life measurements - Euro Quality of Life-5D-5L (EQ-5D-5L).

Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at either Week 4 or Week 6 
based on their Baseline H pylori status. 

Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at Week 4 based on their 
Baseline H pylori status. 

Percentage of subjects with H pylori infection at Baseline who achieve endoscopically confirmed healing of 
duodenal ulcer either at Week 4 or Week 6 based on their H pylori status at follow-up visit F-2. 

Percentage of subjects with H pylori infection at Baseline who achieve endoscopically confirmed healing of 
duodenal ulcer at Week 4 based on their H pylori status at follow-up visit F-2.
The safety endpoints of this study include adverse events (AEs), laboratory test values, electrocardiogram (ECG), vital 
signs, serum gastrin-17, and pepsinogen I/II values (total and ratio). 
Statistical Considerations:
Efficacy Analysis
For the primary efficacy endpoint of Week 4 or 6 healing rate of duodenal ulcer, a 2-sided 95% confidence interval 
will be constructed for the difference between TAK-438 and lansoprazole treatment groups and its lower bound will 
be compared to the noninferiority margin of -6%.
For the secondary efficacy endpoint of eradication rate of H pylori, a 2-sided 95% CI will be constructed for the 
difference between TAK-438 and lansoprazole treatment groups in subjects who were HP+ at Baseline, and its lower 
bound will be compared to the noninferiority margin of -10%.
The secondary endpoint of healing rate of duodenal ulcer at Week 4 will be compared between TAK-438 and 
lansoprazole treatment groups by constructing a 2-sided 95% CI for the rate difference. The additional secondary 
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endpoints related to gastrointestinal symptoms during treatment will be compared between treatment groups using 
Wilcoxon rank-sum tests.
Analysis of additional endpoints includes hierarchical tests for noninferiority and superiority of the primary endpoint 
and the 1st secondary endpoint. Additionally, Quality-of-Life endpoints will be conducted with an Analysis of 
Covariance model with treatment and baseline H pylori status as factors and baseline as a covariate.
Statistical inference will be performed at 2-sided 0.05 level of significance or via 2-sided 95% CIs. 
Safety Analysis
Safety analysis will be performed by summarizing the incidence of AEs, clinical laboratory tests, vital signs, and 
ECGs. No statistical testing or inferential statistics will be generated. 
Sample Size Justification:
Assuming that the true Week 4 or 6 duodenal ulcer healing rate is 95.5% for both TAK-438 and lansoprazole, and 
assuming that the dropout rate is up to 10%, a sample size of 265 subjects per group in the overall population, 
including no fewer than 238 Chinese subjects per group, will provide at least 80% power to establish noninferiority in 
the Chinese population using a 2-sided 95% CI with a -6% noninferiority margin. This sample size will also provide 
83.9% power to establish noninferiority in the overall population.
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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
Coordinating Investigator
TDC 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 drugs, 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
13C-UBT
13Carbon Urea Breath Test
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under curve
BID
twice daily
C difficile
Clostridium difficile
Cmax
Maximum concentration
CYP
cytochrome P-450
ECG
electrocardiogram
eCRF
electronic case report form
EQ-5D-5L
Euro Quality of Life-5D-5L
F-1
Follow-up 2 weeks posttreatment
F-2
Follow-up 4 weeks posttreatment
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HP+
Helicobacter pylori infected
HP-
non-Helicobacter pylori infected
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
LA
Los Angeles
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
Med ID
medication identification
NSAID
nonsteroidal anti-inflammatory drug
pH4 HTR
pH 4 holding time ratio
PPI
proton pump inhibitor
PPS
per-protocol analysis set
PTE
pretreatment event
QD
once daily
QOL
quality of life
SAE
serious adverse event
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SAP
statistical analysis plan
TEAE
treatment emergent adverse event
ULN
upper limit of normal
3.4
Corporate Identification
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe, TDC Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
Peptic ulcers (gastric and duodenal ulcers) are among major acid-related disorders and are 
accounted for in large part by Helicobacter pylori (H pylori) infection and use of nonsteroidal 
anti-inflammatory drugs (NSAIDs) including low-dose aspirin.
Due to the increased use of NSAIDs including low-dose aspirin in recent years, gastric and 
duodenal ulcers remain a major concern in Asian countries.
The proton pump inhibitors (PPIs), such as lansoprazole, represent the drugs of first choice for 
gastric and duodenal ulcers and are being widely used.
The PPIs inhibit the H+, K+-ATPase enzyme (proton pump) which represents the final step in acid 
secretion by the parietal cells in the gastric mucosa, and produce potent anti-secretory efficacy for 
acid-related disorders. 
However, even with these potent acid-inhibitory effects, the PPIs are not without their limitations 
and have not necessarily produced adequate improvements in extent and speed of symptom relief 
[1]. Indeed, the PPIs appear to leave room for improvement, the reasons being that: 
1. being less resistant to acid exposure and provided as enteric-coated drugs, the PPIs vary in time 
for onset of their action; 
2. about 3 to 5 days are required to obtain maximum acid-inhibitory effects with the PPIs; 
3. Acid-inhibitory effects with the PPIs appear to be satisfactory during daytime, but not 
adequate to inhibit acid regurgitations from the stomach to the esophagus occurring during 
nighttime, leading to nocturnal acid breakthroughs in some individuals; 
4. Metabolized by CYP2C19 associated with polymorphisms, the PPIs are associated with 
varying serum concentrations, thus producing disparate acid-inhibitory effects in extensive 
metabolizers versus poor metabolizers. 
Developed at Takeda Pharmaceutical Company Ltd, TAK-438 belongs to a new class of 
acid-inhibitory agents called “potassium-competitive acid blockers.” 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, and requires no particular pharmacological preparations, such as an 
enteric coating, suggesting that TAK-438 may likely vary less in time for onset of action than the 
PPIs among those receiving the drug. Furthermore, in contrast to the PPIs which take 3 to 5 days to 
produce their maximum acid-inhibitory effects, TAK-438 is expected to produce its maximum 
acid-inhibitory effects in a much shorter time and to produce better outcomes than the PPIs with its 
potent and sustained acid-inhibitory effects. In Japan, TAK-438 has been evaluated for the doses 
ranging between 1mg and 120 mg in a phase 1 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 
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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 NSAIDs (eg, loxoprofen sodium, diclofenac sodium, meloxicam) 
(TAK-438/CPH-003), none of these drugs were shown to significantly affect the pharmacokinetics 
of TAK-438.
Studies of single-dose (TAK-438_101) and repeated-dose (TAK-438_107) TAK-438 were 
conducted in the UK as well, where TAK-438 was evaluated for its safety, pharmacokinetics and 
acid-inhibitory effects in the 7-day repeated-dose study at the doses ranging between 10 mg and 
40 mg. TAK-438 was shown to be well tolerated at the dose of 40 mg in the repeated-dose study, 
with the pH4 HTR on day 7 shown to be similar to that in the repeated-dose study conducted in 
Japan at either of the doses examined, supporting the potent and sustained acid-inhibitory effects 
of TAK-438. Again, in a study evaluating interactions between TAK-438 and clarithromycin 
conducted in the UK (TAK-438_110), repeated-dose clarithromycin was examined for its 
influence on the pharmacokinetics of TAK-438, where, while the plasma concentration of 
TAK-438F increased by 1.35-fold for the maximum concentration (Cmax) and by 1.58-fold for area 
under curve (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 (QD) 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 AG-1749 (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 AG-1749, showing the 
noninferiority of TAK-438 to lansoprazole 30 mg at the doses examined. No particular safety 
concerns were identified with TAK-438 at the doses examined.
A phase 3 randomized, double-blind, multicenter parallel group comparison study 
(TAK-438/CCT-101) in subjects with gastric ulcer was conducted to evaluate the efficacy and 
safety of TAK-438 20 mg QD compared with lansoprazole 30 mg QD. The noninferiority of 
TAK-438 20 mg treatment to lansoprazole 30 mg treatment was verified. Resolution rate of 
heartburn was higher in the TAK-438 20 mg group (96.5%) than in the lansoprazole 30 mg group 
(82.0%). The resolution rate of all other symptoms related to gastric ulcer other than epigastric 
pain was higher in the TAK-438 20 mg group compared with the lansoprazole 30 mg group.
A phase 3 randomized, double-blind, multicenter parallel group comparison study in subjects with 
duodenal ulcer (TAK-438/CCT-102) was conducted to evaluate the efficacy and safety of 
TAK-438 20 mg QD compared with lansoprazole 30 mg QD. For the per-protocol analysis set 
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(PPS) and for all full analysis set (FAS) subjects who completed the study drug, the noninferiority 
of TAK-438 20 mg treatment to lansoprazole 30 mg treatment was indicated with respect to the 
endoscopic healing rate during the 6-week treatment period. Both treatments had favorable effects 
on the resolution rates (>80%) of duodenal ulcer.
Of note, in a phase 3 H pylori eradication study, 7-day treatment with TAK-438 20 mg (n=329) or 
lansoprazole 30 mg (n=321) in combination with amoxicillin 750 mg plus clarithromycin 200 or 
400 mg, H pylori eradication rates were 92.6% and 75.9%, respectively. Furthermore, the first 
50 treatment failures with good compliance received second-line triple-therapy with TAK-438 
20 mg (in combination with amoxicillin 750 mg and metronidazole 250 mg) in an open-label 
manner and an eradication rate of 98% was observed. All treatments were well-tolerated. 
Other phase 3 studies have shown that for the treatment and maintenance of GERD and ulcer 
prevention in subjects receiving concomitant medications, TAK-438 demonstrated clinical 
efficacy that was comparable with that of lansoprazole.
In the completed phase 3 studies to date, 3397 subjects were exposed to TAK-438 10 to 40 mg QD 
for up to 104 weeks. TAK-438 treatment was generally well tolerated, with a similar safety profile 
to that of lansoprazole. Incidences of drug-related treatment-emergent adverse events (TEAEs) 
were low and similar between the TAK-438 and lansoprazole treatment groups. The safety of 
TAK-438 has been demonstrated in a number of clinical studies across several indications 
including the treatment of erosive esophagitis healing, gastric ulcer, duodenal ulcer, H pylori, and 
nonerosive esophageal reflux disease. No significant changes in other laboratory test values, vital 
signs, or electrocardiogram (ECG) findings were observed during the studies.
Potential pharmacological class effects of acid-blocking treatments include hepatic function 
abnormal, bone fracture, Clostridium difficile (C difficile) enteric infection, pneumonia 
neuroendocrine tumors, hypomagnesemia, Vitamin B-12 deficiency, iron deficiency, acute 
interstitial nephritis, and drug interaction affected by gastric pH. Although no clear evidence has 
been identified linking them to TAK-438 treatment, hepatic function abnormal, bone fracture, 
C difficile enteric infection, and drug interaction affected by gastric pH are now considered as 
important potential risks based on the safety profile of drugs with a similar mode of action.
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 with TAK-438, demonstrating that 
TAK-438 is noninferior to lansoprazole at the doses tested (5 mg, 10 mg, 20 mg, and 40 mg), with 
no particular safety concerns identified. The rate of endoscopic healing of erosive esophagitis in 
subjects with more severe disease (Los Angeles [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 results of this study indicated TAK-438 20 mg could produce more potent and sustained 
acid-inhibitory effects than lansoprazole 30 mg, with no safety concerns. Given the disease 
similarities, TAK-438 20 mg was expected to be at least as effective as lansoprazole 30 mg for the 
treatment of duodenal ulcer as it was for erosive esophagitis.
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Thus, it was decided that a phase 3 multicenter, randomized, double-blind study of TAK-438 
20 mg versus lansoprazole 30 mg QD (or double these doses in HP+ subjects as part of an 
eradication regimen) would be implemented to demonstrate the noninferior efficacy of TAK-438 
20 mg in subjects with duodenal ulcer.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
To demonstrate the noninferior efficacy of TAK-438 versus lansoprazole in the treatment of 
subjects with duodenal ulcer.
5.1.2
Secondary Objectives
To demonstrate the noninferiority of HP eradication with TAK-438 versus lansoprazole. 
To compare the safety of TAK-438 versus lansoprazole in subjects with duodenal ulcer.
5.2
Endpoints
5.2.1
Primary Endpoint 
The primary endpoint for this study is the percentage of subjects with endoscopically confirmed 
healing* of duodenal ulcer(s) at Week 4 or 6*.
*Rate of endoscopic healing: defined as the proportion of subjects in whom the disappearance of 
all white coats associated with duodenal ulcers has been endoscopically confirmed.
5.2.2
Secondary Endpoints
Secondary endpoints for this study are:

Percentage of HP+ subjects with successful H pylori eradication after 4 or 6 weeks of 
treatment, as determined by 13C Urea Breath Test (13C-UBT) at F-2 (follow-up 4 weeks 
posttreatment).

Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at Week 4.

Percentage of subjects with posttreatment resolution of gastrointestinal symptoms associated 
with duodenal ulcer (epigastric pain [postprandial, fasting, nocturnal], abdominal bloating, 
nausea/vomiting, heartburn, lack of appetite) at Weeks 2 through 6.
5.2.3
Additional Endpoints
Additional efficacy endpoints include:

Quality of life (QOL) measurement Euro Quality of Life-5D-5L (EQ-5D-5L).

Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at either 
Week 4 or Week 6 based on their baseline H pylori status. 

Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at Week 4 
based on their baseline H pylori status. 
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
Percentage of subjects with H pylori infection at Baseline who achieve endoscopically 
confirmed healing of duodenal ulcer either at Week 4 or Week 6 based on their H pylori status 
at Follow-up visit F-2. 

Percentage of subjects with H pylori infection at Baseline who achieve endoscopically 
confirmed healing of duodenal ulcer at Week 4 based on their H pylori status at Follow-up visit 
F-2.
Safety endpoints include adverse events (AEs), laboratory test values, ECG, vital signs, serum 
gastrin-17, and pepsinogen I/II values (total and ratio).
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group, 
noninferiority study of TAK-438 versus lansoprazole in subjects who have endoscopic evidence of 
duodenal ulcer with or without H pylori infection.
Approximately 530 subjects across approximately 60 sites in Asia will be randomized in a 1:1 ratio 
to either TAK-438 20 mg or to lansoprazole 30 mg (265 subjects per treatment arm). The 
randomization will be stratified by HP status:

TAK-438: 265 subjects. 

Lansoprazole: 265 subjects. 
Treatment Period:
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Dosing will begin on Day 1 after randomization (Visit 2) and last for up to 6 weeks. Study drug 
administration will depend on the H pylori infection status of the subject.
Administration of the 2 treatments will be according to the following regimens:

H pylori infected (HP+) subjects will take TAK-438 20 mg or lansoprazole 30 mg (blinded 
with matching placebo) twice daily (BID) in addition to bismuth-containing quadruple 
therapy (amoxicillin 1 g BID, clarithromycin 500 mg BID, and bismuth potassium 
citrate/bismuth tripotassium dicitrate 600 mg [equivalent to 220 mg bismuth] BID) for 
2 weeks. After 2 weeks of eradication therapy, subjects will be required to take only the 
TAK-438 or lansoprazole once a day (QD) for up to 4 weeks (ie, up to a total of 6 weeks of 
treatment). The subject remains in the same treatment arm throughout the study duration. 

