Clinical trial NCT02388737
Conditions: Erosive Esophagitis
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2015-04-01; Completion date: 2018-12-31
Enrollment: 703 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a comparative study of vonoprazan (TAK-438) (10 mg or 20 mg) in participants in whom endoscopic healing of erosive esophagitis has been confirmed with vonoprazan or adequate treatment with a proton pump inhibitor (PPI), to demonstrate the non-inferiority of vonoprazan to lansoprazole in their maintenance treatment (6 months or 24 weeks) as well as to determine the clinically recommended dose for vonoprazan for maintenance therapy in erosive esophagitis.

Detailed description:
The drug being tested in this study is called vonoprazan. Vonoprazan is being tested as a maintenance treatment for people with healed erosive esophagitis (EE). This study will look at participants in whom endoscopic healing of erosive esophagitis has been confirmed with vonoprazan or adequate treatment with a proton pump inhibitor (PPI), to demonstrate the non-inferiority of vonoprazan to Lansoprazole in their maintenance treatment (6 months or 24 weeks) as well as to determine the clinically recommended dose for vonoprazan for maintenance therapy in erosive esophagitis.

The study will enroll approximately 693 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* TAK-438 10 mg
* TAK-438 20 mg
* Lansoprazole 15 mg

Participants with ongoing erosive esophagitis (EE) will receive lansoprazole 30 mg once daily for 4 or 8 weeks (the Healing phase) until healing of EE is confirmed by endoscopy performed at either Week -4 and/or Day 1 before eligible for randomization to maintenance phase. In Maintenance phase, participants with confirming EE healing will be asked to take 2 tablets and a capsule at the same time each morning after breakfast throughout the study. All participants will be asked to record daytime and nighttime (during sleep) subjective symptoms in a diary on a daily basis.

This multi-centre trial will be conducted worldwide. The overall time to participate in this study is 8 months. Participants will make multiple visits to the clinic, and will be contacted by telephone 7-14 days after last dose of study drug for a follow-up assessment.

Arms: arm 1: Lansoprazole 30 mg, capsules or tablets, orally, once, daily, for up to 4 or 8 weeks or until confirmed healing of erosive esophagitis (EE) in healing phase for participants with ongoing EE.

Vonoprazan 10 mg, tablets, orally, once, daily, and Vonoprazan 20 mg, placebo-matching tablets, orally, once, daily, and Lansoprazole 15 mg placebo-matching, capsules, orally, once, daily, for up to 24 weeks in maintenance phase for participants with confirmed EE healing. arm 2: Lansoprazole 30 mg, capsules or tablets, orally, once, daily, for up to 4 or 8 weeks or until confirmed healing of erosive esophagitis (EE) in healing phase for participants with ongoing EE.

Vonoprazan 20 mg, tablets, orally, once, daily, and Vonoprazan 10 mg, placebo-matching tablets, orally, once, daily, and Lansoprazole 15 mg, placebo-matching capsules, orally, once, daily, for up to 24 weeks in maintenance phase for participants with confirmed EE healing arm 3: Lansoprazole 30 mg, capsules or tablets, orally, once, daily, for up to 4 or 8 weeks or until confirmed healing of erosive esophagitis (EE) in healing phase for participants with ongoing EE.

Lansoprazole 15 mg, capsules, orally, once, daily, and Vonoprazan 10 mg, placebo-matching tablets, orally, once, daily, and Vonoprazan 20 mg, placebo-matching tablets, orally, once, daily, for up to 24 weeks in maintenance phase for participants with confirmed EE healing.
Interventions: intervention 1: Vonoprazan intervention 2: Lansoprazole intervention 3: Vonoprazan Placebo intervention 4: Lansoprazole Placebo
Intervention descriptions: intervention 1: Vonoprazan tablets intervention 2: Lansoprazole capsules or tablets intervention 3: Vonoprazan placebo-matching tablets intervention 4: Lansoprazole placebo-matching capsules

Protocol documents:
Prot_001.pdf: 



Title: A Randomized, Double-Blind, Double-Dummy, Parallel-group Phase 3 Study to Evaluate 
the Efficacy and Safety of Oral Once-Daily Administration of TAK-438 10 or 20 mg Compared to 
Lansoprazole 15 mg in the Maintenance Treatment of Subjects With Endoscopic Healing of 
Erosive Esophagitis
NCT Number: NCT02388737
Protocol Approve Date: 15 November 2016
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (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.


1.0 TITLE PAGE
PROTOCOL
A Randomized, Double-Blind, Double-Dummy, Parallel-group Phase 3 Study to Evaluate 
the Efficacy and Safety of Oral Once-Daily Administration of TAK-438 10 or 20 mg 
Compared to Lansoprazole 15 mg in the Maintenance Treatment of Subjects With 
Endoscopic Healing of Erosive Esophagitis
Sponsor:
Takeda Development Center Asia Pte. Ltd.
21 Biopolis Road, Nucleos North Tower, Level 4, Singapore 138567
Study Number:
TAK-438_305
IND Number:
Not Applicable
EudraCT Number:
Not Applicable
Compound:
TAK-438
Date:
15 November 2016
Amendment Number:
06
Amendment History
Date
Amendment Number
Region
29 Aug 2012
Initial Protocol
Asia Pacific
31 Oct 2014
01
Asia Pacific
26 Jan 2015
02
Asia Pacific
23 Apr 2015
03
Asia Pacific
14 Dec 2015
04
Asia Pacific
06 Apr 2016
05
Asia Pacific
15 Nov 2016
06
Asia Pacific
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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Takeda Development Center Asia, Pte. Ltd. sponsored Asia Pacific investigators will be provided 
with emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Issue
Asia Pacific Contact
Serious adverse event pregnancy and special interest 
adverse event reporting
Medical Monitor
(medical advice on protocol, compound, and medical 
management of subjects)
Responsible Medical Officer 
(carries overall responsibility for the conduct of the study)
PPD
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1.2
Approval
REPRESENTATIVES OF TAKEDA