Non-H pylori infected (HP-) subjects will take TAK-438 or lansoprazole (blinded with 
matching placebo) QD for up to 6 weeks.
For all subjects, ulcer healing rates will be assessed by endoscopy at Weeks 4 and 6 of treatment. 
With or without endoscopic evidence of duodenal ulcer healing, the treatment duration of the study 
is no more than 6 weeks. 
Subjects (HP+ or HP-) with endoscopic healing of duodenal ulcer(s) at Week 4 or Week 6 will 
discontinue treatment at that time, and enter into the Follow-up period.
Subjects (HP+ or HP-) without ulcer healing by Week 6 of treatment period will discontinue 
treatment at Week 6 and enter into the Follow-up period.
Follow-up Period:
The subjects to be followed up will include both HP+ and HP- subjects, with or without confirmed 
ulcer healing during the treatment period.
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The recovery of serum gastrin-17 level and pepsinogen I/II ratio in the Follow-up period will be 
monitored for a maximum of 4 weeks. The Follow-up period ends when the recovery of serum 
gastrin-17 level and pepsinogen I/II ratio are confirmed or at the end of the 4-week Follow-up.
All HP+ subjects will provide a follow-up 13C-UBT at the F-2 visit to ascertain HP eradication 
status.
For subjects with no ulcer healing at Week 6 of treatment, the investigator may follow local 
clinical practice and these subjects may be treated with another course of PPI or other anti-acid 
secretory agents or antibiotics, during the safety follow-up period (please see Table 7.a). This 
should be documented during the F-2 visit.
Figure 6.a
Schematic of Study Design
6.2
Justification for Study Design, Dose, and Endpoints
For the subject population studied
Treatment Period
Up to 6 weeks
All subjects 
will have a 
gastrin and 
safety 
follow-up for 
up to 4 weeks.
All HP positive 
subjects will 
undergo a 
breath test for 
H pylori.
Follow-up Period
Up to 4 weeks
TAK-438 20 mg BID (part of HP 
bismuth-containing quadruple
eradication therapy) for 2 weeks, 
followed by 20 mg QD 
Endoscopic
healing at 
Week 4 or 
Week 6
Screening Period
Up to 28 days
Randomization
TAK-438 20 mg QD
Lansoprazole 30 mg QD
HP
+
HP-
Lansoprazole 30 mg BID (part of 
HP bismuth-containing quadruple
eradication therapy) for 2 weeks, 
followed by 30 mg QD
Screening
Assessments 
including 
Informed 
Consent
Endoscopy (Week 4 and Week 6)
No 
Endoscopic
healing at 
Week 6
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Subjects will be included in the study if they are diagnosed as having duodenal ulcer (ie, mucosal 
defects with white coat [including the case associated with blood coagula]) and having one or more 
duodenal ulcers associated with a white coat measuring 5 mm or larger in longest diameter. 
For study design and sample size used
(1) Study design
This study is designed as a randomized, double-blind, parallel-group comparison of TAK-438 
20 mg versus the PPI lansoprazole 30 mg, a first drug of choice for duodenal ulcer as control to 
demonstrate the noninferiority of TAK-438. Subjects with HP+ disease will receive double these 
doses as part of a BID H pylori eradication regimen for 2 weeks.
For all subjects, serum gastrin-17 and pepsinogen I/II recovery status will be monitored during the 
Follow-up period (Visits F-1 [follow-up 2 weeks posttreatment] and F-2), which is planned to last 
up to 4 weeks but to be completed at the time point at which serum gastrin-17 level and pepsinogen 
I/II ratio recovery has been confirmed in these subjects. This is to monitor the dose-dependent 
elevated serum gastrin levels observed in TAK-438 subjects. The 4-week duration of monitoring 
was selected so that subjects who remain HP+ at F-2 may be further treated with alternative HP 
eradication regimens. Data arising from these alternative regimens will not be included in the 
study data.
(2) Sample size
For a description of the rationale for sample size determination, refer to Section 13.3.
For doses of the study drugs 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 at doses 5 mg, 10 mg, 20 mg, 
and 40 mg, and demonstrated its noninferiority to lansoprazole 30 mg at either of the doses 
examined after 4 weeks of treatment, 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. As the clinically recommended dose of lansoprazole 
for duodenal ulcer is the same as that for erosive esophagitis (30 mg), the clinically recommended 
dose of lansoprazole for duodenal ulcer was determined as 30 mg.
The quadruple therapy is a well-established treatment regimen in conjunction with a PPI for the 
treatment of H pylori infection.
For timing of administration 
In a phase 1 single-dose study of TAK-438 in healthy male volunteers conducted in Japan 
(TAK-438 CPH-001 study), 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, 
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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 as a once-daily 
regimen.
It was thus decided that TAK-438 would be given after breakfast or dinner as a once-daily 
regimen. The preference is for the dose to be given after breakfast; however, if the first 
randomization visit was scheduled in the late afternoon, it is acceptable for the dose to be taken 
after dinner.
For duration of treatment used
The PPIs, the first drug of choice for duodenal ulcer, have been approved for use for 6 weeks. 
Thus, the study was so designed to allow the study medication to be given for up to 6 weeks but to 
be completed if endoscopic healing of duodenal ulcer has been confirmed in the subjects after 
4 weeks of treatment.
For endpoints used
1) Primary endpoint
Endoscopic healing of duodenal ulcer represents the goal of treatment for duodenal ulcer, for 
which lansoprazole 30 mg has been approved for use QD for up to 6 weeks.
Thus, the primary endpoint was defined as the rate of endoscopic healing of duodenal ulcer during 
the 6-week treatment period.
2) Secondary endpoints
As eradication of H pylori is standard of care in HP+ subjects, eradication of H pylori has been 
included as the main secondary endpoint.
As TAK-438 is expected to produce more sustained, potent acid-inhibitory effects and earlier 
healing of duodenal ulcer than the PPIs such as lansoprazole 30 mg, before 6 weeks of treatment, 
ie, the duration of treatment approved for the PPIs, the rate of endoscopic healing of duodenal 
ulcer after 4 weeks of treatment was included as a secondary endpoint.
Additionally, as duodenal ulcer may be associated with gastrointestinal symptoms, the occurrence 
of duodenal ulcer-associated symptoms (epigastric pain [postprandial, fasting, nocturnal], 
abdominal bloating, nausea/vomiting, heartburn, lack of appetite) is also included as secondary 
endpoints.
3) Additional Endpoints
Additional endpoints include measurement of QOL, and other endpoints designed to minimize the 
potentially confounding impact of H pylori eradication. 
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4) Safety Endpoints
Safety endpoints include AEs, SAEs, laboratory test values, ECG, vital signs, serum gastrin-17 
and pepsinogen I/II values.
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 drug that 
indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of 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 Sites
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. Subjects with endoscopic evidence of active duodenal ulcer(s) (ie, mucosal defects with white 
coating [including cases associated with blood coagula as long as there is no active bleeding]) 
measuring 5 mm or larger in longest diameter within 14 days prior to randomization. 
4. The subject is male or female, at least 18 years of age (or at least the minimum legal age of 
consent, if that is >18 years), with duodenal ulcer(s) at the time of signing informed consent.
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 4 weeks after last dose of study drug. 
*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 90 days prior to the treatment 
period.
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 dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling), or who may have consented under duress. 
4. The subject has, in the judgment of the investigator, clinically significant abnormal physical 
examinations, hematological parameters of hemoglobin, hematocrit, or erythrocytes at 
Screening. 
5. The subject has a history or clinical manifestations of significant CNS, cardiovascular, 
pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, endocrine or hematological 
disease that, in the opinion of the investigator, would confound the study results or 
compromise subject safety.
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6. The subject has a history of hypersensitivity or allergies to TAK-438 or lansoprazole, 
including any associated excipients. The subject has a known hypersensitivity to any 
component of the formulation of TAK-438 or lansoprazole, for example, 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 treatment period. 
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 4 weeks after participating in this study; or intending to donate ova during such time 
period. 
10. Previous exclusion criterion 10 in Amendment No. 02 has been deleted.
11. Subjects who have been treated with H pylori eradication therapy within 30 days prior to study 
treatment.
12. Previous exclusion criterion 12 in Amendment No. 02 has been deleted.
13. Subjects with a diagnosis of duodenal malignancy or a duodenal ulcer whose morphology 
suggested malignancy as evident by endoscopy within 14 days prior to randomization.
14. Subjects suspected of having acute gastro-duodenal mucosal lesions (AGDML) as evident by 
endoscopy within 14 days prior to randomization.
15. Subjects in whom a linear ulcer (including a linear ulcer scar) is confirmed by endoscopy 
within 14 days prior to randomization.
16. Subjects with active postoperative (eg, endoscopic mucosal resection/endoscopic submucosal 
dissection) ulcer(s) as confirmed by endoscopy within 14 days prior to randomization.
17. Subjects in whom gastric ulcer is confirmed by endoscopy within 14 days prior to 
randomization.
18. Subjects with ulcers for which medical therapy alone is not indicated (eg, perforation, pyloric 
stenosis, duodenal stenosis, major bleeding).
19. Subjects who have undergone therapeutic upper GI endoscopic therapy (eg, endoscopic 
hemostasis, excision biopsy) within 30 days prior to visit 1. Biopsy done for diagnostic 
purposes may be permitted. 
20. Subjects with Zollinger-Ellison syndrome or gastric acid hypersecretion or those with a history 
of gastric acid hypersecretion.
21. Subjects who have undergone major surgical procedures within 30 days prior to Visit 1 or are 
scheduled to undergo surgical procedures that may affect gastric acid secretion (eg, abdominal 
surgery, vagotomy or craniotomy).
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22. The subject has a history of malignancy or was treated for malignancy within 5 years before 
the start of the visit 1 (the subject may be included in the study if he/she has cured cutaneous 
basal cell carcinoma or cervical carcinoma in situ). 
23. The subject has a known acquired immunodeficiency syndrome or hepatitis infection, 
including hepatitis virus carriers (hepatitis B surface antigen [HBsAg] or hepatitis C virus 
[HCV]-antibody-positive) (the subject may be included in the study if he/she is HCV-viral 
load-RNA-negative).
24. Subjects for whom laboratory tests performed prior to randomization revealed any of the 
following abnormalities:
a) Creatinine levels: >2 mg/dL (>177 µmol/L).
b) Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin 
levels: > the upper limit of normal (ULN).
(Note: 1 retest is allowed; if still >ULN, subject should be excluded.)
25. Subjects with hypersensitivity to PPIs, bismuth, clarithromycin, or amoxicillin. Skin testing 
may be performed according to local standard practice (for HP+ subjects only).
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. The investigator should review any additions or 
changes in medications. All medications should be recorded in the source documents or equivalent 
and then transcribed onto the appropriate electronic case report forms (eCRFs).
Medications and treatments that are not permitted prior to or during the study, including the time 
periods during which they must be withdrawn are shown in Table 7.a below.
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Table 7.a
Excluded Medications and Treatments
Excluded Medication/Treatment
Beginning of Exclusion
End of Exclusion
Other investigational drugs or drugs administered due 
to participation in another clinical trial
90 days prior to study treatment
End of Follow-up
Medications that may interfere with 13C-UBT 
(metronidazole, bismuth preparations, ecabet sodium 
hydrate) (a)
At least 14 days prior to 
13C-UBT (at Screening), and 
through to end of 13C-UBT 
testing at F-2 visit
End of 13C-UBT
(HP+ subjects only)
Antibiotics
30 days prior to 13C-UBT (at 
Screening) and through to end 
of 13C-UBT testing at F-2 visit, 
with the exception of subjects 
with non-healed ulcer who
received further treatment at the 
end of study treatment period
End of Follow-up
Antiprotozoals
30 days prior to study treatment 
End of Follow-up
Non–study-related H pylori eradication therapy
30 days prior to study treatment 
End of Follow-up 
Medications contraindicated with clarithromycin: 
pimozide, ergot derivatives, tadalafil, terfenadine, 
astemizole, cisapride simvastatin, lovastatin, 
atorvastatin etc.
Note: other statins such as fluvastatin, pravastatin, and 
rosuvastatin may be allowed but used with caution 
30 days prior to study treatment 
(applies to HP+ subjects only)
End of HP eradication 
therapy
(HP+ subjects only)
Strong inhibitors or inducers of CYP3A4 (eg, 
itraconazole, ketoconazole, indinavir, nelfinavir, 
ritonavir, saquinavir, telithromycin)
30 days prior to study treatment
End of HP eradication 
therapy (HP+ subjects 
only)
Non–study-related PPIs and H2 receptor antagonists.
14 days prior to study treatment 
and at least 14 days prior to 
13C-UBT (at Screening), with 
the exception of subjects with 
non-healed ulcer who received 
further treatment at the end of 
study treatment period
End of Follow-up 
Surgical procedures that could affect gastric acid 
secretion (eg, upper gastrointestinal surgery, 
vagotomy)
Start of study treatment
End of Follow-up
NSAIDs (c)
Start of study treatment
End of Follow-up
Agents affecting digestive organs, including 
muscarinic M3 antagonists, prokinetics, 
anticholinergic agents, prostaglandins, anti-gastrin 
agents or mucosal-protective agents. (b)
Start of study treatment
End of Follow-up
Atazanavir sulfates; rilpivirine hydrochloride 
(contraindicated with TAK-438)
Start of study treatment
End of Follow-up
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Corticosteroids (c), anti-platelets (includes low-dose 
aspirin) (c), anticoagulants (c), psychotropics (c), 
antidepressants (c), bisphosphonates (c, d), 
methotrexate and probenecid* (contraindicated with 
bismuth).
Start of study treatment
End of Follow-up
* For probenecid - End of 
HP eradication therapy
Footnotes are on the following page.
(a) Prohibited period is 14 days prior to any 13C-UBT or as otherwise stated in package insert for 13C urea breath 
testing kit package to be used.
(b) The use of gastric mucosal protective agents may be allowed during the Follow-up period.
(c) Except subjects that were using these agents before signing the informed consent form at visit 1 and the dose and 
administration will not be changed during the study.
(d) 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 who have no GI inflammation or history of such.
7.4
Diet, Fluid, Activity Control 
Subjects should be instructed as follows:

To adhere closely to the scheduled visits, seek medical consultation, and undergo 
predetermined laboratory tests. 

To take study drug(s) after breakfast or dinner at about the same time as he/she usually does 
with approximately 240 ml water (for HP- subjects and for HP+ after the 2-week eradication 
therapy period). For the HP+ subjects in first 2 weeks of HP eradication therapy period, to 
ensure that bismuth and TAK-438/lansoprazole are to be taken 0.5 hour before breakfast and 
dinner. Breakfast and dinner should be completed within 0.5 hour before taking clarithromycin 
and amoxicillin, ie, 1 hour after bismuth and TAK-438/lansoprazole dosing.

To present to the clinic in a fasting state when he/she is scheduled for laboratory tests and/ or 
endoscopy. On such study visit days, subjects will be instructed to take their dose of study 
drug(s) (if appropriate) after study procedures are completed.

Subjects should be instructed according to Section 8.1.3.1 (Missed Doses) and Section 9.2
(Compliance) at every study visit. Details of any missed or forgotten doses should be reported 
to the Investigator or designee at the subsequent study visit.

To store all medications in a cool, dry, safe place which is out of reach of children and to bring 
all study supplies (empty / used / unused drug packets) to each study visit.

If during study participation the subject is prescribed medication by a nonstudy physician or 
other healthcare professional, he/she should consult the investigator beforehand. Such 
treatment or consultation, or the use of over-the-counter medicine should be reported at the 
next study visit.

To 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 an SAE, the subject or his/her family should contact the investigator as soon as 
possible.
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
To use contraception without failure. (A female subject of childbearing potential from signing 
of informed consent throughout the duration of the study and 4 weeks after the final dose of the 
study drug.) Pregnancy in a female subject should be reported immediately. 

Not to donate blood during the study, and to report on any such donation immediately.

To 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 eCRF using the following categories. For screen failure subjects, refer to 
Section 9.1.12.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE 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 PTE or AE.

Liver Function Test (LFT) Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any time 
during study medication treatment:
–
ALT, AST, or total bilirubin >2 × ULN.
2. Significant protocol deviation. The discovery after 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.
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.
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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: noncompliance.
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 study material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term “study drug” refers to any and all of the drugs administered as part of the 
study, including TAK-438 or lansoprazole (and their matching placebo) as well as the companion 
drugs given for H pylori infection eradication in HP+ subjects. The properties of TAK-438 (20 mg 
tablets and matching placebo tablets) and lansoprazole (30 mg capsules and matching placebo 
capsules) are detailed in Table 8.a. These drugs will be packaged in a blinded fashion. The 
companion drugs refer to amoxicillin (500 mg tablets/capsules), clarithromycin (500 mg tablets) 
and bismuth potassium citrate/bismuth tripotassium dicitrate (300 mg tablets/capsules) which will 
be packaged in an open fashion.
8.1.1.1
TAK-438 and Lansoprazole
TAK-438 and lansoprazole will be foil/foil blistered packaged into child-resistant blister cards. 
Each blister card will contain 20 tablets (containing either TAK-438 or placebo) and 20 capsules 
(containing either lansoprazole or placebo). 
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.
TAK-438 20 mg Active and Placebo Tablets
The chemical name of TAK-438 is: 
1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrrol-3-yl]-N-methyl methanamine 
monofumarate. The generic name for TAK-438 is vonoprazan. The active study drug, TAK-438 
(vonoprazan) 20 mg and matching placebo are provided as pink, film-coated tablets manufactured 
by Takeda Pharmaceutical Company, Osaka, Japan.
Lansoprazole 30 mg Active and Placebo Capsules
The chemical name of lansoprazole (AG-1749) is:
2-[(RS)-[[3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl]sulfinyl]-1H-benzimidazole. 
Lansoprazole 30 mg will have a dual supply chain. Lansoprazole 30 mg will be manufactured by 
Tianjin Takeda, Tianjin, China, and matching placebo will be manufactured by Takeda 
Pharmaceutical Company, Osaka, Japan, and will be supplied to all investigational sites in China. 
Takeda Pharmaceutical Company, Osaka, Japan, will manufacture lansoprazole 30 mg and 
matching placebo for all other countries. All lansoprazole 30 mg and matching placebo will be 
supplied as a white colored capsule.
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Table 8.a
TAK-438 and Lansoprazole Properties 
Study medication form
Description
Manufacturer and Location
TAK-438 20 mg tablet
Pale red film-coated tablet 
scored on both sides
Takeda Pharmaceutical Company Limited, Osaka, 
Japan
TAK-438 20 mg matching 
placebo tablet
Pale red film-coated tablet 
scored on both sides 
Takeda Pharmaceutical Company Limited, Osaka, 
Japan
Lansoprazole 30 mg 
capsule
White capsule 
Tianjin Takeda Pharmaceuticals Co., Ltd, China (will 
be supplied to China) / Takeda Pharmaceutical 
Company Limited, Osaka, Japan (will be supplied to 
countries except for China)
Lansoprazole 30 mg 
matching placebo capsule
White capsule 
Takeda Pharmaceutical Company Limited, Osaka, 
Japan
The TAK-438 tablets and the lansoprazole capsules are difficult to distinguish from their matching 
placebos by their appearance.
8.1.1.2
Companion Drugs (for H pylori Positive Subjects Only)
Bismuth-containing quadruple therapy (amoxicillin 1 g BID, clarithromycin 500 mg BID, and 
bismuth potassium citrate/bismuth tripotassium dicitrate 600 mg BID) will be provided by sponsor 
or sourced by other means. 
8.1.1.3
Sponsor-Supplied Study Drugs
All drugs referenced in Section 8.1.1.1 and Section 8.1.1.2 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 medications 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 duodenal ulcer 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.
8.1.2
Storage
TAK-438, lansoprazole and matching placebo should be stored at 25°C; with excursions permitted 
15°C to 30°C. Protect from moisture and humidity. These drugs are to remain in their blister cards 
until time of dosing. Companion drugs should be stored according to the storage conditions on 
each label.
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All sponsor-supplied study drugs must be kept in an appropriate, limited-access, secure place until 
it is used or returned to the sponsor or designee for destruction. All sponsor-supplied study 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 excursions must be reported to the sponsor or designee.
8.1.3
Dose and Regimen
Subjects who qualify for the study will be randomly assigned to receive either TAK-438 or 
lansoprazole. 
At the randomization visit/ Visit 2, H pylori positive subjects will receive 2 blister cards, each card 
containing 20 tablets of TAK-438 (or placebo tablets) and 20 capsules of lansoprazole (or placebo 
capsules). Subjects will be required to take 1 tablet (containing either TAK-438 or placebo) and 
1 capsule (containing either lansoprazole or placebo) twice daily (BID) for 2 weeks. HP+ subjects 
will also receive a 2-week supply of companion drugs (amoxicillin 1 g, clarithromycin 500 mg, 
and bismuth potassium citrate/bismuth tripotassium dicitrate 600 mg), to be taken twice a day BID 
for 2 weeks. Subjects will be instructed to take bismuth potassium citrate/bismuth tripotassium 
dicitrate 600 mg and 1 dose of TAK-438 or lansoprazole BID, 0.5 hours before taking breakfast 
and dinner. Subjects will be advised to complete their meals (breakfast and dinner) within 
0.5 hours. Clarithromycin 500 mg and amoxicillin 1 g are to be taken BID after meals, ie, 1 hour 
after bismuth and study drug dosing. After completing 2 weeks of HP eradication therapy, subjects 
will follow the same dosing regimen as H pylori negative subjects (1 dose daily, described below) 
until the end of treatment period. 
H pylori negative subjects will be dispensed 1 blister card containing TAK-438 or lansoprazole 
(with appropriate placebo) after randomization at Visit 2 and at subsequent visits as required. HP-
subjects will be required to take 1 tablet (containing either TAK-438 or placebo) and 1 capsule 
(containing either lansoprazole or placebo) daily (QD) after breakfast or dinner at about the same 
time as he/she usually does, with approximately 240 mL water. The preference is for the dose to be 
given after breakfast; however, if the first randomization visit was scheduled in the late afternoon, 
it is acceptable for the dose to be taken after dinner.
Subjects should be fasted for laboratory tests and/ or endoscopy. On such study visit days, subjects 
will be instructed to take their dose of study drugs (if appropriate) after study procedures are 
completed.
Table 8.b describes the dose and tablet/capsule count that will be provided to each group. 
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Table 8.b
Dose Regimen of Sponsor-Supplied Drugs
Treatment 
Group Description
Dose
Treatment Description
Active
Placebo
A1
TAK-438
(HP- subjects for 6 weeks)
TAK-438 20 mg 
QD
1 TAK-438 20 mg 
tablet QD
1 placebo matching 
lansoprazole 30 mg 
capsule QD
A2
TAK-438 
(HP+ subjects in first 
2 weeks)
TAK-438 20 mg 
BID
1 TAK-438 20 mg 
tablet BID, with 
amoxicillin 1 g BID, 
clarithromycin 500 mg 
BID, and bismuth 
potassium 
citrate/bismuth 
tripotassium dicitrate 
600 mg, BID
1 placebo matching 
lansoprazole 30 mg 
capsule BID
(HP+ subjects in 
Weeks 3-6)
TAK-438 20 mg 
QD
1 TAK-438 20 mg 
tablet QD
1 placebo matching 
lansoprazole 30 mg 
capsule QD
B1
Lansoprazole
(HP- subjects for 6 weeks)
Lansoprazole 
30 mg QD
1 lansoprazole 30 mg 
capsule QD
1 placebo matching 
TAK-438 20 mg tablet 
QD
B2
Lansoprazole
(HP+ subjects in first 
2 weeks)
Lansoprazole 
30 mg BID
1 lansoprazole 30 mg 
capsule BID with 
amoxicillin 1 g BID, 
clarithromycin 500 mg 
BID, and bismuth 
potassium 
citrate/bismuth 
tripotassium dicitrate 
600 mg, BID
1 placebo matching 
TAK-438 20 mg tablet 
BID
(HP+ subjects in 
Weeks 3-6)
Lansoprazole 
30 mg QD
1 lansoprazole 30 mg 
capsule QD
1 placebo matching 
TAK-438 20 mg tablet 
QD
8.1.3.1
Missed Doses
Subjects should be instructed that all doses of TAK-438 or lansoprazole and companion drugs 
should be taken on time. If any dose is missed inadvertently it is acceptable for that dose to be 
taken within 6 hours of the time that it was due. If more than 6 hours have passed since the dose 
was due, it should not be taken. 
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drugs, to or by 
a study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
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All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0, Pretreatment 
Events and Adverse Events.
SAEs associated with overdose should be reported according to the procedure outlined in Section 
10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically. 
8.2
Study Drug Assignment and Dispensing Procedures
An interactive web response system (IWRS) 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 study drugs after study completion.
The investigator or investigator’s designee will access the IWRS at Screening visit 1 to obtain the 
subject study number. 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 that was assigned at 
screening. The medication identification (Med ID) number of the study drugs to be dispensed will 
then be provided via the IWRS. 
If sponsor-supplied drugs are lost or damaged, the site can request a replacement from IWRS. 
(Refer to IWRS manual provided separately.) At subsequent drug-dispensing visits, the 
investigator or designee will again contact the IWRS to request additional study drug(s) for a 
subject. 
Please refer to the IWRS user guide for the details of the Med ID number assignments for the study 
drugs.
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, stratified 
by HP status using IWRS.
8.4
Investigational Drug Blind Maintenance
The blinding for TAK-438 and lansoprazole will be maintained using the IWRS. 
8.5
Unblinding Procedure
The blinding for TAK-438 and lansoprazole shall not be broken by the investigator unless 
information concerning the investigational drug is necessary for the medical treatment of the 
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subject. In the event of a medical emergency, the investigator will be able to access IWRS to 
determine subject’s treatment group assignment. The investigator will, whenever possible, discuss 
options with the medical monitor before unblinding.
The sponsor must be notified as soon as possible if the drug blinding 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, drug treatment 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 drugs are used in accordance 
with the approved protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drugs, 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 drugs, 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.
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 or designee must record the current inventory of all sponsor-supplied drugs on a 
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 
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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 drug accountability log will include all required 
information as a separate entry for each subject to whom sponsor-supplied drugs are 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 (or age in countries where 
collection of birth date is not allowed), sex, race as described by the subject, and smoking status, 
drinking status, history of consumption of caffeine-containing drinks, history of H pylori
eradication therapy (eg, triple therapy with PPI + amoxicillin + clarithromycin) at Screening. 
Additionally, characteristics of the current duodenal ulcers should be captured as shown in 
Table 9.a.
Table 9.a
Characteristics of Current Duodenal Ulcers
Evaluation
Finding
Location (a)
Superior part (including bulb), descending part
Number of ulcers found
<enter number>
Morphology (a)
Circular, ellipsoidal, other
Size (a)
Minuscule, <5 mm; minor, 5 mm/<10 mm; intermediate, 10 mm/≤20 mm; 
large, >20 mm/<30 mm; giant ≥30 mm 
(a) In case of multiple lesions, information needs to be obtained on the largest of the lesions.
9.1.2.1
History of Duodenal Ulcers
Information needs to be obtained on the following:

Date of onset of current ulcers.