This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with 
the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES 
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 06 Summary of Changes
Rationale for Amendment 06
This document describes the changes in reference to the protocol incorporating Amendment 
No. 06. The primary reason for this amendment is to add an open-label, single-blind Lansoprazole 
treatment arm (the Healing Phase) to permit the enrolment of subjects with ongoing erosive 
esophagitis.
Minor grammatical, editorial, and formatting changes are included for clarification purposes only. 
For specific descriptions of text changes and where the changes are located, see Appendix F
Changes in Amendment 06
1. Updated study team contacts and approvers.
2. Information from phase 3 clinical studies of TAK-438 has been added.
3. Added a 4- or 8-week, open-label single-arm Lansoprazole 30 mg treatment period (the 
Healing Phase); new language to distinguish between the open-label Healing Phase and 
randomized, double-blind Maintenance Phase; defined Healing Phase Failures, and qualified 
that de novo subjects are no longer eligible to enroll.
4. Added the Healing Phase to the Study Design Schematic. 
5. Clarified the primary and secondary objectives.
6. Changed the inclusion criteria.
7. Updated the timings relating to excluded medications and treatments.
8. Stated the dosing instructions for Lansoprazole 30 mg.
9. Stated dosage form, manufacturing, packaging, and labeling for Lansoprazole 30 mg.
10. Clarified dispensing procedures during the Healing Phase.
11. Clarified the total volume of blood collected.
12. Further detailed the site visits for liver function tests.
13. Clarified the classification of endoscopy.
14. Clarified procedures around diary collection on study visit days.
15. Updated compliance instructions to include treatment during the Healing Phase.
16. Clarified that 3 schedules of study-related procedures are included in Appendix A.
17. Clarified the study-related procedures to be conducted during the Screening Phase (Visit 1).
18. Added a description of study procedures during Healing Phase visits. 
19. Repeated the discontinuation criteria for liver function abnormalities.
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20. Confirmed that the questionnaires used to rate a subject’s symptoms and severity of symptoms 
are the same as that used in the Japanese clinical development program.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 06 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Principal Investigator/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..................................................................21
5.1
Objectives................................................................................................................21
5.1.1
Primary Objective(s) ...................................................................................21
5.1.2
Secondary Objectives..................................................................................21
5.1.3
Additional Objectives..................................................................................21
5.2
Endpoints.................................................................................................................21
5.2.1
Primary Endpoints.......................................................................................21
5.2.2
Secondary Endpoints...................................................................................21
5.2.3
Additional Endpoints ..................................................................................22
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................23
6.1
Study Design ...........................................................................................................23
6.1.1
Study Description........................................................................................23
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 Site(s).........................................................28
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............29
7.1
Inclusion Criteria .....................................................................................................29
7.2
Exclusion Criteria ....................................................................................................30
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7.3
Excluded Medications and Treatments.....................................................................31
7.4
Diet, Fluid, Activity Control ....................................................................................32
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................33
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................34
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................35
8.1
Study Medication and Materials...............................................................................35
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................35
8.1.2
Storage........................................................................................................37
8.1.3
Dose and Regimen ......................................................................................37
8.1.4
Overdose.....................................................................................................38
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................38
8.3
Randomization Code Creation and Storage..............................................................39
8.4
Investigational Drug Blind Maintenance ..................................................................39
8.5
Unblinding Procedure..............................................................................................39
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................40
9.0
STUDY PLAN ..............................................................................................................42
9.1
Study Procedures.....................................................................................................42
9.1.1
Informed Consent Procedure.......................................................................42
9.1.2
Demographics, Medical History, and Medication History Procedure...........42
9.1.3
Physical Examination Procedure .................................................................42
9.1.4
Weight, Height and BMI.............................................................................43
9.1.5
Vital Sign Procedure ...................................................................................43
9.1.6
Documentation of Concomitant Medications...............................................43
9.1.7
Documentation of Concurrent Medical Conditions......................................43
9.1.8
Procedures for Clinical Laboratory Samples................................................43
9.1.9
Contraception and Pregnancy Avoidance Procedure....................................45
9.1.10
Pregnancy ...................................................................................................46
9.1.11
ECG Procedure ...........................................................................................47
9.1.12
Documentation of Screen Failure ................................................................47
9.1.13
Documentation of Study Randomization .....................................................47
9.1.14
Endoscopy ..................................................................................................48
9.1.15
Diary for Gastrointestinal symptoms and Health-Related Quality of Life ....49
9.2
Monitoring Subject Treatment Compliance..............................................................50
9.3
Schedule of Observations and Procedures................................................................51
9.3.1
Visit 1: Screening Phase (Day -28 to Day -1) ..............................................51
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9.3.2
Visit 2HP: Healing Phase (Week -8).............................................................52
9.3.3
Visit 3HP: Healing Phase (Week -4).............................................................53
9.3.4
Visit 2: Randomization (Day 1)...................................................................53
9.3.5
Visit 3: Maintenance Phase (Day 15 / Week 2)............................................55
9.3.6
Visit 4: Maintenance Phase (Day 29 / Week 4)............................................55
9.3.7
Visit 5: Maintenance Phase (Day 43 / Week 6)............................................55
9.3.8
Visit 6: Maintenance Phase (Day 57/ Week 8).............................................56
9.3.9
Visit 7: Maintenance Phase (Day 85 / Week 12)..........................................56
9.3.10
Visit 8: End of Treatment (Day 169 / Week 24) or Study Early 
Discontinuation Visit (within 14 days after final dose) ................................57
9.3.11
Follow-up ...................................................................................................57
9.3.12
Post Study Care...........................................................................................58
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................59
10.1
Definitions...............................................................................................................59
10.1.1
Pretreatment Events ....................................................................................59
10.1.2
AEs.............................................................................................................59
10.1.3
Additional Points to Consider for PTEs and AEs.........................................59
10.1.4
SAEs...........................................................................................................61
10.1.5
Special Interest AEs....................................................................................62
10.1.6
Severity of PTEs and AEs ...........................................................................62
10.1.7
Causality of AEs .........................................................................................63
10.1.8
Relationship to Study Procedures................................................................63
10.1.9
Start Date....................................................................................................63
10.1.10
Stop Date ....................................................................................................63
10.1.11
Frequency ...................................................................................................63
10.1.12
Action Concerning Study Medication..........................................................63
10.1.13
Outcome .....................................................................................................64
10.2
Procedures...............................................................................................................64
10.2.1
Collection and Reporting of AEs.................................................................64
10.2.2
Collection and Reporting of SAEs...............................................................66
10.2.3
Reporting of Abnormal Liver Function Tests ..............................................66
10.3
Follow-up of SAEs ..................................................................................................66
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................67
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................68
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12.0
DATA HANDLING AND RECORDKEEPING............................................................69
12.1
eCRFs......................................................................................................................69
12.2
Record Retention .....................................................................................................69
13.0
STATISTICAL METHODS..........................................................................................71
13.1
Statistical and Analytical Plans ................................................................................71
13.1.1
Analysis Sets...............................................................................................71
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................71
13.1.3
Efficacy Analysis........................................................................................71
13.1.4
Handling of Missing Data ...........................................................................72
13.1.5
Safety Analysis ...........................................................................................73
13.2
Interim Analysis and Criteria for Early Termination ................................................73
13.3
Determination of Sample Size..................................................................................73
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................74
14.1
Study-Site Monitoring Visits ...................................................................................74
14.2
Protocol Deviations..................................................................................................74
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................74
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................75
15.1
IRB and/or IEC Approval ........................................................................................75
15.2
Subject Information, Informed Consent, and Subject Authorization .........................76
15.3
Subject Confidentiality ............................................................................................77
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................77
15.4.1
Publication and Disclosure..........................................................................77
15.4.2
Clinical Trial Registration...........................................................................78
15.4.3
Clinical Trial Results Disclosure .................................................................78
15.5
Insurance and Compensation for Injury....................................................................78
16.0
REFERENCES..............................................................................................................79
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications and Treatments...............................................................32
Table 8.a
Investigational Drug...........................................................................................36
Table 8.b
Sponsor-Supplied Drug During the Maintenance Phase......................................38
Table 9.a
Clinical Laboratory Tests...................................................................................44
Table 9.b 
Los Angeles (LA) classification for diagnosis and grading of erosive 
esophagitis .........................................................................................................48
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Table 9.c
Requirements for Subject Diary Entries Regarding Subjective Symptoms..........50
Table 9.d
Severity of Subjective Symptoms.......................................................................50
Table 10.a
Takeda Medically Significant AE List................................................................62
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................25
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................80
Appendix B
Responsibilities of the Investigator.....................................................................86
Appendix C
Elements of the Subject Informed Consent.........................................................88
Appendix D
Investigator Consent to Use of Personal Information..........................................91
Appendix E
Definition of Heartburn/ Regurgitation Severity.................................................92
Appendix F
Detailed Description of Amendments to Text.....................................................93
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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, Parallel-group Phase 3 
Study to Evaluate the Efficacy and Safety of Oral Once-Daily 
Administration of TAK-438, 10 or 20 mg Compared to Lansoprazole 15 mg 
in the Maintenance Treatment of Subjects With Endoscopic Healing of 
Erosive Esophagitis
IND No.: 
not applicable
EudraCT No.:
not applicable 
Study Number: TAK-438_305
Phase: 3
Study Design:
This is a phase 3, multicenter, randomized, double-blind, parallel-group study to demonstrate the noninferiority of 
TAK-438 (10 mg or 20 mg) to Lansoprazole 15 mg in preventing the recurrence of erosive esophagitis in subjects with 
endoscopically confirmed healing of erosive esophagitis. This study also aims to determine the clinically 
recommended dose of TAK-438 for maintenance therapy of erosive esophagitis.
This study is comprised of 2 treatment periods: An open-label, single-arm period in which subjects with ongoing 
erosive esophagitis receive Lansoprazole 30 mg for 4 or 8 weeks (Healing Phase), and a double-blind, parallel-group 
period in which subjects with healed erosive esophagitis are randomized at a 1:1:1 ratio to TAK-438 10 mg, 20 mg or 
Lansoprazole 15 mg once daily for up to 24 weeks (Maintenance Phase). 
To enroll in the study subjects must have ongoing erosive esophagitis or have completed Study TAK-438_303. 
Subjects with ongoing erosive esophagitis are required to undergo the Healing Phase. Once erosive esophagitis 
healing is confirmed by endoscopy, these subjects may be randomized to 1 of 3 treatments in the Maintenance Phase. 
Subjects with endoscopic-confirmed healing of erosive esophagitis following the completion of Study TAK-438_303 
will be randomized into the Maintenance Phase without carrying out the open-label Healing Phase. Subjects who 
previously entered the study (prior to Protocol Amendment 06) after confirmation of healed erosive esophagitis 
following treatment with a proton pump inhibitor outside Study TAK-438_303, or as part of the Healing Phase of the 
current study (termed “de novo” subjects) are no longer eligible to enter the study; any ongoing subjects may continue 
being treated in the Maintenance Phase.
If relapse of erosive esophagitis has been endoscopically confirmed in any subject during the Maintenance Phase, the 
subject will complete the study at that time point (to be construed as “complete cases in the Maintenance Phase”, 
regardless of the time point where relapse of disease is confirmed).
Primary Objectives:

To demonstrate the noninferiority of TAK-438 to Lansoprazole in the reduction of relapse of erosive esophagitis 
in subjects in the Maintenance Phase (24 weeks) in whom endoscopic healing of erosive esophagitis has been 
confirmed after treatment with TAK-438 or a proton pump inhibitor.

To determine the clinically recommended dose of TAK-438 for maintenance therapy in erosive esophagitis in 
whom endoscopic healing of erosive esophagitis has been confirmed after treatment with TAK-438 or a proton 
pump inhibitor.
Secondary Objectives:

To evaluate the efficacy of TAK-438 during the first 12-weeks of treatment in the Maintenance Phase in subjects 
with endoscopically confirmed healed erosive esophagitis receiving TAK-438 or a proton pump inhibitor.

To evaluate the safety of TAK-438 versus Lansoprazole in subjects in the Maintenance Phase (24 weeks) in 
whom endoscopic healing of erosive esophagitis has been confirmed after treatment with TAK-438 or a proton 
pump inhibitor.
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Additional Objectives:
To evaluate the effect of TAK-438 on subjective symptoms of erosive esophagitis (heartburn and regurgitation) and 
improvement in Health Related Quality of Life using the EuroQol (EQ-5D-5L).
Subject Population: Subjects aged 18 or older (and at least the local age of consent) inclusive with endoscopically 
confirmed healed erosive esophagitis following completion of Study TAK-438_303, treatment with a proton pump 
inhibitor during the Healing Phase of the current study, or de novo subjects treated with a proton pump inhibitor 
outside of Study TAK-438_303 or the current study. 
Number of Subjects:
The number of subjects with endoscopically confirmed healed erosive esophagitis to 
be randomized into the Maintenance Phase:
TAK-438 10 mg group: approximately 231
TAK-438 20 mg group: approximately 231
Lansoprazole 15 mg group: approximately 231 
Estimated total: approximately 693 randomized 
Number of Sites:
Estimated total: 
Approximately 70 sites in 
multiple countries
Dose Level(s): 
Subjects entering the study with ongoing erosive esophagitis will receive 
Lansoprazole (one 30 mg capsule/tablet) given once daily as per the local approved 
package insert. 
Following confirmation of endoscopic healing of erosive esophagitis subjects will be 
randomized to receive:
TAK-438 10 mg group: TAK-438 (one 10 mg tablet) + TAK-438 placebo (matching 
20 mg tablet) + Lansoprazole placebo (1 capsule) given once daily after breakfast
TAK-438 20 mg group: TAK-438 (one 20 mg tablet) TAK-438 placebo (matching 
10 mg tablet) + Lansoprazole placebo (1 capsule) given once daily after breakfast
Lansoprazole 15 mg group: TAK-438 placebo (matching 10 mg tablet) + TAK-438 
placebo (matching 20 mg tablet) + Lansoprazole (one 15 mg capsule) given once 
daily after breakfast
Route of Administration:
Oral
Duration of Treatment:
Up to 8 months (32 weeks).
Period of Evaluation:
Healing Phase: up to 2 months 
(4 or 8 weeks). Maintenance 
Phase up to 6 months (24 
weeks).
Follow-up Phase: up to 
14 days.
Main Criteria for Inclusion:
All subjects are to be evaluated for eligibility for entry in the study based on the following criteria.
The subject has endoscopically confirmed erosive esophagitis (LA classification grades A to D) within 84 days of 
Day 1, and has endoscopically confirmed healed erosive esophagitis after completion of Study TAK-438_303 or 
completion of 4 or 8 weeks Lansoprazole 30 mg treatment in the open-label arm of the current study (for subjects who 
have not participated in TAK-438_303 study, this endoscopy must be taken within 14 days before the enrollment in 
the TAK-438_305 study). Subjects must also have provided (or when applicable their legally acceptable 
representative has provided) informed consent, are capable of understanding and complying with the study procedures 
and agree to use appropriate contraception. 
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Main Criteria for Exclusion:
Subjects who have hypersensitivity to TAK-438 or related compounds and Lansoprazole, a significant history of 
central nervous system (CNS), cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, 
endocrine or hematological disease, or any significant results from physical examinations, subjects with a liver 
function test > upper limit of normal, or clinical laboratory results as deemed by the investigator. Subjects that have 