Use of NSAIDs or low-dose aspirin (except topical preparations) at the time of ulcer onset. If 
any of these agents was being used by the subject at the time of ulcer onset, the principal or 
co-investigator should record the agent(s) used in the medication history and/or as concomitant 
medications (see Section 9.1.6) in the eCRF.
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
Primary/recurrent ulcers (if recurrent, obtain information on the date of onset of previous 
ulcers).
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). 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 30 days prior to signing of informed 
consent.
Medication history will include the following medications if stopped within 30 days prior to 
visit 1, note that information on the NSAID(s) and low-dose aspirin used should also be obtained 
between onset of current ulcers and signing of informed consent:

Agents affecting the digestive organs (PPIs, Histamine H2 receptor antagonists, muscarinic M3
receptor antagonists, gastrointestinal prokinetic agents, anti-cholinergic agents, 
prostaglandins, anti-gastrin agents, gastric mucosal protective agents).

H pylori eradication therapy (eg, triple therapy with PPI + 2 antibiotics).

Atazanavir sulfates.

Corticosteroids.

Anti-platelet agents (including low-dose aspirin).

Anticoagulants.

Psychotropics.

Antidepressants.

NSAIDs.

Bisphosphonates.
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; 
(10) lymph nodes; and (11) other. All subsequent physical examinations should assess clinically 
significant changes from the baseline examination.
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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 Schedule of Study Procedures (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 drug. 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 drug (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, ECG, or physical 
examination abnormalities noted at the Screening examination. The condition (ie, diagnosis) 
should be described.
9.1.8
Procedures for Clinical Laboratory Samples 
Clinical laboratory tests are shown in Table 9.b. All samples will be collected in accordance with 
acceptable laboratory procedures. The maximum volume of blood at any single visit is 
approximately 25 mL, and the approximate total volume of blood for the study is 93 mL, 
depending on the subject’s number of follow-up visits. Details of these procedures and required 
safety monitoring will be given in the laboratory manual. 
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Table 9.b
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cells
White blood cells
Hemoglobin
Hematocrit
Platelets
White blood cell fractions 
(neutrophils, eosinophils, 
basophils, monocytes, 
lymphocytes)
ALT (fasting)
Albumin
Alkaline phosphatase (ALP) (fasting)
AST (fasting)
Total bilirubin (fasting)
Direct bilirubin (fasting)
Total cholesterol (fasting)
Triglycerides (fasting)
Calcium
Chloride
Creatinine
Creatine kinase
Blood urea nitrogen (BUN)
γ-Glutamyl transferase (GGT)
Serum gastrin-17 (fasting)
Glucose (fasting)
Inorganic phosphate
Serum iron
Lactate dehydrogenase (LDH)
Magnesium
Pepsinogen I/II (fasting) (a)
Potassium
Total protein
Sodium
Uric acid (fasting)
Vitamin B12
Hepatitis B & C Analysis 
HBsAg
HCV antibody
HCV-viral load-RNA (b)
Appearance
Color
pH
Specific gravity
Ketones
Protein
Glucose
Nitrite
Urobilinogen
Blood
Other: 
13C-UBT
Serum
Urine
Female subjects if menopause is suspected only
–
Follicle-stimulating hormone (FSH)
Female subjects of child-bearing potential only
–
hCG (for pregnancy)
(a) This includes pepsinogen I, pepsinogen II and pepsinogen I/II ratio.
(b) Subjects with negative HCV antibody test results may be randomized before HCV-viral load-RNA test results are 
available. If the HCV-viral load-RNA test result is positive, the subject will be withdrawn from the study.
The central laboratory will perform laboratory tests for hematology, serum chemistries, hepatitis 
and urinalysis. The results of the laboratory tests will be returned to the investigator, who is 
responsible for reviewing and filing these results. Refer to Appendix A for the laboratory test 
schedule at each study visit.
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If subjects experience an increase in any one of ALT, AST or total bilirubin >2 × ULN, the study 
drug shall be stopped due to the discontinuation criteria having been met (Section 7.5). Follow-up 
laboratory tests (at a minimum, serum alkaline phosphatase, ALT, AST, total bilirubin, γ-glutamyl 
transferase, and INR) should be performed within a maximum of 7 days and preferably within 
48 to 72 hours after the abnormality was found.
(Note for ALT/AST and total bilirubin: >ULN to ≤2 × ULN. Kindly re-test LFT in 2 weeks to 
monitor abnormal LFT. This abnormal LFT value should not be reported as AE unless is clinically 
significant. An unscheduled visit may be performed if necessary.)
TAK-438 or lansoprazole may be associated with increases in serum gastrin-17 and pepsinogen 
I/II levels. Thus, all subjects will be examined for gastrin-17 and pepsinogen I/II levels (total and 
ratio) to investigate the magnitude of these increases during the Treatment and Follow-up periods. 
Increases in serum gastrin and pepsinogen I/II levels are physiological responses to gastric acid 
suppression and elevation in gastric content pH, due to the pharmacological action of the study 
drugs.
To establish H pylori infection status, a 13C-UBT will be performed via the central laboratory. 
Exhaled air samples will be taken in accordance with instructions for use of central analysis to test 
for H pylori infection status determination.
Additional blood may be collected per the investigator’s discretion.
Local laboratories may be used to perform laboratory tests for HBV, HCV and LFT tests, etc, only 
under special circumstances, on case by case basis with sponsor’s agreement. The Investigator will 
maintain a copy of the laboratory accreditation and the reference ranges for the laboratory used.
Please refer to Section 10.2.3 for the appropriate guidance on Reporting of Abnormal LFTs as 
SAEs.
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:
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Barrier methods (each time the subject has 
intercourse) where applicable (a):
Intrauterine devices (IUDs):
Cap (plus spermicidal cream or jelly) PLUS 
male condom 
Diaphragm (plus spermicidal cream or jelly) 
PLUS male condom 
Copper T 
(a) Barrier methods are only applicable in countries where spermicide is 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, donation of ova, and sperm donation 
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). 
Female subjects must have a negative urine hCG pregnancy test on Day 1 prior to receiving any 
dose of study medication.
9.1.10 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drugs 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. 
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 
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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.
If a routine ECG is done within 14 days prior to randomization, it can be used as study data.
9.1.12 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible prior to randomization, the investigator should complete 
the eCRF. The IWRS should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria.

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal.

Study termination.

Other.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.13 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment period.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
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.
9.1.14 Endoscopy 
Endoscopy should be performed while subjects are fasted and according to the usual practice of the 
institution. Use of pre-medications for endoscopy (e.g. analgesics, local anesthetics, 
anticholinergic agents, sedatives, anticholinergics/antispasmodics, antifoaming agents) may be 
allowed at the discretion of the Investigator as per local standard practice.
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During endoscopy the Investigator, or designee, should ensure that the duodenal mucosa is 
observed for a sufficient duration that the subject’s eligibility is confirmed and ensure that any 
white coat (including the case associated with blood coagulation, with no active bleeding) present 
in the subject is measured for its longest diameter using the endoscopic clamp or open biopsy 
forceps as a measure and determine the characteristics of current ulcers in accordance with 
Section 9.1.2. The Investigator should judge the ulcers as “Healed” or “Unhealed” based on
endoscopy findings from Visit 4 onward. Digital images of the current ulcers 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.
To ensure the accuracy of the duodenal ulcer evaluation, a second review process of the endoscopy 
images will be established at each site. The first reviewer, ie, the endoscopist, should take 
sufficient images or videotape the process at each endoscopic examination. The second reviewer 
will evaluate the duodenal ulcer according to the endoscopic images. 
Preferably, the principal investigator performs as the second reviewer and conducts the second
review in a timely manner after the endoscopy is performed by the first reviewer who is a 
subinvestigator in this study.
In cases where the principal investigator is the first reviewer, a subinvestigator at the same site can 
be delegated as the second reviewer and conducts the second review in a timely manner.
Only investigators (either principal investigators or subinvestigators) can be delegated as the 
second reviewer.
If the evaluations of duodenal ulcer by the 2 reviewers are consistent, this result becomes the final 
report. If not, the 2 reviewers will discuss their findings and reach a consensus, which will then 
become the final report.
After the endoscopy, the Investigator should promptly record any findings or observations in the 
subject’s medical record.
Study-specific endoscopy may be waived at the investigator’s discretion if endoscopy with 
associated images has been performed within 14 days before Day 1.
9.1.15 Gastrointestinal Symptoms of Duodenal Ulcer and Quality of Life
Any gastrointestinal symptoms related to duodenal ulcer (epigastric pain [postprandial, 
fasting/nocturnal], abdominal bloating, nausea/vomiting, heartburn, lack of appetite) will be 
captured at the start of the treatment period (Visit 2). At all visits from Visit 2 through the 
completion of the study drug administration, symptoms noted at Visit 2 will be followed up. If any 
symptom resolved during the treatment period, the date of resolution will be recorded in the eCRF.
Additionally, during study visits the EQ-5D-5L will be completed before all other procedures at 
that study visit. This questionnaire will be available in the local language in a paper format. It 
should be completed by the subject directly while attending the study visit.
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9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study drug containers/unused medications to each dispensing 
site visit. Investigators or designee should perform subject treatment compliance checks by 
reviewing the returned medications. If a subject is persistently noncompliant with the study drug 
(eg, at more than 2 consecutive compliance checks to have taken less than 75% or more than 133% 
of the study drug, including HP eradication therapy), 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 
drug 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).
Visit windows should be calculated from the day of randomization. Visit windows are listed in 
Appendix A. Unscheduled nonstudy visits can be held, if in the opinion of the investigator a closer 
follow-up regimen is required for the subject.
9.3.1
Visit 1 (Screening)
Subjects will be screened within 28 days prior to Randomization/ Visit 2. Subjects will be screened 
in accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See
Section 9.1.12 for procedures for documenting screening failures.
Procedures to be completed during the Screening Period are detailed in Appendix A.

Informed consent.

Demographics, vital signs, weight, height, medical and medication history.

Physical examination including concurrent medical conditions and concomitant medications.

FSH (when menopause is suspected).

Urine pregnancy test (for females of child bearing potential).

Guidance on the avoidance of pregnancy.

Eligibility review (inclusion and exclusion criteria).

Access IWRS to obtain subject number.

Complete QOL questionnaire (EQ-5D-5L). 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.
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
Pretreatment event assessment.
The following additional screening assessments have to be completed within 14 days prior to 
Day 1 and must also be documented in the subject’s medical record: 

Fasting clinical laboratory tests (hematology, chemistry, urinalysis, hepatitis B & C screening 
tests).

Endoscopy to confirm duodenal ulcer.

ECG procedure.

13C-UBT.
9.3.2
Visit 2 (includes Randomization)
Randomization will take place on Day 1 after the following procedures have been performed and 
documented:

Physical examination including concomitant medications.

Vital signs.

Gastrointestinal symptoms associated with duodenal ulcer.

Urine pregnancy test (for females of child bearing potential).

Fasting clinical laboratory tests for gastrin-17, pepsinogen I/II levels [total and ratio].

Guidance on the avoidance of pregnancy.

Eligibility review (inclusion and exclusion criteria).

Randomization using IWRS and also to obtain Med ID numbers of study drug(s) that should be 
dispensed.

Study drug(s) dispensed. 

Pretreatment and AE assessments.
If the subject satisfies all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject will be randomized (stratified by HP status) using the IWRS as 
described in Section 8.2. Subjects will be instructed on when to take the first dose of 
investigational drug as described in Section 6.1. The procedure for documenting Screening 
failures is provided in Section 9.1.12. For all randomized subjects, the investigator must also 
complete the End of Study eCRF page. 
9.3.3
Treatment Period – Visit 3
At treatment Week 2/Visit 3 the subject should return to the study site to complete the following 
procedures:

Physical examination including concomitant medications review.
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
Vital signs.

Collect QOL questionnaire (EQ-5D-5L). In order to avoid subject’s bias, this shall be 
completed by the subjects as the first priority of all procedures at this visit.

Fasting clinical laboratory test for liver function.

Urine pregnancy test (for females of child bearing potential).

Gastrointestinal symptoms associated with duodenal ulcer. 

Collect study drug card issued at visit 2, review treatment compliance, and access IWRS to 
obtain Med ID numbers for dispensing of new study drug.

AE assessment.

Guidance on the avoidance of pregnancy.
9.3.4
Treatment Period – Visit 4
At treatment Week 4/Visit 4 the subject should return to the study site to complete the following 
procedures:

Physical examination including concomitant medications review.

Vital signs.

Collect QOL questionnaire (EQ-5D-5L). In order to avoid subject’s bias, this shall be 
completed by the subjects as the first priority of all procedures at this visit.

Endoscopy (if healing is confirmed subject will move into the follow-up period and subject 
should be registered complete via IWRS).

Fasting clinical laboratory tests (hematology, chemistry including gastrin-17, pepsinogen I/II 
levels [total and ratio], and urinalysis).

Urine pregnancy test (for females of child bearing potential).

ECG procedure (only if endoscopic healing is confirmed).

Gastrointestinal symptoms associated with duodenal ulcer.

Collect study drug card issued at visit 3 and review treatment compliance, and if endoscopic 
healing is not confirmed access IWRS to obtain Med ID numbers for dispensing of new study 
drug.

AE assessment.

Guidance on the avoidance of pregnancy.
If endoscopic healing is confirmed the subject is considered to have completed the study. The 
subject should discontinue study drug therapy and move into the follow-up period directly.
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9.3.5
End of Treatment Period – Visit 5
At treatment Week 6/Visit 5 the subject should return to the study site to complete the following 
procedures:

Physical examination including concomitant medications review.

Vital signs.

Collect QOL questionnaire (EQ-5D-5L). In order to avoid subject’s bias, this shall be 
completed by the subjects as the first priority of all procedures at this visit.

Endoscopy.

Fasting clinical laboratory tests (hematology, chemistry including gastrin-17 and pepsinogen 
I/II levels (total and ratio), urinalysis).

Urine pregnancy test (for females of child bearing potential).

ECG procedure.

Gastrointestinal symptoms associated with duodenal ulcer.

Collect study drug card issued at visit 4, review treatment compliance.

AE assessment.

Guidance on the avoidance of pregnancy.

Register subjects as completed via IWRS.
If after 6 weeks treatment endoscopic healing is confirmed the subject should move into the 
follow-up period. If endoscopic healing is not confirmed, the subject should be treated according 
to the Investigator’s judgment. In either case the subject is considered to have completed the study. 
Follow-up will also be performed for HP+ subjects who do not have endoscopically confirmed 
healing after 6 weeks treatment.
9.3.6
Early Termination
If a subject discontinues study treatment prematurely and does not have endoscopically confirmed 
healing an Early Termination Visit will be performed within 14 days of the last dose of study drug. 
The following procedures will be performed and documented:

Physical examination including concomitant medications review.

Vital signs.

Collect QOL questionnaire (EQ-5D-5L). In order to avoid subject’s bias, this shall be 
completed by the subjects as the first priority of all procedures at this visit. 

Endoscopy (if healing is confirmed subject may move into the follow-up period).
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
Fasting clinical laboratory tests (hematology, chemistry including gastrin-17, pepsinogen I/II 
levels [total and ratio], and urinalysis).

Urine pregnancy test (for females of child bearing potential).

ECG procedure.

Gastrointestinal symptoms associated with duodenal ulcer.

Collect study drug card issued at previous visit, review treatment compliance.

AE assessment.

Guidance on the avoidance of pregnancy.

Register subjects as discontinued (if not healed) or completed (if healed) via IWRS.
9.3.7
Follow-up Period – Visits F-1 and F-2 
The follow-up period comprises a maximum of 2 subject visits, and will begin the first day after 
the end of the treatment period. Subjects with endoscopically confirmed healing of ulcer(s) at 
Week 4 or at Week 6 will discontinue treatment at that time and enter the follow-up period. 
Subjects without endoscopically confirmed ulcer healing by Week 6 of the treatment period will 
discontinue treatment at Week 6 and enter the follow-up period.
The following procedures will be performed and documented during each of the 2 Follow-up 
visits:

Physical examination including concomitant medications review.

Fasting blood sampling for serum gastrin-17 and pepsinogen I/II levels (total and ratio).

13C-UBT for subjects treated with HP eradication therapy only (at visit F-2). 

AE assessment.
After completion of the 2 visits, or when serum gastrin-17 levels and the pepsinogen I/II ratio have 
returned to normal and the subject has provided the 13C-UBT sample (if applicable), the subject is 
considered to have completed the follow-up period.
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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Events
A 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 drug; 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 drug, or of a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.
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
If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study drug) or an AE 
(worsening or complication occurs after start of study drug). Investigators should ensure that 
the event term recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study drug, the worsening or complication should be recorded appropriately as an AE. 
Investigators should ensure that the AE term recorded captures the change in the condition (eg, 
“worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
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Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
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 AEs.
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 fulfil 1 or more of the serious criteria above are also to be considered 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 nonserious) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication by 
the investigator to Takeda may be appropriate. Such events may require further investigation in 
order to characterize and understand them and would be described in protocols and instructions 
provided for investigators as to how and when they should be reported to Takeda. 
There are no AEs of Special Interest in this study.
10.1.6 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.7 Causality of AEs
The relationship of each AE to study drug(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.
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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 (eg, vomiting) or those which occur repeatedly over a period of 
consecutive days are intermittent. All other events are continuous.
10.1.12
Action Concerning Study Drug(s)

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped 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

Dose Interrupted - The study drug 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”.
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
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 (eg, 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 drug (study Visit 
2) or until screen failure. For subjects who discontinue prior to study drug 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 drug 
(Visit 2, randomization). Routine collection of AEs will continue until the subject’s last study visit 
(ie, Early Termination or Follow-up visit).
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. 
Nonserious 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 drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All 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:
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
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.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s)

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1.
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 LFTs as SAEs (Medically Significant Event)
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 (medically significant event - Hy's Law) and reported as per Section 10.2.2. 
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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 
transmit it immediately within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
Drug Dictionary.
12.1
CRFs
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 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, subject evaluability, 
and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
In this study, 3 kinds of analysis sets are defined: FAS, PPS and safety analysis set. The FAS, the 
main analysis set used for primary efficacy analysis, will be defined as “all subjects who were 
randomized and received at least 1 dose of the study drug.” The definition of each analysis set will 
be described in the SAP.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized overall and by treatment 
group using the FAS.
13.1.3 Efficacy Analysis
(1) Primary endpoint and analytical methods
Primary endpoint
The primary endpoint for this study is the percentage of subjects with endoscopically confirmed 
healing of duodenal ulcer(s) at Week 4 or 6.
Primary analysis
The following analyses will be based on the FAS.
The healing rate of duodenal ulcer at Week 4 or Week 6 and the 2-sided 95% CI will be provided 
by treatment group. The healing rate difference between the TAK-438 treatment group and the 
lansoprazole treatment group (the TAK-438 treatment group minus the lansoprazole group) at 
Week 4 or Week 6 and the 2-sided 95% CIs using Newcombe methods will be provided.
Secondary analysis
To check the robustness of the results, the same analyses as the primary analyses will be performed 
using the PPS.
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(2) Secondary endpoints and analytical methods
Eradication rate of H pylori
The evaluation of the H pylori eradication rate will be based on a pooled analysis described in item 
(7) below, rather than from separate analyses of data from TAK-438_302 or TAK-438_304. 
Eradication rates and the 2-sided 95% CIs will be provided by treatment group. The eradication 
rate difference between the TAK-438 treatment group and the lansoprazole group (the TAK-438 
treatment group minus the lansoprazole group) and the 2-sided 95% CI will also be provided.
Healing rate of duodenal ulcer during the 4-week treatment
The same analyses as the primary analyses of the primary endpoint will be conducted.
Gastrointestinal symptoms associated with duodenal ulcer
For each symptom (epigastric pain [postprandial, fasting, nocturnal], abdominal bloating, 
nausea/vomiting, heartburn, lack of appetite), the frequency distribution will be provided by 
treatment group, and the point estimates and 2-sided 95% CIs will be calculated, and the point 
estimates and 2-sided 95% CIs of the proportion differences between the treatment groups will be 
calculated.
(3) Multiple Comparison/Multiplicity
Statistical inference will be performed at 2-sided 0.05 level of significance, or via 2-sided 95% 
CIs. Adjustment for multiplicity will be performed for the primary efficacy endpoint and the 
secondary efficacy endpoints in the following order under the closed testing procedure: 

The primary endpoint of healing rate of duodenal ulcer during the 6-week treatment will be 
tested for noninferiority between the TAK-438 group and the lansoprazole group based on the 
FAS. If the lower bound of the 95% CI is ≥-6%, noninferiority for TAK-438 relative to 
lansoprazole with regard to duodenal ulcer healing will be declared.