any co-morbidities, medical or surgical history that may affect the esophagus or have an acute upper gastrointestinal 
bleeding, gastric or duodenal ulcer within 30 days, with history or treatment of malignancy within 5 years are also 
excluded.
Main Criteria for Evaluation and Analyses:
Efficacy:
The primary efficacy endpoint for this study is the rate of recurrence of erosive esophagitis as confirmed on endoscopy 
during the 24-week Maintenance Phase.
The secondary efficacy endpoint for this study is the rate of recurrence of erosive esophagitis during the first 12 weeks 
of treatment in the Maintenance Phase.
Other efficacy endpoints include subjective symptoms of erosive esophagitis (heartburn and regurgitation) and 
Health-Related Quality of Life measures. 
Safety:
The safety endpoints of this study include adverse events, laboratory test values, electrocardiogram (ECG), vital signs, 
serum gastrin and pepsinogen I/II values.
Statistical Considerations:
Efficacy Analysis:
For the primary efficacy endpoint of rate of endoscopic recurrence of erosive esophagitis during the 24-week 
Maintenance Phase, a 2-sided 95% confidence interval (CI) will be constructed for the difference between each 
TAK-438 group and Lansoprazole and its upper bound will be compared to the noninferiority margin of 10%.
The secondary endpoint of rate of endoscopic recurrence of erosive esophagitis during the first 12 weeks of treatment 
in the Maintenance Phase will be compared between each TAK-438 group and Lansoprazole by constructing a 2-sided 
95% CI for the recurrence rate difference.
The additional endpoints related to GERD symptoms that occur during treatment in the Maintenance Phase will be 
compared between treatment groups using Wilcoxon rank-sum tests. Analysis of Health-Related Quality of Life 
endpoints will be conducted with an Analysis of Covariance model with treatment and baseline EE grade (A/B vs 
C/D) as factors and baseline as a covariate.
Statistical inference will be performed at a 2-sided 0.05 level of significance or via 2-sided 95% CIs. The primary 
endpoint will be tested for TAK-438 20 mg and 10 mg groups, sequentially, versus Lansoprazole.
Safety Analysis:
Safety analysis will be performed by summarizing the incidence of adverse events, clinical laboratory tests including 
gastrin and pepsinogen I/II levels, vital signs, and ECGs in the Maintenance Phase. No statistical testing or inferential 
statistics will be generated.
Sample Size Justification: 
Assuming that the true Week 24 recurrence rate is 30.4% for Lansoprazole, 22.0% for TAK-438 10 mg, and 13.6% for 
TAK-438 20 mg, and assuming that the dropout rate is approximately 30%, a sample size of 208 subjects per group 
will provide an overall power of 90% to establish noninferiority using a 2-sided 95% CI with a 10% noninferiority 
margin. 231 subjects per group will be included to allow adequate numbers for the regulatory requirements of various 
countries.
The assumption of the true recurrence rate is based on a phase 3 study that showed a Week 24 recurrence rate of 30.4% 
for Lansoprazole 15 mg and 13.6% for Lansoprazole 30 mg.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator
Takeda Development Center Asia, Pte. Ltd will select a Signatory Coordinating Investigator from 
the investigators who participate in the study. Selection criteria for this investigator will include 
significant knowledge of the study protocol, the study medication, their expertise in the therapeutic 
area and the conduct of clinical research as well as study participation. The Signatory Coordinating 
Investigator will be required to review and sign the clinical study report and by doing so agrees 
that it accurately describes the results of the study.
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3.3
List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BMI
body mass index
BUN
blood urea nitrogen
CEC
Clinical Endpoint Committee
CFR
Code of Federal Regulations
CK/CPK
creatine phosphokinase
Cl
chlorine
Cmax
maximum observed plasma concentration
CNS
central nervous system
eCRF
electronic case report form 
CRO
contract research organization
CYP
cytochrome P450 enzyme
DNA
deoxyribonucleic acid
ECG
electrocardiogram
EDC
electronic data capture
EE
erosive esophagitis
EM
extensive metabolizers 
FDA
Food and Drug Administration
FAS
full analysis set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GGT
-glutamyl transferase
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HCV-RNA
hepatitis C virus- ribonucleic acid
HIV