If the previous test is successful, the secondary endpoint of eradication rate of H pylori will be 
tested for noninferiority between the TAK-438 group and the lansoprazole group based on the 
FAS. If the lower bound of the 95% CI of the difference is ≥-10%, noninferiority for TAK-438 
relative to lansoprazole with regard to H pylori eradication will be declared.

If the previous test is successful, the primary endpoint of healing rate of duodenal ulcer during 
the 6-week treatment will be tested for superiority between the TAK-438 group and the 
lansoprazole group based on the FAS. If the lower bound of the 95% CI is ≥0%, superiority for 
TAK-438 relative to lansoprazole with regard to duodenal ulcer healing will be declared.

If the previous test is successful, the secondary endpoint of eradication rate of H pylori will be 
tested for superiority between the TAK-438 group and the lansoprazole group based on the 
FAS. If the lower bound of the 95% CI of the difference is ≥0%, superiority for TAK-438 
relative to lansoprazole with regard to H pylori eradication will be declared.
The noninferiority margin for H pylori eradication is based on literature on 
omeprazole/amoxicillin/clarithromycin/bismuth quadruple therapy (bismuth-containing).
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Limited data are available from clinical trials with PPI/amoxicillin/clarithromycin/bismuth 
quadruple therapy (bismuth-containing). In previous phase 3 trials, the eradication rate of H pylori 
with PPI-based triple therapy in HP+ subjects with gastric or duodenal ulcers was shown to be 
86.4% to 89.2% for lansoprazole/amoxicillin/clarithromycin, 78.8% to 83.0% for 
omeprazole/amoxicillin/clarithromycin, and 85.7% to 91.4% for 
rabeprazole/amoxicillin/clarithromycin; the range of these eradication rates (78.8% to 91.4%) 
corresponds to a difference of ≥10%. Hence the noninferiority margin is specified as -10%.
(4) Additional efficacy endpoints and methods
QOL endpoints (EQ-5D-5L)
QOL endpoints will be conducted with an analysis of covariance model with treatment and 
baseline H pylori status as factors and baseline as a covariate.
Confirmed healing of duodenal ulcer

Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at either 
Week 4 or Week 6 based on their baseline H pylori status.

Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at Week 4 
based on their baseline H pylori status.
Percentage of subjects with endoscopically confirmed healing of duodenal ulcer and the 2-sided 
95% CI will be provided by treatment group and baseline H pylori status. Healing percentage 
difference between the TAK-438 treatment group and the lansoprazole treatment group (the 
TAK-438 treatment group minus the lansoprazole group) and the 2-sided 95% stratified 
Newcombe CI with baseline H pylori status as a stratified factor will be provided.

Percentage of subjects with H pylori infection at Baseline who achieve endoscopically 
confirmed healing of duodenal ulcer either at Week 4 or Week 6 based on their H pylori status 
at Follow-up visit F-2.

Percentage of subjects with H pylori infection at Baseline who achieve endoscopically 
confirmed healing of duodenal ulcer at Week 4 based on their H pylori status at Follow-up visit 
F-2.
With regard to the percentage of subjects with H pylori infection at Baseline and endoscopically 
confirmed healing of duodenal ulcer, a similar approach to the aforementioned will be applied.
(5) Methods of data transformation and handling of missing data
Details will be described in the SAP.
(6) Significance level and confidence coefficient

Significance level: 5% (2-sided test)

Confidence coefficient: 95% (2-sided)
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(7) Pooled analysis for eradication rate of H pylori
Eradication rate difference between the TAK-438 treatment group and the lansoprazole group (the 
TAK-438 treatment group minus the lansoprazole group) and the 2-sided 95% CI will be provided. 
Eradication rate of H pylori and its 2-sided 95% stratified Newcombe CI with study as a stratified 
factor will be provided by treatment group, using pooled FAS dataset from studies TAK-438_302 
and TAK-438_304.
Furthermore, assuming that the true eradication rate of H pylori is 90% for both TAK-438 and 
lansoprazole bismuth-containing quadruple therapies, a sample size of more than 150 HP+
subjects per group across both studies TAK-438_302 and TAK-438_304 will provide over 80% 
power to establish noninferiority using a 2-sided 95% CI with a -10% noninferiority margin in the 
Chinese population.
13.1.4 Safety Analysis
Safety analysis will be performed using the safety analysis set.
The number and percentage of subjects with TEAEs will be summarized by 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 TEAEs overall and by severity. 
Change from Baseline in clinical laboratory tests, vital signs and quantitative ECG variables will 
be summarized by treatment group. For qualitative ECG assessments, postbaseline 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.
13.3
Determination of Sample Size
The protocol for TAK-438_304 study was written in 2012 while the TAK-438 duodenal ulcer 
pivotal study (CCT-102) was still ongoing in Japan. The sample size of 640 was based on the 
assumption that the Week 6 duodenal ulcer healing rate would be 97.8% for both TAK-438 and 
lansoprazole, and assuming a dropout rate of up to 20%. The assumption for the ulcer healing rate 
was based on historical studies with lansoprazole. In a phase 3 study in Japan to compare the 
efficacy of lansoprazole and famotidine for healing of duodenal ulcer, the Week 6 healing rate was 
97.8% for lansoprazole and 91.5% for famotidine.
TAK-438 CCT-102 study was completed in 2013. The duodenal ulcer healing rate was 95.5% in 
the TAK 438 treatment arm. The design of TAK-438-304 study is based on TAK-438 CCT-102 
study with identical key enrollment criteria. Therefore, the sample size has been recalculated based 
on a 95.5% healing rate. In addition, since H pylori eradication rate is a secondary endpoint, this 
endpoint has not been used for sample size calculation.
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Assuming that the true Week 6 duodenal ulcer healing rate is 95.5% for both TAK-438 and 
lansoprazole, and assuming that the dropout rate is up to 10%, a sample size of 265 subjects per 
group in the overall population, including no fewer than 238 Chinese subjects per group, will 
provide at least 80% power to establish noninferiority in the Chinese population using a 2-sided 
95% CI with a -6% noninferiority margin. This sample size will also provide 83.9% power to 
establish noninferiority in the overall population.
In a phase 3 study in Japan to compare the efficacy of lansoprazole and famotidine for healing of 
duodenal ulcer, the Week 6 healing rate was 97.8% for lansoprazole and 91.5% for famotidine, 
corresponding to a difference of 6.3%. Additionally, in studies of lansoprazole versus placebo in 
US (M87-090), the Week 4 healing rate was 91.7% for lansoprazole 30 mg and 46.1% for placebo 
in one study, corresponding to a difference of 45.6%, and 80.3% for lansoprazole 30 mg and 
47.5% for placebo in the other study, corresponding to a difference of 32.8%. A noninferiority 
margin of -6% is specified, which is less than the difference between lansoprazole and famotidine 
in the Japanese study and less than half of the difference between lansoprazole and placebo in the 
US studies.
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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 (contract research organization) 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 (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drugs or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will [ship drug/notify site] once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received 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.
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 
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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.
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.
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15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s 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.
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 subjects that it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before trial initiation. Takeda contact information, along with 
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investigator’s city, 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, Dekel R, Sewell J. Systematic review: proton-pump inhibitor failure in 
gastro-oesophageal reflux disease--where next? Aliment Pharmacol Ther 2005;22(2):79-94.
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Appendix A
Schedule of Study Procedures
Screening 
Period
Treatment Period (b)
Follow-up Period (d)
Study Day/Week:
Day -28 to 
Day -1
Day 1 
(a, u)
Week 2
(Day 
15)
Week 4
(Day 
29) (u)
Week 6
(Day 
43) (u)
Early 
Termination 
Visit (c)
2 Weeks 
Post-
treatment
4 Weeks 
Post-
treatment
Visit Windows 
(Days):
-
±3 
days
±3 
days
±3 
days
Within 14 
days of last 
dose
Day 15 to 28 Day 29 to 42
Visit Number:
1
2
3
4
5
-
F-1
F-2
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demographics and 
medical history
X
Medication history
X
Physical 
examination
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Weight and height
X
Concomitant 
medications
X
X
X
X
X
X
X (e)
X (e)
Concurrent medical 
conditions
X
Clinical laboratory 
tests (f)
X(g)
X
X
X
LFT (r)
X
Serum gastrin-17 / 
Pepsinogen I/II 
levels (total and 
ratio)
X
X
X
X
X(s)
X(t)
Urine pregnancy test 
(hCG) (h)
X
X
X
X
X
X
Hepatitis B and C 
tests (o)
X(g)
FSH (i)
X
Guidance on 
avoidance of 
pregnancy (h) 
X
X
X
X
X
X
ECG
X(k)
X(j)
X
X
Endoscopy 
X(k)
X
X
X
Footnotes are on last table page.
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Appendix A
Schedule of Study Procedures (continued)
Screening 
Period
Treatment Period (b)
Follow-up Period (d)
Study Day/Week:
Day -28 
to 
Day -1
Day 1 
(a, u)
Week 2
(Day 
15)
Week 4
(Day 
29) (u)
Week 6
(Day 
43) (u)
Early 
Termination 
Visit (c)
2 weeks 
post-
treatment
4 weeks 
post-
treatment
Visit Windows 
(Days):
-
± 3 
days
± 3 
days
± 3 
days
within 14 
days of last 
dose
Day 15 to 28 Day 29 to 42
Visit Number:
1
2
3
4
5
-
F-1
F-2
13C-UBT to confirm 
H infection status
X(g)
X(n)
Investigator review 
of gastrointestinal 
symptoms
X
X
X
X
X
QOL questionnaire 
(EQ-5D-5L) (p)
X
X
X
X
X
Randomization via 
IWRS
X(l)
Obtain subject 
number via IWRS
X
Dispense TAK-438/
lansoprazole via 
IWRS
X
X
X(m)
Dispense companion 
drug via IWRS 
X(q)
Drug return/ 
accountability/ 
compliance
X
X
X
X
Register subject as 
discontinued or 
completed via IWRS
X(j)
X
X
X
PTE assessment
X
X
AE assessment
X
X
X
X
X
X
X
Footnotes are on last table page.
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(a) 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.
(b) If and when endoscopic healing of duodenal ulcer has been confirmed in the subject, he/she will complete the 
treatment period and move directly into the Follow-up period.
(c) Conduct Final Visit procedures for subjects discontinued from treatment early per Section 9.3.6. 
(d) The subject will move on to the Follow-up period after discontinuation of treatment, either after Visit 4 (Week 4) 
for subjects with endoscopic healing of duodenal ulcer[s] only, or after Visit 5 (Week 6) for all subjects regardless of 
ulcer healing. All subjects will complete the scheduled Follow-up period visits until the recovery of serum gastrin-17 
level and pepsinogen I/II ratio are confirmed or for a maximum of 4 weeks. HP+ subjects will provide the 13C-UBT 
sample at F-2. 
(e) The use of gastric mucosal protective agents may be allowed during the Follow-up period. F-2 will be performed 
for 13C-UBT.
(f) Hematology, serum chemistries, and urinalysis tests will be done at the central laboratory. Local laboratories may 
be used to perform laboratory tests only under special circumstances, on case by case basis with sponsor’s agreement.
(g) Visit window: Day –14 to Day 1 (predose).
(h) Women of childbearing potential.
(i) Only if menopause is suspected. 
(j) ECG and registration in IWRS of study completion to be performed at Week 4 only for those subjects in whom 
endoscopic healing is confirmed; thereafter those subjects will move directly into the Follow-up period.
(k) Visit window: Day –14 to Day 1 (predose). If endoscopy with associated images has been performed within 
14 days prior to Day 1, the study-specific endoscopy may be waived in favor of the existing results. If an ECG has 
been performed within 14 days prior to randomization, the study-specific ECG may be waived.
(l) Subjects must not have been given any other agent affecting the digestive organs on the day of randomization and 
must take the first dose of study medication on the day of randomization during the Day 1 visit. 
(m) To be performed as appropriate for those subjects in which endoscopic healing has not been confirmed during 
visits involving endoscopy.
(n) 13C-UBT should be repeated for HP+ subjects at F-2 to ascertain HP eradication status.
(o) Hepatitis B and C analysis in accordance with Section 9.1.8 Table 9.b will be conducted at the central laboratory. 
Hepatitis B and C tests performed as per local routine practice within 14 days prior to randomization (Day 1), before 
signing of informed consent form will be accepted. 
(p) EQ-5D-5L questionnaire shall be the first priority in all procedures (except signing the ICF) at each visit.
(q) Only for HP+ subjects.
(r) LFTs include ALT, AST, total bilirubin and direct bilirubin.
(s) Completed by subjects with or without ulcer healing regardless of HP status.
(t) Completed by subjects with or without ulcer healing regardless of HP status, only if no serum gastrin-17 or 
pepsinogen I/II recovery at F-1 visit.
(u) The subject will be instructed to present to the clinic prior to taking the study medication at the visits during the 
treatment phase in which serum gastrin and pepsinogen I/II levels will be measured or endoscopy will be performed. 
The study medication will be taken by the subject after completion of assessments on the days of those study visits. 
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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 (nonroutine/nonstandard 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 subjects, 
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. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening throughout the duration of the study. If the partner or wife of the subject is found to 
be pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information.
26. 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
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 03 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Removal of reference to Study TAK-438_115 as part of rationale for study design.
The primary change occurs in Section 4.2 Rationale for the Proposed Study:
Deleted text:
An ongoing drug-drug interaction study in Korea, TAK-438_115, is investigating 
the possible pharmacokinetic (PK) and safety effects of the co-administration of 
TAK-438 with clarithromycin, amoxicillin, and bismuth as a quadruple therapy in 
HP+ subjects. 
Rationale for Change:
TAK-438_115 is now complete and found no evidence of interaction between TAK-438 and 
quadruple therapy with clarithromycin, amoxicillin, and bismuth in subjects who are HP+.
The following sections also contain this change:
Section 2.0 STUDY SUMMARY
Section 6.1 Study Design and footnote to Figure 6.a
Section 7.1 Inclusion Criteria, criterion #3
Change 2Subjects with no ulcer healing at Week 6 could be treated with another course of PPI or 
other anti-acid secretory agents or antibiotics, at the discretion of the investigator.
The primary change occurs in Section 6.1 Study Design:
Added text:
For subjects with no ulcer healing at Week 6 of treatment, the investigator 
may follow local clinical practice and these subjects may be treated with 
another course of PPI or other anti-acid secretory agents, or antibiotics,
during the safety follow-up period (please see Table 7.a). This should be 
documented during the follow-up
Rationale for Change:
To allow investigator’s to treat subjects with no ulcer healing during the study according to local 
practice 
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Change 3 Exclusion criterion 10 concerning subjects participating in another clinical study within 
30 days of Visit 1, is deleted.
The primary change occurs in Section 7.2 Exclusion Criteria:
Deleted text:
10. The subject has participated in another clinical study within the past 30 days 
from Visit 1.
Rationale for Change:
Exclusion criterion 10 has been removed to align the current protocol with the protocol for the 
pivotal study. This criterion will be covered under exclusion criterion #1 that excludes subjects 
receiving any investigational compound within 90 days prior to the treatment period.
Change 4: Exclusion criterion 12 is deleted to allow subjects with ulcer size >2 cm in any 
diameter and those with >3 separate duodenal ulcers to enter the study.
The primary change occurs in Section 7.2 Exclusion Criteria:
Deleted text:
12. Subjects with any duodenal ulcer of >2 cm in any diameter or with >3 separate 
duodenal ulcers in total as evident by endoscopy within 14 days prior to 
randomization.
Rationale for Change:
Exclusion criterion 12 was originally intended to prevent subjects with potential malignant ulcers 
being recruited into the study. However, the retained exclusion criteria specifically exclude 
inclusion of subjects with a diagnosis of gastric malignancy or a duodenal ulcer whose 
morphology suggested malignancy as evident by endoscopy within 14 days prior to 
randomization.
Change 5: A footnote is added to Table 9.b to clarify that subjects with negative hepatitis C virus 
antibody test results may be randomized before hepatitis C-viral load-RNA test results are 
available.
The primary changes occur in Section 9.1.8 Procedures for Clinical Laboratory Samples
Table 9.b:
Initial wording: Table 9.b
Clinical Laboratory Tests
Hepatitis B & C Analysis 
HBsAg
HCV antibody
HCV-viral load-RNA
Amended or 
new wording:
Table 9.b
Clinical Laboratory Tests
Hepatitis B & C Analysis 
HBsAg
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HCV antibody
HCV-viral load-RNA (b)
(b) Subjects with negative HCV antibody test results may be randomized 
before HCV-viral load-RNA test results are available. If the HCV-viral 
load-RNA test result is positive, the subject will be withdrawn from the 
study.
Rationale for Change:
To clarify that while all subjects will undergo testing for both HCV antibody and HCV-viral 
load-RNA, subjects with negative HCV antibody test results may be randomized before the 
results of the HCV-viral load-RNA test are available.
Change 6: Procedure for retesting of abnormal liver function tests, and a clarification concerning 
elevated serum gastrin and pepsinogen I and II levels, which are physiological responses to 
increased gastric pH and the suppression of gastric acid secretion.
The primary changes occur in Section 9.1.8 Procedures for Clinical Laboratory Samples: 
Initial wording: Given the possibility that the use of TAK-438 or lansoprazole may be associated 
with increases in serum gastrin-17 and pepsinogen I/II levels, the subjects will be 
examined for gastrin-17 and pepsinogen I/II levels (total and ratio) to investigate 
the magnitude of these increases during the Treatment and Follow-up periods (as 
appropriate).
Amended or 
new wording:
(Note for ALT/AST and total bilirubin: >ULN to ≤2 × ULN. Kindly re-test 
LFT in 2 weeks to monitor abnormal LFT. This abnormal LFT value should 
not be reported as AE unless is clinically significant. An unscheduled visit 
may be performed if necessary.)
Given the possibility that the use of TAK-438 or lansoprazole may be associated 
with increases in serum gastrin-17 and pepsinogen I/II levels, the. Thus, all
subjects will be examined for gastrin-17 and pepsinogen I/II levels (total and 
ratio) to investigate the magnitude of these increases during the Treatment and 
Follow-up periods (as appropriate). Increases in serum gastrin and pepsinogen 
I/II levels are physiological responses to gastric acid suppression and 
elevated content pH due to the pharmacological action of the study drugs.
Rationale for Change:
Because ALT, AST, or total bilirubin >2 × ULN will result in discontinuation and withdrawal of a 
subject, close monitoring of the LFT is required. Increases in serum gastrin and pepsinogen I/II 
level are due to the pharmacological action of TAK-438 or lansoprazole.
Section 2.0 STUDY SUMMARY
Section 7.2 Exclusion Criteria
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Change 7: The liver function test at Visit 3 is clarified as a fasting clinical laboratory test.
The primary change occurs in Section 9.3.3 Treatment Period – Visit 3: 
Initial wording: 
Liver function tests.
Amended or 
new wording:

Liver function tests Fasting clinical laboratory test for liver function.
Rationale for Change:
To clarify that clinical laboratory tests for liver function are performed after fasting, as specified in 
Section 9.1.8.
Change 8: The sample sizes for the overall study population and the Chinese subpopulation have 
been recalculated on the basis of an estimated dropout rate of 10% (previously 20%), resulting in 
sample size re-estimation.
The primary change occurs in Section 13.3 Determination of Sample Size:
Initial wording: Assuming that the true Week 6 duodenal ulcer healing rate is 95.5% for both 
TAK-438 and lansoprazole, and assuming that the dropout rate is up to 20%, a 
sample size of 385 subjects per group will provide 92% power to establish 
noninferiority using a 2-sided 95% CI with a -6% noninferiority margin and to 
provide a sample size of 269 subjects for regulatory requirements in China. 
Furthermore, assuming the proportion of subjects with H pylori infection at 
Baseline is about 80%, a sample size of 308 subjects per group will provide 85% 
power for noninferiority based on same effect size as overall population. The 
assumption of rate for ulcer healing is based on historical studies with 
lansoprazole.
Amended or 
new wording:
Assuming that the true Week 6 duodenal ulcer healing rate is 95.5% for both 
TAK-438 and lansoprazole, and assuming that the dropout rate is up to 20% 10%, 
a sample size of 385 265 subjects per group in the overall population, including 
no fewer than 238 Chinese subjects per group, will provide 92% at least 80%
power to establish noninferiority in the Chinese population using a 2-sided 95% 
CI with a -6% noninferiority margin and provide a sample size of 269 subjects for 
regulatory requirements in China. This sample size will also provide 83.9% 
power to establish noninferiority in the overall population. Furthermore, 
assuming the proportion of subjects with H pylori infection at baseline is about 
80%, a sample size of 308 subjects per group with H pylori infection at baseline 
will provide 85% power for noninferiority based on the same effect size as overall 
population. The assumption of rate for ulcer healing is based on historical studies 
with lansoprazole. 
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Rationale for Change:
Data from completed studies indicate that the dropout rate used for the power calculations should 
be reduced to 10%. In the Japanese Study CCT-102, in subjects with duodenal ulcer, the dropout 
rate was 5.9% and in Study TAK-438_303, in subjects with erosive esophagitis, it was 4.8%. 
Additionally, in Japanese Studies CCT-301 and CCT-302, in subjects with gastric or duodenal 
ulcers, the dropout rates were 8.4% and 7.6%, respectively.
The following sections also contain this change:
Section 2.0 STUDY SUMMARY.
Section 6.1 Study Design.
Change 9: H pylori eradication data from this study (TAK-438_304) will be pooled with data 
from TAK-438_302.
The primary change occurs in Section 13.1.3 Efficacy Analysis (3):
Initial wording: 
If the previous test is successful, the secondary endpoint of eradication rate of 
H pylori will be tested for superiority between the TAK-438 group and the 
lansoprazole group based on the FAS. If the lower bound of the 95% CI of the 
difference is ≥0%, superiority for TAK-438 relative to lansoprazole with 
regard to H pylori eradication will be declared.
Amended or 
new wording:

If the previous test is successful, the secondary endpoint of eradication rate of 
H pylori will be tested for superiority between the TAK-438 group and the 
lansoprazole group based on the FAS. If the lower bound of the 95% CI of the 
difference is ≥0%, superiority for TAK-438 relative to lansoprazole with 
regard to H pylori eradication will be declared.
The noninferiority margin for H pylori eradication is based on literature on 
omeprazole/amoxicillin/clarithromycin/bismuth quadruple therapy 
(bismuth-containing).
Limited data are available from clinical trials with 
PPI/amoxicillin/clarithromycin/bismuth quadruple therapy 
(bismuth-containing). In previous phase 3 trials, the eradication rate of H 
pylori with PPI-based triple therapy in HP+ subjects with gastric or 
duodenal ulcers was shown to be 86.4% to 89.2% for 
lansoprazole/amoxicillin/clarithromycin, 78.8% to 83.0% for 
omeprazole/amoxicillin/ clarithromycin, and 85.7% to 91.4% for 
rabeprazole/amoxicillin/clarithromycin; the range of these eradication rates 
(78.8% to 91.4%) corresponds to a difference of ≥10%. Hence the 
noninferiority margin is specified as -10%.
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New text also added to Section 13.1.3 Efficacy Analysis:
Added text:
(7) Pooled analysis for eradication rate of H pylori
Eradication rate difference between the TAK-438 treatment group and the 
lansoprazole group (the TAK-438 treatment group minus the lansoprazole 
group) and the 2-sided 95% CI will be provided. Eradication rate of H pylori
and its 2-sided 95% stratified Newcombe CI with study as a stratified factor 
will be provided by treatment group, using pooled FAS dataset from studies 
TAK-438_302 and TAK-438_304.
Furthermore, assuming that the true eradication rate of H pylori is 90% for 
both TAK-438 and lansoprazole bismuth-containing quadruple therapies, a 
sample size of more than 150 HP+ subjects per group across both studies 
TAK-438_302 and TAK-438_304 will provide over 80% power to establish 
noninferiority using a 2-sided 95% CI with a -10% noninferiority margin in 
the Chinese population.
Rationale for Changes:
Study TAK-438_302 is no longer powered separately for analysis of H pylori eradication as it is 
now proposed to evaluate HP eradication using pooled data from the current study and from Study 
TAK-438_302, instead of undertaking separate evaluations from each study. 
Change 10: Study-specific endoscopy may be waived at the investigator’s discretion if endoscopy 
with associated images has been performed within 14 days before Day 1..
The primary change occurs in Section 9.1.14 Endoscopy:
Added text:
Study-specific endoscopy may be waived at the investigator’s discretion if 
endoscopy with associated images has been performed within 14 days 
before Day 1.
Rationale for Change:
To waive the need for repeat endoscopy fewer than 14 days after a prescreening endoscopy has 
been undertaken.
Appendix A Schedule of Study Procedures, footnote l, also contains this change.
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Change 11: Time of dosing of TAK-438 amended to after breakfast or dinner (previously after 
breakfast only).
The primary change occurs in Section 8.1.3 Dose and Regimen:
Initial wording: H pylori negative subjects will be dispensed one blister card containing TAK-438 
or lansoprazole (with appropriate placebo) after randomization at Visit 2 and at 
subsequent visits as required. HP- subjects will be required to take one tablet 
(containing either TAK-438 or placebo) and one capsule (containing either 
lansoprazole or placebo) daily (QD) after breakfast at about the same time as 
he/she usually does, with approximately 240 ml water.
Amended or 
new wording:
H pylori negative subjects will be dispensed 1 blister card containing TAK-438 or 
lansoprazole (with appropriate placebo) after randomization at Visit 2 and at 
subsequent visits as required. HP- subjects will be required to take 1 tablet 
(containing either TAK-438 or placebo) and 1 capsule (containing either 
lansoprazole or placebo) daily (QD) after breakfast or dinner at about the same 
time as he/she usually does, with approximately 240 mL water. The preference 
is for the dose to be given after breakfast; however, if the first 
randomization visit was scheduled in the late afternoon, it is acceptable for 
the dose to be taken after dinner.
Rationale for Change:
To correct an inconsistency between the dosing instructions and the study drug label. The drug 
label indicates that study drugs will be taken after breakfast or dinner, while the protocol 
previously stated that study drugs will be taken after breakfast only. The preference is for subjects 
to take study drugs after breakfast. However, if the first randomization is scheduled late in the 
afternoon, it is acceptable for the dose to be taken after dinner.
The following sections also contain this change:
Section 6.2 Justification for Study Design, Dose, and Endpoints.
Section 7.4 Diet, Fluid, Activity Control.
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Change 12: Clarification of follow-up guidance on excluded medications and treatments in 
Table 7.a, amended for proton pump inhibitors, histamine H2 receptor antagonists, insulin, 
antidiabetic agents, and antibiotics.
The primary change occurs in Section 7.3 Excluded Medications and Treatments Table 7.a:
Description of 
change:
The following modifications were made to the table:
The phrase ‘excluding of PPIs and antibiotics’ has been removed from the row 
describing medications that may interfere with the 13C-UBT
Definitions of beginning and end of exclusion periods for the different classes of 
medication have been revised and made more specific relative to timings relative 
to the 13C-UBT and applicability to HP+ subjects
Medications contraindicated with clarithromycin have been extended to include 
simvastatin, lovastatin, atorvastatin etc and other statins such as fluvastatin, 
pravastatin, and rosuvastatin may be allowed but used with caution.
H2 receptor antagonists have been deleted and probencid (contraindicated with 
bismuth) has been added to the row describing exclusion of agents affecting 
digestive organs
In the row about the medications contradicted with bismuth, insulin or oral 
antibiotic medications and tetracycline antibiotics have been deleted.
Rationale for Change:
To conform to 13C-UBT product insert, which states the following:
The test should be performed following at least:

4 weeks after a treatment against a bacterial infection.

2 weeks after the last administration of a medicine to reduce release of stomach acid.
Bismuth used in this study is not contraindicated with insulin and antidiabetic medication.
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Change 13 Provision has been made for the use of premedication for endoscopy to be provided at 
investigator’s discretion.:
The primary change occurs in Section 9.1.14 Endoscopy:
Initial wording: 
Endoscopy should be performed while subjects are fasted and according to the 
usual practice of the institution (i.e. in regard to premedications or 
concomitant therapies as long as they are not prohibited in Section 7.3 of this 
protocol).
Amended or 
new wording:

Endoscopy should be performed while subjects are fasted and according to the 
usual practice of the institution (i.e. in regard to premedications or 
concomitant therapies as long as they are not prohibited in Section 7.3 of this 
protocol). Use of pre-medications for endoscopy (e.g. analgesics, local 
anesthetics, anticholinergic agents, sedatives, 
anticholinergics/antispasmodics, antifoaming agents) may be allowed at 
the discretion of the Investigator as per local standard practice.
Rationale for Change:
To clarify that premedication can be administered for endoscopy according to local practice.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-438
Study No. TAK-438_304
Page 96 of 98
Protocol Incorporating Amendment No. 03
30 August 2018
Change 14: Formulation of bismuth for use in Korean sites is specified in relevant sections of the 
protocol.
The primary change occurs in Section 6.1 Study Design:
Initial 
wording:

H pylori infected (HP+) subjects will take TAK-438 20 mg or lansoprazole 30 mg 
(blinded with matching placebo) twice daily (BID) in addition to 
bismuth-containing quadruple antibiotic therapy (amoxicillin 1 g BID, 
clarithromycin 500 mg BID, and bismuth potassium citrate 600 mg [equivalent to 
220 mg bismuth] BID) for 2 weeks. After 2 weeks of eradication therapy, subjects 
will be required to take only TAK-438 or lansoprazole once a day (QD) for up to 4 
weeks (ie, up to a total of 6 weeks of treatment). The subject will remain in the 
same treatment arm throughout the study duration.
Amended 
or new 
wording:

H pylori infected (HP+) subjects will take TAK-438 20 mg or lansoprazole 30 mg 
(blinded with matching placebo) twice daily (BID) in addition to 
bismuth-containing quadruple antibiotic therapy (amoxicillin 1 g BID, 
clarithromycin 500 mg BID, and bismuth potassium citrate/bismuth 
tripotassium dicitrate 600 mg [equivalent to 220 mg bismuth] BID) for 2 weeks. 
After 2 weeks of eradication therapy, subjects will be required to take only 
TAK-438 or lansoprazole once a day (QD) for up to 4 weeks (ie, up to a total of 6 
weeks of treatment). The subject will remain in the same treatment arm throughout 
the study duration.
Rationale for Change:
To include the formulation of bismuth available in Korea
The following sections also contain this change:
Section 2.0 STUDY SUMMARY.
Section 8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling.
Section 8.1.3 Dose and Regimen.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-438
Study No. TAK-438_304
Page 97 of 98
Protocol Incorporating Amendment No. 03
30 August 2018
Change 15: Provision for serum gastrin follow-up for all subjects.
The primary change occurs in Section 6.1 Study Design:
Initial wording:
For all subjects, ulcer healing rates will be assessed by endoscopy at Weeks 4 
and 6 of treatment. With or without endoscopic evidence of duodenal ulcer 
healing, the treatment duration of the study is no more than 6 weeks. 
Subjects (HP+ or HP-) with endoscopic evidence of duodenal ulcer(s) healing 
at Week 4 or at Week 6 will discontinue treatment at that time, and enter into 
the Follow-up period.
HP+ subjects with no healing at Week 6 will discontinue treatment and enter 
Follow-up.
HP- subjects with no ulcer healing by Week 6 of the treatment period will be 
considered “completed cases” and be discontinued from the study.
Follow-up period:
The subjects to be followed up will include both HP+ and HP- subjects with 
confirmed ulcer healing during the treatment period. HP+ subjects with no 
ulcer healing during treatment period will require one follow-up visit (F-2) to 
provide a post-study 13C urea breath test (13C-UBT) to ascertain HP 
eradication status. HP- subjects with no ulcer healing are not required to be 
followed-up.
The recovery of serum gastrin-17 level in follow-up period will be monitored 
for a maximum of 4 weeks in subjects with endoscopic healing of duodenal 
ulcer confirmed during the treatment period. The follow-up period ends when 
the recovery of serum gastrin-17 level is confirmed. No additional follow-up is 
planned for subjects without recovery during the 4-week follow-up period.
Amended or 
new wording:
For all subjects, ulcer healing rates will be assessed by endoscopy at Weeks 4 and 
6 of treatment. With or without endoscopic evidence of duodenal ulcer healing, 
the treatment duration of the study is no more than 6 weeks. 
Subjects (HP+ or HP-) with endoscopic healing of duodenal ulcer(s) at Week 4 or 
Week 6 will discontinue treatment at that time, and enter into the Follow-up 
period. 
HP+ subjects with no healing at Week 6 will discontinue treatment and enter 
Follow-up.
HP- subjects with no ulcer healing by Week 6 of the treatment period will be 
considered “completed cases” and be discontinued from the study.
Subjects (HP+ or HP-) without ulcer healing by Week 6 of treatment period 
will discontinue treatment at Week 6, and enter into the Follow up period. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-438
Study No. TAK-438_304
Page 98 of 98
Protocol Incorporating Amendment No. 03
30 August 2018
Follow-up Period:
The subjects to be followed up will include both HP+ and HP- subjects, with or 
without confirmed ulcer healing during the treatment period. HP+ subjects with 
no ulcer healing during treatment period will require one follow-up visit (F-2) to 
provide a post-study 13C urea breath test (13C-UBT) to ascertain HP eradication 
status. HP- subjects with no ulcer healing are not required to be followed-up.
The recovery of serum gastrin-17 level and pepsinogen I/II ratio in the
Follow-up period will be monitored for a maximum of 4 weeks in subjects with 
endoscopic healing of duodenal ulcer confirmed during the treatment period. The 
Follow-up period ends when the recovery of serum gastrin-17 level and 
pepsinogen I/II ratio are confirmed or at the end of the 4-week follow-up. No 
additional follow-up is planned for subjects without recovery during the 4-week 
follow-up period.
All HP+ subjects will provide a follow-up 13C-UBT at the F-2 visit to 
ascertain HP eradication status.
For subjects with no ulcer healing at Week 6 of treatment, the investigator 
may follow local clinical practice and these subjects may be treated with 
another course of PPI or other anti-acid secretory agents, or antibiotics,
during the safety follow-up period (please see Table 7.a). This should be 
documented during the follow-up visit 2.
Rationale for Change:
To ensure adequate monitoring of subjects with increased serum gastrin and pepsinogen I/II levels 
during the study.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY. 

Figure 6.a Schematic of Study Design.

Section 6.2 Justification for Study Design, Dose, and Endpoints.

Section 9.3.7 Follow-up Period – Visits F-1 and F-2.

Appendix A Schedule of Study Procedures, footnotes d, s, and t
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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PPD

SAP_001.pdf: 


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 TAK-438 20 mg Compared to Lansoprazole 30 mg Once- or Twice-Daily in the 
Treatment of Endoscopically Confirmed Duodenal Ulcer Subjects With or Without 
Helicobacter pylori Infection
NCT Number: NCT03050359
SAP Approve Date: 23 July 2019
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 (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
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.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-438_304
A Randomized Double-Blind, Double-Dummy, Phase 3 Study to Evaluate the Efficacy and 
Safety of Oral TAK-438 20 mg Compared to Lansoprazole 30 mg Once- or Twice-Daily in 
the Treatment of Endoscopically Confirmed Duodenal Ulcer Subjects With or Without 
Helicobacter pylori Infection
PHASE 3
Version: 3.0
Date: 23 July 2019
Prepared by:
Based on:
Protocol Version: Amendment 03
Protocol Date: 30 August 2018
Prope
keda: For non-c
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Evalua
Evalu
mg On
mg O
lcer Sub
lcer Su
ion
on
ion
on: : 3.0.
e: 23
23 Ju
J
l Versi
Versi
l
o
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col Da
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PPD


TAK-438_304
Page 2 of 50
Statistical Analysis Plan Version 3.0
23 July 2019
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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TAK-438_304
Page 3 of 50
Statistical Analysis Plan Version 3.0
23 July 2019
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................7
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objectives ....................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Study Design .............................................................................................................8
5.0
ANALYSIS ENDPOINTS.............................................................................................13
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................14
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................15
7.1
General Principles....................................................................................................15
7.1.1
Study Definitions ...............................................................................................15
7.1.2
Definition of Study Visit Windows ....................................................................18
7.1.3
Data Handling Rules ..........................................................................................19
7.1.3.1 Handling of Rate of Endoscopic Healing......................................................19
7.1.3.2 Handling of Percentage of Subjects with Posttreatment Resolution of Each 
Gastrointestinal Symptom Associated with Duodenal Ulcer at Week 2 
through 6......................................................................................................20
7.1.3.3 Handling of EQ-5D-5L.................................................................................20
7.1.4
Conventions for Missing AE Dates ....................................................................20
7.1.5
Conventions for Missing Concomitant Medication Dates...................................20
7.2
Analysis Sets ...........................................................................................................20
7.3
Disposition of Subjects ............................................................................................21
7.3.1
Study Information..............................................................................................21
7.3.2
Screen Failures...................................................................................................21
7.3.3
Subject Eligibility ..............................................................................................22
7.3.4
Number of Subjects Randomized by Country, Site, and Treatment Group..........22
7.3.5
Disposition of Subjects ......................................................................................23
7.3.6
Protocol Deviations and Analysis Sets ...............................................................23
7.3.6.1 Protocol Deviations......................................................................................23
7.3.6.2 Analysis Sets................................................................................................24
7.4
Demographic and Other Baseline Characteristics.....................................................24
7.5
Medical History and Concurrent Medical Conditions...............................................25
7.6
Medication History and Concomitant Medications...................................................26
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TAK-438_304
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Statistical Analysis Plan Version 3.0
23 July 2019
7.7
Study Drug Exposure and Compliance.....................................................................26
7.7.1
TAK-438/Lansoprazole and Matching Placebo Exposure and Compliance.........26
7.7.2
Companion Drugs Exposure and Compliance.....................................................26
7.8
Efficacy Analysis.....................................................................................................27
7.8.1
Primary Efficacy Endpoint(s).............................................................................27
7.8.1.1 Primary Analysis..........................................................................................27
7.8.1.2 Secondary Analysis......................................................................................27
7.8.2
Secondary Efficacy Endpoint(s).........................................................................27
7.8.2.1 Percentage of Subjects with Endoscopically Confirmed Healing of 
Duodenal Ulcer at Week 4............................................................................27
7.8.2.2 Percentage of HP+ Subjects with Successful H pylori Eradication after 4 
or 6 Weeks of Treatment, as Determined by 13C-UBT at F-2........................28
7.8.2.3 Percentage of Subjects with Posttreatment Resolution of Gastrointestinal 
Symptoms Associated with Duodenal Ulcer at Weeks 2 Through 6..............28
7.8.3
Additional Efficacy Endpoint(s).........................................................................28
7.8.3.1 QOL Measurement EQ-5D-5L.....................................................................28
7.8.3.2 Percentage of Subjects with Endoscopically Confirmed Healing of 
Duodenal Ulcer at either Week 4 or Week 6 Based on Their Baseline H 
pylori Status.................................................................................................29
7.8.3.3 Percentage of Subjects with Endoscopically Confirmed Healing of 
Duodenal Ulcer at Week 4 Based on Their Baseline H pylori Status.............29
7.8.3.4 Percentage of Subjects with H pylori Infection at Baseline Who Achieve 
Endoscopically Confirmed Healing of Duodenal Ulcer Either at Week 4 or 
Week 6 Based on Their H pylori Status at Follow-up Visit F-2.....................30
7.8.3.5 Percentage of Subjects with H pylori Infection at Baseline Who Achieve
Endoscopically Confirmed Healing of Duodenal Ulcer at Week 4 Based 
on Their H pylori Status at Follow-up Visit F-2............................................30
7.8.4
Statistical/Analytical Issues................................................................................30
7.8.4.1 Adjustments for Covariates ..........................................................................30
7.8.4.2 Handling of Dropouts or Missing Data.........................................................31
7.8.4.3 Interim Analyses and Data Monitoring.........................................................31
7.8.4.4 Multicenter Studies ......................................................................................31
7.8.4.5 Multiple Comparison/Multiplicity ................................................................31
7.8.4.6 Use of an “Efficacy Subset” of Subjects .......................................................32
7.8.4.7 Active-Control Studies Intended to Show Equivalence or Non-Inferiority....32
7.8.4.8 Subgroup Analysis .......................................................................................33
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................33
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Statistical Analysis Plan Version 3.0
23 July 2019
7.9.1
Pharmacokinetic Analysis ..................................................................................33
7.9.2
Pharmacodynamic Analysis ...............................................................................33
7.10
Other Outcomes.......................................................................................................33
7.11
Safety Analysis........................................................................................................34
7.11.1 Treatment-Emergent Adverse Events .................................................................34
7.11.1.1
Overview of Treatment-Emergent Adverse Events .................................34
7.11.1.2
Displays of Treatment-Emergent Adverse Events...................................35
7.11.2 Pretreatment Events ...........................................................................................37
7.11.2.1
Displays of Pretreatment Events .............................................................37
7.11.3 Clinical Laboratory Evaluations .........................................................................37
7.11.3.1
Hematology and Serum Chemistry .........................................................37
7.11.3.2
Urinalysis ...............................................................................................38
7.11.3.3
Serum Gastrin, Pepsinogen I/II...............................................................39
7.11.4 Vital Signs .........................................................................................................39
7.11.5 12-Lead ECGs ...................................................................................................40
7.11.6 Other Observations Related to Safety.................................................................40
7.11.6.1
Physical Examination .............................................................................40
7.12
Interim Analysis ......................................................................................................41
7.13
Changes in the Statistical Analysis Plan...................................................................41
8.0
REFERENCES..............................................................................................................42
9.0
APPENDIX...................................................................................................................43
9.1
Flowcharts for Imputing Missing or Partial Dates for Adverse Events and 
Concomitant Medications ........................................................................................43
9.2
Criteria for Markedly Abnormal Values...................................................................45
9.2.1
Hematology, Serum Chemistry, Urinalysis, Vital Signs, and 12-lead ECG 
(except Upper MAV Criteria of QTcF Interval)..................................................45
9.2.2
12-lead ECG (Upper MAV Criteria of QTcF Interval) .......................................48
9.3
Criteria for Elevated Liver Enzyme..........................................................................48
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TAK-438_304
Page 6 of 50
Statistical Analysis Plan Version 3.0
23 July 2019
LIST OF IN-TEXT TABLES
Table 4.a
Schedule of Study Procedures............................................................................11
Table 7.a
Electronic Case Report Form (eCRF) Data to be Applied for Duration of 
Exposure............................................................................................................17
Table 7.b
Number of Study Drug to Be Taken Per Day......................................................18
Table 7.c
Visit Analysis Window for Efficacy and Safety Variables..................................19
Table 9.a
Markedly Abnormal Values Criteria for Hematology.........................................46
Table 9.b
Markedly Abnormal Values Criteria for Serum Chemistry.................................47
Table 9.c
Markedly Abnormal Values Criteria for Vital Signs...........................................47
Table 9.d
Markedly Abnormal Values Criteria for 12-lead ECG........................................48
Table 9.e
Markedly Abnormal Values Criteria for 12-lead ECG (Upper MAV Criteria of 
QTcF Interval) ...................................................................................................48
Table 9.f
Markedly Abnormal Values Criteria for Elevated Liver Enzyme........................49
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ................................................................................10
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TAK-438_304
Page 7 of 50
Statistical Analysis Plan Version 3.0
23 July 2019
3.0
LIST OF ABBREVIATIONS
13C-UBT
13Carbon Urea Breath Test
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BID
twice daily
CI
confidence interval
CMH
Cochran–Mantel–Haenszel
ECG
electrocardiogram
eCRF
electronic case report form
EQ-5D-5L
Euro Quality of Life-5D-5L
F-1
Follow-up 2 weeks posttreatment
F-2
Follow-up 4 weeks posttreatment
FAS
full analysis set
hCG
human chorionic gonadotropin
HP
Helicobacter pylori
HP+
Helicobacter pylori infected
HP-
non-Helicobacter pylori infected
LLN
lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
PPI
proton pump inhibitor
PPS
per protocol set
PTE
pretreatment event
Q1
25th percentile
Q3
75th percentile
QD
once daily
QOL
quality of life
SAF
safety analysis set
SD
standard deviation
TEAE
Treatment-emergent adverse event
ULN
upper limit of normal
VAS
visual analogue scale
WHO Drug
World Health Organization Drug Dictionary
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TAK-438_304
Page 8 of 50
Statistical Analysis Plan Version 3.0
23 July 2019
4.0
OBJECTIVES
4.1
Primary Objectives
To demonstrate the noninferior efficacy of TAK-438 versus lansoprazole in the treatment of 
subjects with duodenal ulcer.
4.2
Secondary Objectives
To demonstrate the noninferiority of Helicobacter pylori (HP) eradication with TAK-438 versus 
lansoprazole.
To compare the safety of TAK-438 versus lansoprazole in subjects with duodenal ulcer.
4.3
Study Design
This is a phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group, 
noninferiority study of TAK-438 versus lansoprazole in subjects who have endoscopic evidence 
of duodenal ulcer with or without H pylori infection.
Approximately 530 subjects across approximately 60 sites in Asia will be randomized in a 
1:1 ratio to either TAK-438 20 mg or to lansoprazole 30 mg (265 subjects per treatment arm). 
The randomization will be stratified by HP status, ie,