human immunodeficiency virus
H. pylori
Helicobacter pylori
HRQoL
Health-Related Quality of Life
IC
informed consent
ICH
International Conference on Harmonisation
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ID
identification 
IEC
independent ethics committee
INN
International Nonproprietary Name
INR
international normalized ratio
IRB
institutional review board
IU
International unit(s)
IUDs
intrauterine devices
IVRS
interactive voice response system
IWRS
interactive web response system
LA classification
Los Angeles classification
LDH
lactate dehydrogenase
LLN
lower limit of normal
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
NERD
non-erosive reflux disease
NSAIDs
non-steroidal anti-inflammatory drugs 
P-CAB
potassium-competitive acid blockers
pH4 HTR
pH4 holding time ratio
PM
poor metabolizers 
PPI
proton pump inhibitor
PPS
per-protocol analysis set
PTP
Press Through Package
QD
quaque die, every day
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
TBil
total bilirubin 
TBC
to be confirmed
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
3.4
Corporate Identification 
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
Erosive esophagitis is among the gastric acid-related disorders in which gastric acid reflux to the 
esophagus leads to problems in affected individuals. In 1994, the concept of a “mucosal break,” 
defined as “‘an area of slough or an area of erythema with a discrete lined demarcation from the 
adjacent or normal looking mucosa,” was introduced in the Los Angeles classification for 
diagnosis and grading of erosive esophagitis. Erosive esophagitis is graded in severity into 
4 grades (A-D) based on the extent of mucosal breaks. Acid reflux induces prolonged, unpleasant 
subjective symptoms, such as heart burn or gastric acid reflux, in symptomatic patients with 
erosive esophagitis, often aggravating their Health-Related Quality of Life. 
Due to westernization of diet in Asia, there is an increase in the patients with erosive esophagitis. 
The proton pump inhibitors (PPIs), such as Lansoprazole, represent the drugs of first choice for 
erosive esophagitis, and are being widely used all over the world. 
The PPIs inhibit the H+, K+-ATPase enzyme (proton pump) which represents the final step in acid 
secretion by the parietal cells in the gastric mucosa, and produce potent anti-secretory efficacy for 
acid-related disorders. 
However, even with these potent acid-inhibitory effects, the PPIs are not without their limitations 
and have not necessarily produced adequate improvements in extent and speed of symptom relief 
[1]. Indeed, the PPIs appear to leave room for improvement, the reason being that: 
1. Being less resistant to acid exposure and provided as enteric-coated drugs, the PPIs vary in 
time for onset of their action; 
2. About 3 to 5 days are required to obtain maximum acid-inhibitory effects with the PPIs; 
3. Acid-inhibitory effects with the PPIs appear to be satisfactory during daytime, but not 
adequate to inhibit acid regurgitations from the stomach to the esophagus occurring during 
nighttime, leading to nocturnal acid breakthroughs in some individuals; 
4. Metabolized by CYP2C19 associated with polymorphisms, the PPIs are associated with 
varying serum concentrations, thus producing disparate acid-inhibitory effects in extensive 
metabolizers (EM) versus poor metabolizers (PM). 
Developed at Takeda Pharmaceutical Company Ltd, TAK-438 belongs to a new class of 
acid-inhibitory agents called “potassium-competitive acid blockers” (P-CAB). TAK-438 is shown 
not only to inhibit the H+,K+-ATPase enzyme in the final step of acid secretion, as the PPIs do, but 
does not require the presence of acid for its activation and inhibits the H+,K+-ATPase enzyme in a 
potassium-competitive fashion. Furthermore, TAK-438 is shown to be stable in the presence of 
acid, is water-soluble, and requires no particular pharmacological preparations, such as an enteric 
coating, suggesting that the time to onset of action of TAK-438 may be less variable compared 
with PPIs. 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 
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much shorter time and to produce better outcomes than the PPIs with its potent and sustained 
acid-inhibitory effects. 
In Japan, TAK-438 has been evaluated for the doses ranging between 1 mg and 120 mg in a phase 
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 when given at the dose of 40 mg in the 7-day 