TAK-438: 265 subjects.

Lansoprazole: 265 subjects.
Enrollment of Helicobacter pylori (H pylori) negative (ie, non-Helicobacter pylori infected) 
(HP-) subjects will be initiated first, until the availability of PK and safety data from a drug-drug 
interaction study to assess the effects of co-administration of TAK-438 with clarithromycin, 
amoxicillin, and bismuth as quadruple therapy in Helicobacter pylori infected (HP+) subjects.
Treatment Period:
A schematic of the study design is included as Figure 4.a. A schedule of assessments is listed in 
Table 4.a.
Dosing will begin on Day 1 after randomization (Visit 2) and last for up to 6 weeks. Study drug 
administration will depend on the Helicobacter pylori (H pylori) infection status of the subject.
Administration of the 2 treatments will be according to the following regimens:

H pylori infected (HP+) subjects will take TAK-438 20 mg or lansoprazole 30 mg (blinded 
with matching placebo) twice daily (BID) in addition to bismuth-containing quadruple 
antibiotic therapy (amoxicillin 1 g BID, clarithromycin 500 mg BID, and bismuth potassium 
citrate/bismuth tripotassium dicitrate 600 mg [equivalent to 220 mg bismuth] BID) for 
2 weeks. After 2 weeks of eradication therapy, subjects will be required to take only the 
TAK-438 or lansoprazole once daily (QD) for up to 4 weeks (ie, up to a total of 6 weeks of 
treatment). The subject remains in the same treatment arm throughout the study duration. 
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TAK-438_304
Page 9 of 50
Statistical Analysis Plan Version 3.0
23 July 2019

Non-H pylori infected (HP-) subjects will take TAK-438 or lansoprazole (blinded with 
matching placebo) QD for up to 6 weeks.
For all subjects, ulcer healing rates will be assessed by endoscopy at Weeks 4 and 6 of treatment. 
With or without endoscopic evidence of duodenal ulcer healing, the treatment duration of the 
study is no more than 6 weeks. 
Subjects (HP+ or HP-) with endoscopic healing of duodenal ulcer at Week 4 or at Week 6 will 
discontinue treatment at that time, and enter into the Follow-up period.
Subject (HP+ or HP-) without healing at Week 6 will discontinue treatment at Week 6 and enter 
into Follow-up period.
HP- subjects with no ulcer healing by Week 6 of the treatment period will be considered 
“completed cases” and be discontinued from the study.
Follow-up Period:
The subjects to be followed up will include both HP+ and HP- subjects with or without 
confirmed ulcer healing during the treatment period.
The recovery of serum gastrin-17 level and pepsinogen I/II ratio in Follow-up period (Visits F-1 
[follow-up 2 weeks posttreatment] and F-2 [follow-up 4 weeks posttreatment]) will be monitored 
for a maximum of 4 weeks. The Follow-up period ends when the recovery of serum gastrin-17 
level and pepsinogen I/II ratio are confirmed or at the end of 4-week Follow-up.
All HP+ subjects will provide a follow-up 13C-UBT at F-2 visit to ascertain HP eradication 
status.
For subjects with no ulcer healing at Week 6 of treatment, the investigator may follow local 
clinical practice and these subjects may be treated with another course of proton pump inhibitor
(PPI) or other anti-acid secretory agents or antibiotics, during the safety follow-up period (please 
see protocol Table 7.a). This should be documented during the F-2 visit.
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Figure 4.a
Schematic of Study Design
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Table 4.a
Schedule of Study Procedures
Screening 
Period
Treatment Period (b)
Follow-up Period (d)
Study Day/Week:
D -28 to 
D -1
D1
(a, u)
W2
(D15)
W4
(D29) 
(u)
W6
(D43) 
(u)
ET Visit 
(c)
2w Post-
treatment
4w Post-
treatment
Visit Windows (Days):
-
±3d
±3d
±3d
Within 
14d of 
last dose
D15 to 28
D29 to 42
Visit Number:
1
2
3
4
5
-
F-1
F-2
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history
X
Physical examination
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Weight and height
X
Concomitant medications
X
X
X
X
X
X
X(e)
X(e)
Concurrent medical conditions
X
Clinical laboratory tests (f)
X(g)
X
X
X
Liver function test (r)
X
Serum gastrin-17 / 
Pepsinogen I/II levels (total and ratio)
X
X
X
X
X(s)
X(t)
Urine pregnancy test - human chorionic 
gonadotropin (hCG) (h)
X
X
X
X
X
X
Hepatitis B and C tests (o)
X(g)
FSH (i)
X
Guidance on avoidance of pregnancy (h) 
X
X
X
X
X
X
Electrocardiogram (ECG)
X(k)
X(j)
X
X
Endoscopy 
X(k)
X
X
X
13C-UBT to confirm H infection status
X(g)
X(n)
Investigator review of gastrointestinal symptoms
X
X
X
X
X
Quality of life (QOL) questionnaire - Euro 
Quality of Life-5D-5L (EQ-5D-5L) (p)
X
X
X
X
X
Randomization via IWRS
X(l)
Obtain subject number via IWRS
X
Dispense TAK-438/
lansoprazole via IWRS
X
X
X(m)
Dispense companion drug via IWRS 
X(q)
Drug return/ accountability/ compliance
X
X
X
X
Register subject as discontinued or completed 
via IWRS
X(j)
X
X
X
Pretreatment event (PTE) assessment
X
X
AE assessment
X
X
X
X
X
X
X
D=Day, W=Week, ET=Early Termination.
(a) 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.
(b) If and when endoscopic healing of duodenal ulcer has been confirmed in the subject, he/she will complete the treatment 
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period and move directly into the Follow-up period.
(c) Conduct Final Visit procedures for subjects discontinued from treatment early per Section 3.9.6. 
(d) The subject will move on to the Follow-up period after discontinuation of treatment, either after Visit 4 (Week 4) for subjects 
with endoscopic healing of the duodenal ulcer[s] only, or after Visit 5 (Week 6) for all subjects regardless of ulcer healing. All 
subjects will complete the scheduled Follow-up period visits for a maximum of 4 weeks until the recovery of serum gastrin-17 
level and pepsinogen I/II ratio are confirmed or for a maximum of 4 weeks. and the HP+ subjects will provide the 13C-UBT
sample at F-2.
(e) The use of gastric mucosal protective agents may be allowed during the Follow-up period. F-2 will be performed for 
13C-UBT.
(f) Hematology, serum chemistries, and urinalysis tests will be done at the central laboratory. Local laboratories may be used to 
perform laboratory tests only under special circumstances, on case by case basis with sponsor’s agreement.
(g) Visit window: Day –14 to Day 1 (predose).
(h) Women of childbearing potential.
(i) Only if menopause is suspected. 
(j) ECG and registration in IWRS of study completion to be performed at Week 4 only for those subjects in whom endoscopic 
healing is confirmed; thereafter those subjects will move directly into the Follow-up period.
(k) Visit window: Day –14 to Day 1 (predose). If endoscopy with associated images has been performed within 14 days prior to 
Day 1, the study-specific endoscopy may be waived in favor of the existing results, providing that the subject has not been using 
agents that affect the digestive organs since that examination. If an ECG has been performed within 14 days prior to 
randomization, the study-specific ECG may be waived.
(l) Subjects must not have been given any other agent affecting the digestive organs on the day of randomization and must take 
the first dose of study medication on the day of randomization during the Day 1 visit. 
(m) To be performed as appropriate for those subjects in which endoscopic healing has not been confirmed during visits 
involving endoscopy.
(n) 13C-UBT should be repeated at least 4 weeks after eradication therapy for all HP+ subjects at F-2 to ascertain HP eradication 
status. 
(o) Hepatitis B and C analysis in accordance with Section 9.1.8 Table 9.b will be conducted at the central laboratory. Hepatitis B 
and C tests performed as per local routine practice within 14 days prior to randomization (Day 1), before signing of informed 
consent form will be accepted. 
(p) EQ-5D-5L questionnaire shall be the first priority in all procedures (except signing the ICF) at each visit.
(q) Only for HP+ subjects.
(r) Liver function tests include alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and direct 
bilirubin.
(s) Completed by subjects with or without ulcer healing regardless of HP status.
(t) Completed by subjects with or without ulcer healing regardless of HP status, only if no serum gastrin-17 or pepsinogen I/II 
recovery at F-1 visit.
(u) The subject will be instructed to present to the clinic prior to taking the study medication at the visits during the treatment 
phase in which serum gastrin and pepsinogen I/II levels will be measured or endoscopy will be performed. The study medication 
will be taken by the subject after completion of assessments on the days of those study visits. 
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5.0
ANALYSIS ENDPOINTS
Primary Endpoint 
The primary endpoint for this study is the percentage of subjects with endoscopically confirmed 
healing* of duodenal ulcer at Week 4 or 6.
*Rate of endoscopic healing: defined as the proportion of subjects in whom the disappearance of 
all white coats associated with duodenal ulcers has been endoscopically confirmed.
Secondary Endpoints
Secondary endpoints for this study are:

Percentage of HP+ subjects with successful H pylori eradication after 4 or 6 weeks of 
treatment, as determined by 13C-UBT at F-2.

Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at Week 4.

Percentage of subjects with posttreatment resolution of gastrointestinal symptoms associated 
with duodenal ulcer (epigastric pain [postprandial, fasting, nocturnal], abdominal bloating, 
nausea/vomiting, heartburn, lack of appetite) at Weeks 2 through 6.
Additional Endpoints
Additional efficacy endpoints include:

QOL measurement EQ-5D-5L.

Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at either 
Week 4 or Week 6 based on their baseline H pylori status. 

Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at Week 4 
based on their baseline H pylori status. 

Percentage of subjects with H pylori infection at Baseline who achieve endoscopically 
confirmed healing of duodenal ulcer either at Week 4 or Week 6 based on their H pylori 
status at Follow-up visit F-2. 

Percentage of subjects with H pylori infection at Baseline who achieve endoscopically 
confirmed healing of duodenal ulcer at Week 4 based on their H pylori status at Follow-up 
visit F-2.
Safety endpoints include adverse events (AEs), serious adverse events (SAEs), laboratory test 
values, ECG, vital signs, serum gastrin-17, and pepsinogen I/II values (total and ratio).
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6.0
DETERMINATION OF SAMPLE SIZE
The protocol for TAK-438_304 study was written in 2012 while the TAK-438 duodenal ulcer 
pivotal study (CCT-102) was still ongoing in Japan. The sample size of 640 was based on the 
assumption that the Week 6 duodenal ulcer healing rate would be 97.8% for both TAK-438 and 
lansoprazole, and assuming a dropout rate of up to 20%. The assumption for the ulcer healing 
rate was based on historical studies with lansoprazole. In a phase 3 study in Japan to compare the 
efficacy of lansoprazole and famotidine for healing of duodenal ulcer, the Week 6 healing rate 
was 97.8% for lansoprazole and 91.5% for famotidine.
TAK-438 CCT-102 study was completed in 2013. The duodenal ulcer healing rate was 95.5% in 
the TAK 438 treatment arm. The design of TAK-438-304 study is based on TAK-438 CCT-102 
study with identical key enrollment criteria. Therefore, the sample size has been recalculated 
based on a 95.5% healing rate. In addition, since H pylori eradication rate is a secondary 
endpoint, this endpoint has not been used for sample size calculation.
Assuming that the true Week 6 duodenal ulcer healing rate is 95.5% for both TAK-438 and 
lansoprazole, and assuming that the dropout rate is up to 10%, a sample size of 265 subjects per 
group in the overall population, including no fewer than 238 Chinese subjects per group, will 
provide at least 80% power to establish noninferiority in the Chinese population using a 2-sided 
95% confidence interval (CI) with a -6% noninferiority margin. This sample size 83.9% power to 
establish noninferiority in the overall population.
In a phase 3 study in Japan to compare the efficacy of lansoprazole and famotidine for healing of 
duodenal ulcer, the Week 6 healing rate was 97.8% for lansoprazole and 91.5% for famotidine, 
corresponding to a difference of 6.3%. Additionally, in studies of lansoprazole versus placebo in 
US (M87-090), the Week 4 healing rate was 91.7% for lansoprazole 30 mg and 46.1% for 
placebo in one study, corresponding to a difference of 45.6%, and 80.3% for lansoprazole 30 mg 
and 47.5% for placebo in the other study, corresponding to a difference of 32.8%. A 
noninferiority margin of -6% is specified, which is less than the difference between lansoprazole 
and famotidine in the Japanese study and less than half of the difference between lansoprazole 
and placebo in the US studies.
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.4, or higher.
All CIs, statistical tests, and resulting P-values will be reported as 2-sided and will be assessed at 
α=0.05 significance level unless otherwise stated. P-values will be rounded to 4 decimal places 
prior to assessment of statistical significance.
Means, 25th percentile (Q1), medians, and 75th percentile (Q3) will be presented to 1 more 
decimal place than the recorded data. The standard deviations (SDs) will be presented to 2 more 
decimal places than the recorded data. Minimum and maximum values will be presented using 
the same number of decimal places as the recorded data. CIs about a parameter estimate will be 
presented using the same number of decimal places as the parameter estimate.
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportions of each possible value will be tabulated by treatment group. 
The denominator for the proportion will be based on the number of subjects who provided 
non-missing responses to the categorical variable. The proportion will be reported to 1 decimal 
place.
For continuous variables, the number of subjects with non-missing values, mean, Q1, median, 
Q3, SD, minimum, and maximum values will be tabulated unless otherwise noted. 
7.1.1
Study Definitions
The following definitions and calculation formulas will be used.

Descriptive statistics: number of subjects with non-missing values, mean, SD, maximum, 
minimum, Q1, median, Q3.

Percentage of subjects with endoscopically confirmed healing of duodenal ulcer (ie, the rate 
of endoscopic healing): The proportion of subjects in whom the disappearance of all white 
coats associated with duodenal ulcers has been endoscopically confirmed.

Screening Failure: Subject who is not eligible prior to randomization.

Treatment Emergent Adverse Event (TEAE): An AE whose date of onset occurs on or after 
the start of study drug. A TEAE whose relationship to study drug is missing will be 
considered drug-related. A TEAE whose intensity is missing will be considered severe.

Significant TEAE: Any TEAE (not including serious TEAEs) that led to an intervention, 
including withdrawal of drug treatment, dose increase, dose reduction, dose interrupted or 
significant additional concomitant therapy.

Pretreatment Events: A 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 drug; it does not necessarily have to have a causal relationship 
with study participation.
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
CI for one sample proportion: Exact (Clopper-Pearson) CI will be used.

CI for two sample proportion difference: Wald CI will be used unless otherwise specified.

CI for two sample proportion difference for efficacy endpoints of healing rate of duodenal 
ulcer: Newcombe methods will be used.

Age (years): Age was obtained at screening visit and presented in years.

Multiracial: Any subject who selects more than one race category will be classified as 
‘Multiracial’.

BMI (kg/m2): weight (kg) / (height (m))2 (rounded to 1 decimal place).

Time Since Onset of Current Ulcers (Days): Time since onset of current ulcers to informed 
consent signed.

Time Since Onset of Recurrent Ulcers (Days): Time since onset of recurrent ulcers to 
informed consent signed.

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).
Definition of Study Days and Baseline

Study Days: Study Day 1 is defined as the date on which a subject is administered their first 
dose of the medication [‘Date of Dose’ in First Dose (QD Treatment) CRF page for 
HP-subjects; ‘Date of Dose’ in First Dose (BID Treatment) for HP+ subjects]. Other study 
days are defined relative to the Study Day 1 with Day 1 being Study Day 1 and Day -1 being 
the day prior to Study Day 1.
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.
If the date of an event is on or after the date of first dose then Study Day = date of event – date of 
first dose + 1. If the date of an event is prior to the date of first dose then Study Day = date of 
event – date of first dose.

Baseline values are defined as the last observed value before the first dose of study 
medication on Day 1 (including a screening value or unscheduled assessment, if necessary).
Duration of Exposure

Duration of exposure to double-blind study medication (days): date of last dose of 
double-blind study medication - date of first dose of double-blind study medication + 1.
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Table 7.a
Electronic Case Report Form (eCRF) Data to be Applied for Duration of 
Exposure
eCRF Data to be Applied for Duration of Exposure
Date of First Dose
Date of Last Dose
Double-Blind Study Medication
For HP+ subjects
‘Date of Dose’ in First Dose (BID 
Treatment)
‘Date of Last Dose’ in End of Study
For HP- subjects
‘Date of Dose’ in First Dose (QD 
Treatment)
‘Date of Last Dose’ in End of Study
Each Companion Drug
For HP+ subjects 
in the first 2 
weeks
‘Date of Dose’ in First Dose (BID 
Treatment)
‘Date of Dose End’ in Last Dose (BID 
treatment)
Study Drug Compliance

Study drug compliance (%). 
= (number of days the study medication taken) / duration of exposure to study medication x
100% (rounded to 1 decimal place)
= (number of study medication dispensed – number of study medication returned) ÷ Θ / (date of 
last dose -date of first dose +1) x 100%
Θ: Number of tablet/capsules required to be taken per day.
Overall study drug compliance for double-blind study medication (HP+ subjects)=
∑
[(number of study medication dispensed – number of study medication returned) ÷  Θι]
2
=1
date of last dose of study medication - date of first dose of study medication + 1
x100%
Θ1: Number of tablet/capsules required to be taken per day in the first 2 weeks for HP+ subjects.
Θ2: Number of tablet/capsules required to be taken per day in Weeks 3-6 for HP+ subjects.
Overall study drug compliance for double-blind study medication (HP- subjects)=
(number of study medication dispensed –  number of study medication returned) ÷  Θ
date of last dose of study medication - date of first dose of study medication + 1
x100%
Θ: Number of tablet/capsules required to be taken per day in the 6 weeks for HP- subjects.
Study drug compliance for each companion drug=
(number of study medication dispensed –  number of study medication returned) ÷  Θ
date of last dose of BID treatment - date of first dose of BID treatment + 1
x100%
Θ: Number of tablet/capsules required to be taken per day.
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Table 7.b
Number of Study Drug to Be Taken Per Day
Planned Dose 
Θ: Number of Tablet/Capsules Required to Be Taken Per Day
Double-Blind Study Medication
For HP+ subjects in the first 2 weeks
TAK-438 20 mg (or TAK-438 20 mg matching placebo) BID
2
tablets
Lansoprazole 30 mg (or lansoprazole 30 mg matching placebo) BID
2
capsules
For HP+ subjects in Weeks 3-6 and HP- subjects for 6 weeks
TAK-438 20 mg (or TAK-438 20 mg matching placebo) QD
1
tablets
Lansoprazole 30 mg (or lansoprazole 30 mg matching placebo) QD
1
capsules
Each Companion Drug
For HP+ subjects in the first 2 weeks
Amoxicillin 1 g BID 
4
capsules
Clarithromycin 500 mg BID
2
tablets
Bismuth potassium citrate/bismuth tripotassium dicitrate 600 mg BID
4
tablets
Note: Amoxicillin 500 mg/cap, Clarithromycin 500 mg/tab, bismuth potassium citrate/bismuth tripotassium dicitrate
300 mg/tab.
7.1.2
Definition of Study Visit Windows
For each visit, all evaluable observation (ie, non-missing) obtained in the corresponding time 
interval (ie, window) will be used. This window will establish a time interval around which data 
will be considered for the analysis of the scheduled visit pertaining to that window. 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. The visit windows and applicable study day ranges are 
presented in Table 7.c. 
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Table 7.c
Visit Analysis Window for Efficacy and Safety Variables
Visit Window (Days)
Visit
Scheduled 
Visit Day
(a) 
Variables 
Scheduled 
at Week 4, 
Week 6
(b) 
Variables 
Scheduled 
at Week 2, 
Week 4, 
Week 6
(c) 
Variables 
Scheduled 
at Week 2, 
Week 4, 
Week 6
(d) 
Variables 
Scheduled 
at Week 2, 
Week 4, 
Week 6, 
F-1, F-2
Serum gastrin-
17, Pepsinogen 
I/II (total and 
ratio) 
Scheduled at 
Week 4, Week 
6, 
F-1, F-2
13C-UBT 
Scheduled at F-2
Baseline
1
Day -14 –
<=1
Day -14 –
<=1
Day -28 –
<=1
Day -28 –
<=1
<=1
Day -14 – <=1
Week 2
15
2 – 21 
and <= 
14 Days 
after the 
Last Dose
2 – 21
and <= 
14 Days 
after the 
Last Dose
2 – 21
and <= 
14 Days 
after the 
Last Dose
Week 4
29
2 – 35
and <= 14 
Days after 
the Last 
Dose
22 – 35
and <= 14 
Days after 
the Last 
Dose
22 – 35
and <= 14 
Days after 
the Last 
Dose
22 – 35
and <= 14 
Days after 
the Last 
Dose
2 – 35
and <= 14 Days 
after the Last
Dose
Week 6
43
36 – 57
and <= 14 
Days after 
the Last 
Dose
36 – 57
and <= 14 
Days after 
the Last 
Dose
36 – 57
and <= 14 
Days after 
the Last 
Dose
36 – 57
and <= 14 
Days after 
the Last 
Dose
36 – 57
and <= 14 Days 
after the Last 
Dose
2 Weeks Post-
Treatment (F-1)
Follow-up 
Day 15
Follow-up 
Day 15 - 28
Follow-up 
Day 15 - 28
4 Weeks Post-
Treatment (F-2)
Follow-up 
Day 29
Follow-up 
Day 29 - 42
Follow-up 
Day 29 – 42 (e)
Day 2 - (f)
Note: Baseline values are defined as the last observed value before the first dose of study medication on Day 1 (including 
a screening value or unscheduled assessment, if necessary). Any value collected on Day 1 but after the administration of 
first dose will be grouped under Week 2.
Note: All efficacy data in treatment period (eg, week 2, 4 and 6) tested 15 days after last dose were excluded from the 
analysis. The day after the last dose of the study medication will be defined as 1 Day after the last dose. 
(a) Clinical laboratory tests including hematology, serum chemistries (variables other than ALT, AST, total bilirubin, and 
direct bilirubin), and urinalysis tests, Endoscopy, ECG.
(b) Variables of liver function tests including ALT, AST, total bilirubin, and direct bilirubin.
(c) Vital signs, Urine pregnancy test (hCG), Gastrointestinal symptoms, QOL questionnaire (EQ-5D-5L).
(d) Physical examination.
(e) Only if no serum gastrin-17 or pepsinogen I/II recovery at F-1 visit.
(f) 13C-UBT should be repeated for HP+ subjects at F-2 to ascertain HP eradication status. If subjects have administered 
antibiotics (defined as “J01” of the second level ATC code), PPIs (defined as “A02BC” of the fourth level ATC code), or 
study drug within 14 days prior to 13C-UBT, the data will be excluded from the analysis.
7.1.3
Data Handling Rules
7.1.3.1
Handling of Rate of Endoscopic Healing
A subject in whom the disappearance of all white coats associated with duodenal ulcers has been 
endoscopically confirmed at Week 4 or Week 6 will be considered as a healed subject. Subjects 
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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.
7.1.3.2
Handling of Percentage of Subjects with Posttreatment Resolution of Each 
Gastrointestinal Symptom Associated with Duodenal Ulcer at Week 2 through 6
Each gastrointestinal symptom related to duodenal ulcer (epigastric pain [postprandial, 
fasting/nocturnal], abdominal bloating, nausea/vomiting, heartburn, lack of appetite) will be 
captured at the start of the treatment period (Visit 2) in “Gastrointestinal Symptoms” eCRF page. 
At all visits from Visit 2 through the completion of the study drug administration, symptoms 
noted at Visit 2 will be followed up. If any symptom resolved during the treatment period, the 
date of resolution will be recorded in the “Gastrointestinal Symptoms” eCRF page. Subjects with 
symptoms at baseline who do not have any information on date of resolution or end of treatment 
status will be excluded from the efficacy analysis for the corresponding symptom. Subjects 
without any symptom at baseline will also be excluded from the efficacy analysis for the 
corresponding symptom.
Percentage of subjects with posttreatment resolution of each gastrointestinal symptom associated 
with duodenal ulcer at Week 2 through 6 = (number of subjects with date of resolution reported 
in “If Yes, and resolved, date of resolution” field at the specified gastrointestinal symptom) / 
(number of subjects with “Yes” selected for the specified gastrointestinal symptom associated 
with duodenal ulcer at the start of treatment period) * 100 (rounded to 1 decimal place).
7.1.3.3
Handling of EQ-5D-5L
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.
7.1.4
Conventions for Missing AE Dates
Imputing Missing or Partial Dates for AEs is described in Appendix 9.1 Flowcharts for Imputing 
Missing or Partial Dates for AEs and Concomitant Medications (Guideline for Data Handling 
Rule Version 1.0, dated of September 20, 2011).
AEs with onset occurring from the time that the subject is first administered study drug (visit 2, 
randomization) to the subject’s last study visit (ie, early termination or follow-up visit) should be 
included in data listings but not summary tables.
7.1.5
Conventions for Missing Concomitant Medication Dates
Imputing Missing or Partial Dates for Concomitant Medications is described in Appendix 9.1
Flowcharts for Imputing Missing or Partial Dates for AEs and Concomitant Medications.
7.2
Analysis Sets
Subjects whose sites failed CFDA inspection will be excluded from all analysis sets.
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Analysis of efficacy variables will be conducted in the full analysis set defined as all subjects 
who were randomized and received at least 1 dose of the study drug (ie, TAK-438 or 
lansoprazole or matching placebo). Subjects in this set will be analyzed according to the original 
randomization.
The primary efficacy endpoint will also be analyzed in the per-protocol analysis set (PPS) 
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.

Subjects who met exclusion criteria #8, #11, #12, #13, #14, #15, #16, #17, or #18.

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 (ie, TAK-438 or lansoprazole or matching placebo)
and will be based on the treatment received.
7.3
Disposition of Subjects
7.3.1
Study Information
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables:
Date First Subject Signed Informed Consent Form
Date of Last Subject’s Last Visit/Contact
MedDRA Version
WHO Drug Version
SAS Version Used for Creating the Datasets
Analytical Methods:
(1) Study Information
Study information shown in the analysis variables section will be provided.
7.3.2
Screen Failures
Analysis Set:
All Subjects Who 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, Multiracial]
Analytical Methods:
(1) Screen Failures
Frequency distributions for categorical variables and descriptive statistics for continuous 
variables will be provided.
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Statistical Analysis Plan Version 3.0
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7.3.3
Subject Eligibility
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables:
Is the subject eligible for randomization into the 
Treatment Phase?
[Yes, No]
Primary Reason for Subject Not Being Eligible
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation, 
Lost to Follow-Up, 
Voluntary Withdrawal, 
Study Termination, 
Did Not Meet Entrance Criteria, 
Other]
Analytical Methods:
(1) Eligibility for 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.
7.3.4
Number of Subjects Randomized by Country, Site, and Treatment Group
Analysis Set:
Randomized Set
Analysis Variables:
Randomization Status
[Yes]
Stratum:
Country
[China, Korea, Philippines, 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.
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Statistical Analysis Plan Version 3.0
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7.3.5
Disposition of Subjects
Analysis Set:
Randomized Set
Analysis Variables:
Double-Blind Study Drug Administration 
Status
[No]
Reason for Not Being Treated
with Double-Blind Study Drug
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation, 
Lost to Follow-Up, 
Voluntary Withdrawal, Study Termination, 
Pregnancy, Lack of Efficacy, Other]
Double-Blind Study Drug Completion Status [Completed Study Drug, 
Prematurely Discontinued Study Drug]
Reason for Discontinuation of 
Double-Blind Study Drug
[Pretreatment Event/Adverse Event, 
Significant 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.
7.3.6
Protocol Deviations and Analysis Sets
7.3.6.1
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 
category. A subject who has several deviations that can be classified into the same category 
will be counted only once.
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Statistical Analysis Plan Version 3.0
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7.3.6.2
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.
7.4
Demographic and Other Baseline Characteristics
Analysis Set:
Randomized Set
Analysis Variables:
Country
[China, Korea, Philippines, 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, Multiracial]
Height (cm)
[Min<= - <150, 150<= - <160, 
160<= - <170, 170<= - <=Max]
Weight (kg) 
[Min<= - <50, 50<= - <60, 
60<= - <70, 70<= - <80, 
80<= - <=Max]
BMI (kg/m2) 
[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 (More Than 5 Times Per Week), 
No (Never Drink or Less Than 5 Times Per 
Week)]
History of H. pylori Eradication
Therapy
[Yes (Therapy Received Ever), 
No (Never Receive Any Therapy)]
H. pylori Infection Status (Result of 13-C 
Urea Breath Test)
[Positive, Negative]
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Statistical Analysis Plan Version 3.0
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Characteristics of Duodenal Ulcers
Location (a)
[Superior Part (Including Bulb), 
Descending Part]
Number of Ulcers Found
Ulcer Morphology (a)
[Circular, Ellipsoidal, Other]
Ulcer Size (a)
[Minuscule (<5 mm), 
Minor (>=5 mm/<10 mm), 
Intermediate (>=10 mm/<=20 mm), 
Large (>20 mm/<30 mm), 
Giant (>=30 mm)]
History of Duodenal Ulcers
Time Since Onset of Current Ulcers 
(Days)
Use of NSAIDs or Low-dose Aspirin 
(Except Topical Preparations) at the 
Time of Ulcer Onset
[Yes, No]
Type of Ulcers
[Primary, Recurrent]
Time Since Onset of Recurrent Ulcers 
(Days)
EQ-5D-5L
EQ-5D-5L Index Value (Screening)
EQ Visual Analogue Scale (VAS) Score (Screening)
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.
(a) In case of multiple lesions, information needs to be obtained on the largest of the lesions.
7.5
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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Statistical Analysis Plan Version 3.0
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7.6
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.
7.7
Study Drug Exposure and Compliance
7.7.1
TAK-438/Lansoprazole and Matching Placebo Exposure and Compliance
Analysis Set:
Safety Analysis Set
Analysis Variables:
Duration of Exposure to Study Drug (days)
[1<= - <=14, 15<= - <=28, 29<= - <=42, 
43<= - <=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 of TAK-438/Lansoprazole and matching placebo for categorical 
variables and descriptive statistics for continuous variables will be provided by treatment 
group and overall.
7.7.2
Companion Drugs Exposure and Compliance
Analysis Set:
Safety Analysis Set with HP+ Subjects at baseline
Analysis Variables:
Duration of Exposure to Amoxicillin(days)
[1<= - <=14, 15<= - <=Max]
Duration of Exposure to Clarithromycin 
(days)
[1<= - <=14, 15<= - <=Max]
Duration of Exposure to Bismuth(days)
[1<= - <=14, 15<= - <=Max]
Amoxicillin Compliance (%)
[Min<= - <50.0, 50.0<= - <70.0, 
70.0<= - <90.0, 90.0<= - <=Max]
Clarithromycin Compliance (%)
[Min<= - <50.0, 50.0<= - <70.0, 
70.0<= - <90.0, 90.0<= - <=Max]
Bismuth Compliance (%)
[Min<= - <50.0, 50.0<= - <70.0, 
70.0<= - <90.0, 90.0<= - <=Max]
Analytical Methods:
(1) Companion Drugs Exposure and Compliance
Frequency distributions of each companion drug (amoxicillin, clarithromycin, and bismuth 
potassium citrate/bismuth tripotassium dicitrate) for categorical variables and descriptive 
statistics for continuous variables will be provided by treatment group and overall.
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Statistical Analysis Plan Version 3.0
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7.8
Efficacy Analysis
7.8.1
Primary Efficacy Endpoint(s)
7.8.1.1
Primary Analysis
Analysis Set:
Full Analysis Set
Analysis Variable:
Percentage of subjects with endoscopically confirmed healing* of duodenal ulcer at Week 4
or 6.
*Rate of endoscopic healing: defined as the proportion of subjects in whom the 
disappearance of all white coats associated with duodenal ulcers has been endoscopically 
confirmed.
Analytical Methods:
The healing rate of duodenal ulcer at Week 4 or Week 6 and the 2-sided 95% CI will be 
provided by treatment group. The healing rate difference between the TAK-438 treatment 
group and the lansoprazole treatment group (the TAK-438 treatment group minus the 
lansoprazole group) at Week 4 or Week 6 and the 2-sided 95% CIs using newcombe 
methods will be provided. If the lower bound of the 95% CI is ≥-6%, non-inferiority for 
TAK-438 relative to lansoprazole with regard to duodenal ulcer healing will be declared.
7.8.1.2
Secondary Analysis
Analysis Set:
Per Protocol Set
Analysis Variable:
Percentage of subjects with endoscopically confirmed healing* of duodenal ulcer at Week 4
or 6 (%)
*Rate of endoscopic healing: defined as the proportion of subjects in whom the 
disappearance of all white coats associated with duodenal ulcers has been endoscopically 
confirmed.
Analytical Methods:
A sensitivity analysis will be performed to check the robustness of the results, the same 
analyses as those in section 7.8.1.1 will be performed using the PPS.
7.8.2
Secondary Efficacy Endpoint(s)
7.8.2.1
Percentage of Subjects with Endoscopically Confirmed Healing of Duodenal Ulcer at 
Week 4
Analysis Set:
Full Analysis Set
Analysis Variable:
Percentage of Subjects with Endoscopically Confirmed Healing of Duodenal Ulcer at Week 
4 (%)
Analytical Methods:
The healing rate of duodenal ulcer at Week 4 and the 2-sided 95% CI will be provided by 
treatment group. The healing rate difference between the TAK-438 treatment group and the 
lansoprazole treatment group (the TAK-438 treatment group minus the lansoprazole group) 
at Week 4 and the 2-sided 95% CIs using newcombe methods will be provided. If the lower 
bound of the 95% CI is ≥-6%, noninferiority for TAK-438 relative to lansoprazole with 
regard to duodenal ulcer healing will be declared. Details concerning interpretation are 
described in section 7.8.4.5.
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Statistical Analysis Plan Version 3.0
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7.8.2.2
Percentage of HP+ Subjects with Successful H pylori Eradication after 4 or 6 Weeks of 
Treatment, as Determined by 13C-UBT at F-2
Analysis Set:
Full Analysis Set with HP+ Subjects at baseline
Analysis Variable:
Percentage of HP+ Subjects with Successful H pylori Eradication after 4 or 6 Weeks of 
Treatment, as Determined by 13C-UBT at F-2 (%)
Analytical Methods:
Frequency distributions will be provided by treatment group along with rates and the two-
sided 95% CIs. 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% 
CIs will be provided.
7.8.2.3
Percentage of Subjects with Posttreatment Resolution of Gastrointestinal Symptoms 
Associated with Duodenal Ulcer at Weeks 2 Through 6
Analysis Set:
Full Analysis Set
Analysis Variable:
Percentage of Subjects with Posttreatment Resolution of Gastrointestinal Symptoms 
Associated with Duodenal Ulcer at Weeks 2 Through 6 (%)
Analytical Methods:
For each symptom (epigastric pain [postprandial, fasting, nocturnal], abdominal bloating, 
nausea/vomiting, heartburn, lack of appetite), Frequency distributions will be provided by 
treatment group along with rates and the two-sided 95% CIs. 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% CIs will be provided.
7.8.3
Additional Efficacy Endpoint(s)
Additional efficacy endpoints include:
7.8.3.1
QOL Measurement EQ-5D-5L
EQ-5D-5L Index Value
Analysis Set:
Full Analysis Set
Analysis Variables:
EQ-5D-5L Index Value
Covariates:
H pylori status (Baseline)
[HP+, HP-]
EQ-5D-5L Index Value (Baseline)
Visit:
Baseline, Week 2, Week 4, Week 6
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Statistical Analysis Plan Version 3.0
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Analytical Methods:
(1) Summary of EQ-5D-5L Index Value
Descriptive statistics will be provided for each visit for the observed values and for each 
post-baseline visit for the changes from baseline (each post-baseline visit - baseline) by 
treatment group. The mean differences in the changes from baseline between the TAK-438
group and the lansoprazole group (the TAK-438 group – the lansoprazole group) and the 
two-sided 95% CIs will be provided for each post-baseline visit. Two sample t-tests will be 
used to test for treatment differences at each post-baseline visit.
(2) ANCOVA
The changes from baseline (each post baseline visit - baseline) in the analysis variable will 
be analyzed using an ANCOVA model with treatment and baseline H pylori Status as factors 
and baseline EQ-5D-5L index value as a covariate. The ANCOVA analysis will be 
performed at each post baseline visit.
LS means and the two-sided 95% CIs will be provided for each treatment group. The 
difference in the LS means between the TAK-438 group and the lansoprazole group (the
TAK-438 group – the lansoprazole group) and the two-sided 95% CI will be provided. The 
difference in the LS means will be tested for treatment differences.
EQ VAS Score
Analysis Set:
Full Analysis Set
Analysis Variables:
EQ VAS Score
Covariates:
H pylori Status (Baseline)
[HP+, HP-]
EQ VAS Score (Baseline)
Analytical Methods:
The same analyses as those in section 7.8.3.1 “EQ-5D-5L Index Value” will be conducted 
for the EQ VAS score.
7.8.3.2
Percentage of Subjects with Endoscopically Confirmed Healing of Duodenal Ulcer at 
either Week 4 or Week 6 Based on Their Baseline H pylori Status 
Analysis Set:
Full Analysis Set
Analysis Variable:
Percentage of Subjects with Endoscopically Confirmed Healing of Duodenal Ulcer at either 
Week 4 or Week 6 Based on Their Baseline H pylori Status [HP+, HP-]
Analytical Methods:
(1) Percentage of Subjects with Endoscopically Confirmed Healing of Duodenal Ulcer 
at either Week 4 or Week 6 Based on Their Baseline H pylori Status
Percentage of subjects with endoscopically confirmed healing of duodenal ulcer and the 2-
sided 95% CI will be provided by treatment group and baseline H pylori status. Healing 
percentage difference between the TAK-438 treatment group and the lansoprazole treatment 
group (the TAK-438 treatment group minus the lansoprazole group) and the 2-sided 95% 
stratified newcombe CI with baseline H pylori status as a stratified factor will be provided.
7.8.3.3
Percentage of Subjects with Endoscopically Confirmed Healing of Duodenal Ulcer at 
Week 4 Based on Their Baseline H pylori Status 
Analysis Set:
Full Analysis Set
Analysis Variable:
Percentage of Subjects with Endoscopically Confirmed Healing of Duodenal Ulcer at Week 
4 Based on Their Baseline H pylori Status [HP+, HP-]
Analytical Methods:
The same analyses as those in section 7.8.3.2 “Percentage of Subjects with Endoscopically 
Confirmed Healing of Duodenal Ulcer at either Week 4 or Week 6 Based on Their Baseline 
H pylori Status” will be applied.
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Statistical Analysis Plan Version 3.0
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7.8.3.4
Percentage of Subjects with H pylori Infection at Baseline Who Achieve Endoscopically 
Confirmed Healing of Duodenal Ulcer Either at Week 4 or Week 6 Based on Their H 
pylori Status at Follow-up Visit F-2 
Analysis Set:
Full Analysis Set with HP+ Subjects at baseline
Analysis Variable:
Percentage of Subjects with H pylori Infection at Baseline Who Achieve Endoscopically 
Confirmed Healing of Duodenal Ulcer Either at Week 4 or Week 6 Based on Their H pylori
Status at Follow-up Visit F-2 (%)
Analytical Methods:
Percentage of Subjects with Endoscopically Confirmed Healing of Duodenal Ulcer at 
either Week 4 or Week 6 Based on Their Baseline H pylori Status 
Percentage of subjects with endoscopically confirmed healing of duodenal ulcer and the 2-
sided 95% CI will be provided by treatment group and H pylori status at Follow-up Visit F2. 
Healing percentage difference between the TAK-438 treatment group and the lansoprazole 
treatment group (the TAK-438 treatment group minus the lansoprazole group) and the 2-
sided 95% stratified newcombe CI with H pylori status at Follow-up Visit F-2 as a stratified 
factor will be provided.
7.8.3.5
Percentage of Subjects with H pylori Infection at Baseline Who Achieve Endoscopically 
Confirmed Healing of Duodenal Ulcer at Week 4 Based on Their H pylori Status at 
Follow-up Visit F-2
Analysis Set:
Full Analysis Set with HP+ Subjects at baseline
Analysis Variable:
Percentage of Subjects with H pylori Infection at Baseline Who Achieve Endoscopically 
Confirmed Healing of Duodenal Ulcer at Week 4 Based on Their H pylori Status at Follow-
up Visit F-2 (%)
Analytical Methods:
The same analyses as those in section 7.8.3.4 “Percentage of Subjects with Endoscopically 
Confirmed Healing of Duodenal Ulcer at either Week 4 or Week 6 Based on Their H pylori
Status at Follow-up Visit F-2” will be applied.
7.8.4
Statistical/Analytical Issues
7.8.4.1
Adjustments for Covariates
Analysis Set:
Full Analysis Set
Analysis Variable:
Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at Week 4 or 
6 (%)
Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at Week 4
(%)
Percentage of subjects with posttreatment resolution of gastrointestinal symptoms associated 
with duodenal ulcer at Weeks 2 through 6 (%)
Stratified Variable:
H pylori status (Baseline)
[HP+, HP-]
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Statistical Analysis Plan Version 3.0
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Analytical Methods: (1) CMH Test for Percentage of subjects with endoscopically confirmed healing of 
duodenal ulcer at Week 4 or 6 (%)
(2) CMH Test for Percentage of subjects with endoscopically confirmed healing of 
duodenal ulcer at Week 4 (%)
(3) CMH Test for Percentage of subjects with posttreatment resolution of gastrointestinal 
symptoms associated with duodenal ulcer at Weeks 2 through 6 (%)
A Cochran–Mantel–Haenszel (CMH) test with baseline H pylori status 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% CI using the Wald method will also be provided.
7.8.4.2
Handling of Dropouts or Missing Data
For the primary endpoint “Percentage of subjects with endoscopically confirmed healing of 
duodenal ulcer at Week 4 or 6” and the secondary efficacy endpoints “Percentage of subjects 
with endoscopically confirmed healing of duodenal ulcer at Week 4” and “Percentage of subjects 
with posttreatment resolution of gastrointestinal symptoms associated with duodenal ulcer 
(epigastric pain [postprandial, fasting, nocturnal], abdominal bloating, nausea/vomiting, 
heartburn, lack of appetite) at Weeks 2 through 6”, 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.
7.8.4.3
Interim Analyses and Data Monitoring
No interim analysis is planned in this study.
7.8.4.4
Multicenter Studies
Treatment-by-center interaction will not be explored in this study.
7.8.4.5
Multiple Comparison/Multiplicity
Statistical inference will be performed at 2-sided 0.05 level of significance or via 2-sided 95% 
CIs. Adjustment for multiplicity will be performed for the primary efficacy endpoint and the 
secondary efficacy endpoints in the following order under the closed testing procedure: 

The primary endpoint of healing rate of duodenal ulcer during the 6-week treatment will be 
tested for noninferiority between the TAK-438 group and the lansoprazole group based on 
the FAS. If the lower bound of the 95% CI is ≥-6%, noninferiority for TAK-438 relative to 
lansoprazole with regard to duodenal ulcer healing will be declared.

If the previous test is successful, the secondary endpoint of eradication rate of H pylori will 
be tested for noninferiority between the TAK-438 group and the lansoprazole group based on 
the FAS. If the lower bound of the 95% CI of the difference is ≥-10%, noninferiority for 
TAK-438 relative to lansoprazole with regard to H pylori eradication will be declared.
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Statistical Analysis Plan Version 3.0
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
If the previous test is successful, the primary endpoint of healing rate of duodenal ulcer 
during the 6-week treatment will be tested for superiority between the TAK-438 group and 
the lansoprazole group based on the FAS. If the lower bound of the 95% CI is ≥0%, 
superiority for TAK-438 relative to lansoprazole with regard to duodenal ulcer healing will 
be declared.

If the previous test is successful, the secondary endpoint of eradication rate of H pylori will 
be tested for superiority between the TAK-438 group and the lansoprazole group based on 
the FAS. If the lower bound of the 95% CI of the difference is ≥0%, superiority for TAK-438 
relative to lansoprazole with regard to H pylori eradication will be declared.
7.8.4.6
Use of an “Efficacy Subset” of Subjects
In addition to analyses on the primary efficacy endpoint using the FAS, sensitivity analyses will 
also be performed using the PPS to examine the robustness of the results.
7.8.4.7
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 FAS using a non-inferiority margin of 6% as described in section 7.8.1.1
“Primary Analysis”.
For the secondary efficacy endpoint of eradication rate of H pylori, non-inferiority for TAK-438 
relative to lansoprazole will be confirmed in the FAS using a non-inferiority margin of 10% as 
described in section 7.8.2.2 “Secondary Analysis”.
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Statistical Analysis Plan Version 3.0
23 July 2019
7.8.4.8
Subgroup Analysis
Analysis Set:
Full Analysis Set
Analysis Variable:
Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at Week 4
or 6 (%)
Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at Week 4
(%)
Percentage of subjects with posttreatment resolution of gastrointestinal symptoms associated 
with duodenal ulcer at Weeks 2 through 6 (%)
Subgroups:
Age (years)
[Min<= - <65, 65<= - <75, 75<= - <=Max]
Gender
[Male, Female]
H pylori status (Baseline)
[HP+, HP-]
Analytical Methods:
For subgroup of age and gender, summaries (1), (2), and (3) will be provided by treatment 
group.
For subgroup of H pylori status (Baseline), summaries (3) will be provided by treatment 
group.
(1) Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at 
Week 4 or 6 (%)
(2) Percentage of subjects with endoscopically confirmed healing of duodenal ulcer at 
Week 4 (%)
(3) Percentage of subjects with posttreatment resolution of gastrointestinal symptoms 
associated with duodenal ulcer at Weeks 2 through 6 (%)
The same analyses as those in section 7.8.1 and 7.8.2 will be performed for each of the 
above subgroups.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
Not applicable.
7.9.1
Pharmacokinetic Analysis
Not applicable.
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
Not applicable.
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Statistical Analysis Plan Version 3.0
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7.11
Safety Analysis
7.11.1 Treatment-Emergent Adverse Events
7.11.1.1 Overview of Treatment-Emergent Adverse Events
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Relationship to TAK-438/Lansoprazole
[Yes, No]
Relationship to Clarithromycin
[Yes, No]
Relationship to Amoxicillin
[Yes, No]
Relationship to Bismuth
[Yes, No]
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) 
2.1) Relationship of Treatment-Emergent Adverse Events to TAK-438/Lansoprazole (number 
of events, number and percentage of subjects)
2.2) Relationship of Treatment-Emergent Adverse Events to Clarithromycin (number of 
events, number and percentage of subjects)
2.3) Relationship of Treatment-Emergent Adverse Events to Amoxicillin (number of events, 
number and percentage of subjects)
2.4) Relationship of Treatment-Emergent Adverse Events to Bismuth (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 Double-Blind Study Drug Discontinuation 
(number of events, number and percentage of subjects) 
5) Relationship to TAK-438/Lansoprazole of Treatment-Emergent Adverse Events Leading to 
Double-Blind 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) 
7.1) Relationship of Serious Treatment-Emergent Adverse Events to TAK-438/Lansoprazole
(number of events, number and percentage of subjects)
7.2) Relationship of Serious Treatment-Emergent Adverse Events to Clarithromycin (number 
of events, number and percentage of subjects)
7.3) Relationship of Serious Treatment-Emergent Adverse Events to Amoxicillin (number of 
events, number and percentage of subjects)
7.4) Relationship of Serious Treatment-Emergent Adverse Events to Bismuth (number of 
events, number and percentage of subjects)
8) Serious Treatment-Emergent Adverse Events Leading to Double-Blind Study Drug 
Discontinuation (number of events, number and percentage of subjects) 
9) Treatment-Emergent Adverse Events Resulting in Death (number of events, number and 
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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), 7.1), 7.2), 7.3) and 7.4)
A subject with occurrences of TEAE in both categories (ie, Yes and No) will be counted 
once in the Related category.
・
Summary for 3)
A subject with multiple occurrences of TEAE will be counted once for the TEAE with 
the maximum intensity.
・
Summaries other than 2), 3), 5), 7.1), 7.2), 7.3) and 7.4)
A subject with multiple occurrences of TEAE will be counted only once.
Number of events
For each summary, the total number of events will be calculated.
7.11.1.2 Displays of Treatment-Emergent Adverse Events
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Intensity
[Mild, Moderate, Severe]
Time of Onset (day)
[1<= - <=14, 15<= - <=28, 29<= - <=42, 43<= - <=Max]
Stratified Variable:
H pylori status (Baseline) [HP+, HP-]
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
(4.1) TAK-438/Lansoprazole-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term
(4.2) Clarithromycin-Related Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term
(4.3) Amoxicillin-Related Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term
(4.4) Bismuth-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 TAK-438/Lansoprazole-Related Treatment-Emergent Adverse Events by 
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System Organ Class, and Preferred Term
(7) Treatment-Emergent Adverse Events Leading to Double-Blind Study Drug 
Discontinuation by System Organ Class and Preferred Term
(8) TAK-438/Lansoprazole-Related Treatment-Emergent Adverse Events Leading to 
Double-Blind 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 TAK-438/Lansoprazole-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
(14) TAK-438/Lansoprazole-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) TAK-438/Lansoprazole-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
(18) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
stratified by H pylori status at Baseline
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 
(ie, 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)
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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.
7.11.2 Pretreatment Events
7.11.2.1 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.
Pretreatment Events will be coded using the MedDRA and will be summarized using SOC and 
PT. SOC will be sorted alphabetically and PT will be sorted in decreasing frequency.
(1) Pretreatment Events by System Organ Class and Preferred Term
(2) Serious pretreatment Events by System Organ Class and Preferred Term
The frequency distribution will be provided according to the rules below.
Number of subjects
A subject with multiple occurrences of Pretreatment Event within a SOC will be counted only 
once in that SOC. A subject with multiple occurrences of Pretreatment Event within a PT will 
be counted only once in that PT.
7.11.3 Clinical Laboratory Evaluations
7.11.3.1 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)
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Magnesium (mmol/L)
Calcium (mmol/L)
Inorganic Phosphorus (mmol/L)
Chloride (mmol/L)
Serum Iron (μmol/L)
Vitamin B12 (pmol/L)
Note: 1) Fasting laboratory test in planned per protocol. 2) The central laboratory will perform 
laboratory tests for hematology, serum chemistries, hepatitis and urinalysis.
Visit:
Variables of Liver function tests including ALT, AST, Total Bilirubin, and Direct Bilirubin:
Baseline, Week 2, Week 4, Week 6
Variables other than ALT, AST, Total Bilirubin, and Direct Bilirubin:
Baseline, Week 4, Week 6
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.
(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.
ALT=Alanine Aminotransferase, ALP=Alkaline Phosphatase, AST=Aspartate Aminotransferase, GGT=-Glutamyl 
Transferase, LDH=Lactate Dehydrogenase, CK=Creatine Kinase, BUN=Blood Urea Nitrogen.
7.11.3.2 Urinalysis
Analysis Set:
Safety Analysis Set
Analysis Variables : Urinalysis
Appearance
Color
pH
Ketones
Protein
Urine Glucose
Nitrite
Urobilinogen
Blood
Specific Gravity
Note: For Urinalysis laboratory tests, only specific gravity variable is continuous variable with 
numeric results, the others are categoric variables with character results.
Visit:
Baseline, Week 4, Week 6
Analytical Methods: For specific gravity variable, summaries (1) and (2) will be provided by treatment group. 
For each variable other than specific gravity, summaries (2) will be provided by treatment 
group.
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(1) Summary of Urine Laboratory Test Results and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline (each post-baseline visit -
baseline) will be provided for each visit.
(2) 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. For specific gravity laboratory test, the laboratory values will be 
classified as “Low”, “Normal” or “High” and for each variable other than specific gravity will 
be classified as “Normal” or “Abnormal” relative to the normal reference range provided by 
the central laboratory. The shift tables will be based on these classifications.
7.11.3.3 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
Note: 1) Fasting laboratory test in planned per protocol. 2) The central laboratory will perform 
laboratory tests for hematology, serum chemistries, hepatitis and urinalysis.
Visit:
Baseline, Week 4, Week 6, Visit F-1, Visit F-2
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.
7.11.4 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 6
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.
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7.11.5 12-Lead ECGs
Analysis Set:
Safety Analysis Set
Analysis Variables: Heart Rate (bpm)
RR Interval (msec)
PR Interval (msec)
QT Interval (msec)
QTcF Interval (msec)
QRS Interval (msec)
Interpretation
[“Within Normal Limits”,
“Abnormal, Not Clinically Significant”,
“Abnormal, Clinically Significant”]
Visit:
Baseline, Week 4, Week 6
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 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.
7.11.6 Other Observations Related to Safety
7.11.6.1 Physical Examination
Analysis Set:
Safety Analysis Set
Analysis Variables: Results 
[“Yes”, “No”]
Visit:
Screening, Baseline, Week 2, Week 4, Week 6, Visit F-1, Visit F-2
Analytical Methods: Summary (1) will be provided by treatment group.
(1) Number and Percentage of Subjects with Any Significant Changes from Baseline
Overall frequency distributions of physical examination results during treatment phase will be 
provided. 
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7.11.7 Subgroup Analysis for China
Analysis Set:
Subjects in China
Subjects in Countries other than China
Analytical Methods: (1) The same analyses as those in section 7.3 to 7.11.6 will be conducted for the subjects in 
China.
(2) The same analyses as those in section 7.3 to 7.11.6 will be conducted for the subjects in 
countries other than China.
7.12
Interim Analysis
Not applicable.
7.13
Changes in the Statistical Analysis Plan 
The changes from the original SAP (Version: 2.0, Date: 29 May 2019) to the amended SAP were
described below with a rationale for changes provided.

Based on the discussion, the algorithm of Visit Analysis Window on C-UBT has changed.

Based on the discussion, the stratified analysis on the display of TEAE by SOC and PT has 
been added.
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8.0
REFERENCES
1. Fass R, Shapiro M, Swell J. Systematic review: proton-pump inhibitor failure in gastro-
oesophageal reflux disease—where next? Aliment Pharmacol Ther. 2005; 22:79-94.
2. Peter J, et al. A randomized, comparative study of three doses of AZD0865 and 
esomeprazole for healing of reflux esophagitis. Clin Gastroenterol Hepatol. 2007; 5: 12.
3. Liang J, et al. Helicobacter pylori Eradication with Ecabet Sodium, Omeprazole, 
Amoxicillin, and Clarithromycin Versus Bismuth,Omeprazole, Amoxicillin, and 
Clarithromycin Quadruple Therapy: A Randomized, Open-Label, Phase IV Trial. 
Helicobacter. 2012 17: 458–465.
4. Sun Q, et al. High Efficacy of 14-Day Triple Therapy-Based, Bismuth-Containing Quadruple 
Therapy for Initial Helicobacter pylori Eradication. 2010 15: 233–238.
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9.0
APPENDIX
9.1
Flowcharts for Imputing Missing or Partial Dates for Adverse Events and 
Concomitant Medications
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9.2
Criteria for Markedly Abnormal Values
9.2.1
Hematology, Serum Chemistry, Urinalysis, Vital Signs, and 12-lead ECG (except 
Upper MAV Criteria of QTcF Interval)
For each parameter, all evaluable data (ie, non-missing data) obtained up to 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.
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Table 9.a
Markedly Abnormal Values Criteria for 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
LLN=Lower limit of normal, ULN=Upper limit of normal.
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Table 9.b
Markedly Abnormal Values Criteria for Serum Chemistry
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Alanine Aminotransferase (ALT) (U/L)
-
>3×ULN
Albumin (g/L)
<25
-
Alkaline Phosphatase (ALP) (U/L)
-
>3×ULN
Aspartate Aminotransferase (AST) (U/L)
-
>3×ULN
Total Bilirubin (μmol/L)
-
>34.2
Direct Bilirubin (μmol/L)
-
>2×ULN
Total Cholesterol (mmol/L)
-
>7.72
Triglycerides (mmol/L)
-
>2.5×ULN
Calcium (mmol/L)
<1.75
>2.88
Chloride (mmol/L)
<75
>126
Creatinine (μmol/L)
-
>177
Creatine Kinase (U/L)
>5×ULN
Blood Urea Nitrogen (BUN) (mmol/L)
-
>10.7
γ-Glutamyl Transferase (γ-GTP)
-
>3×ULN
Glucose (mmol/L)
<2.8
>19.4
Inorganic Phosphorus (mmol/L)
<0.52
>2.00
Magnesium (mmol/L)
<0.5
>1.2
Potassium (mmol/L)
<3.0
>6.0
Total Protein (g/L)
<0.8×LLN
>1.2×ULN
Sodium (mmol/L)
<130
>150
Uric Acid (mmol/L)
-
>0.773
Vitamin B12 (pmol/L)
<92
-
Table 9.c
Markedly Abnormal Values Criteria for Vital Signs
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Body Temperature (C)
<35.6
>37.7
Systolic Blood Pressure (mmHg)
<85
>180
Diastolic Blood Pressure (mmHg)
<50
>110
Pulse (bpm)
<50
>120
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Table 9.d
Markedly Abnormal Values Criteria for 12-lead ECG
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Heart Rate (bpm)
<50
>120
QT Interval (msec)
<=50
>=460
QTcF Interval (msec)
<=50
See Section 9.2.2
9.2.2
12-lead ECG (Upper MAV Criteria of QTcF Interval)
All evaluable data (ie, 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.
Table 9.e
Markedly Abnormal Values Criteria for 12-lead ECG (Upper MAV Criteria 
of QTcF Interval)
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
9.3
Criteria for Elevated Liver Enzyme
All evaluable data (ie, 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.
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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.
Table 9.f
Markedly Abnormal Values 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
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 
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Table 9.f
Markedly Abnormal Values Criteria for Elevated Liver Enzyme
Label
Criteria for Elevated Liver Enzyme
(a) Elevated
(b) Not Elevated
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
Prope
keda: For non-c
al use only and subject to the applicable Terms of Use


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