repeated-dose study, where the pH4 holding time ratio (pH4 HTR) with TAK-438 10 mg on day 7 
was shown to be similar to that with Lansoprazole 30 mg. However pH4 HTR was found to 
increase greatly with TAK-438 15 mg and 20 mg, and exceed 90% and remain stable with 
TAK-438 30 mg and 40 mg, thus providing evidence of TAK-438’s potent and sustained 
acid-inhibitory effects. Furthermore, no specific trend was found with any of the CYP2C19 
polymorphisms, suggesting that these polymorphisms lead to very little difference in the 
pharmacokinetics of TAK-438. Additionally, in a study evaluating interactions between TAK-438 
and various non-steroidal anti-inflammatory drugs (NSAIDs) (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 TAKl-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 serum concentration of 
TAK-438F increased by 1.35-fold for Cmax and by 1.58-fold for AUC in combination with 
clarithromycin, a potent inhibitor of the CYP3A4 enzyme, TAK-438 was shown to be well 
tolerated.
In a phase 2 dose-ranging study of TAK-438 in subjects with erosive esophagitis 
(TAK-438/CCT-001), TAK-438, given once daily at doses 5 mg, 10 mg, 20 mg, and 40 mg for 
8 weeks, was evaluated for its dose-response efficacy and safety in a randomized, double-blind, 
parallel-group comparison with Lansoprazole serving as control, demonstrating that the rate of 
endoscopic healing of erosive esophagitis 4 weeks after the start of treatment, the primary endpoint 
of the study, was 92.3%, 92.5%, 94.4%, and 97.0% with TAK-438 5 mg, 10 mg, 20 mg and 40 mg, 
respectively, compared to 93.2% with Lansoprazole, showing the 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.
TAK-438 has been studied in a number of acid-related diseases and noninferiority with 
Lansoprazole has been confirmed in several phase 3 studies including reflux esophagitis healing 
and prevention of recurrence studies, gastric/duodenal ulcer healing and for the prevention of 
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recurrence of a gastric or duodenal ulcer during NSAID or aspirin administration and has 
subsequently been launched in Japan for these indications. All treatments were well-tolerated.
4.2
Rationale for the Proposed Study
In a phase 2 dose-ranging study of TAK-438 in subjects with erosive esophagitis 
(TAK-438/CCT-001), dose-response efficacy was shown for TAK-438, showing TAK-438 to be 
non-inferior to Lansoprazole at either of the doses tested (5 mg, 10 mg, 20 mg, and 40 mg), with no 
particular safety concerns identified. Furthermore, the rate of endoscopic healing of erosive 
esophagitis in subjects with more severe disease (LA classification grades C/D) was 95% or higher 
with TAK-438 at doses 20 mg or higher compared to 87% with Lansoprazole 30 mg, which led to 
the clinically recommended dose of TAK-438 for erosive esophagitis being determined as 20 mg.
In light of these considerations, it was decided that a phase 3 double-blind study would be 
conducted to validate the noninferiority of TAK-438 to Lansoprazole in the reduction of relapse of 
erosive esophagitis in subjects in the Maintenance Phase (24 weeks) in whom endoscopic healing 
of erosive esophagitis has been confirmed after treatment with TAK-438 20 mg, following PPI 
treatments, or Lansoprazole 30 mg. This study will further examine the effectiveness and safety of 
TAK-438 in Asian subjects outside of Japan for the maintenance treatment of subjects with 
endoscopically confirmed healed erosive esophagitis.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective(s)

To demonstrate the noninferiority of TAK-438 to Lansoprazole in the reduction of relapse of 
erosive esophagitis in subjects in the Maintenance Phase (24 weeks) in whom endoscopic 
healing of erosive esophagitis has been confirmed after treatment with TAK-438 or a PPI.

To determine the clinically recommended dose of TAK-438 for maintenance therapy in 
erosive esophagitis in whom endoscopic healing of erosive esophagitis has been confirmed 
after treatment with TAK-438 or a PPI.
5.1.2
Secondary Objectives 

To evaluate the efficacy of TAK-438 during the first 12-weeks of treatment in the Maintenance 
Phase in subjects with endoscopically confirmed healed erosive esophagitis receiving 
TAK-438 or a PPI.

To evaluate the safety of TAK-438 versus Lansoprazole in subjects in the Maintenance Phase 
(24 weeks) in whom endoscopic healing of erosive esophagitis has been confirmed after 
treatment with TAK-438 or a PPI.
5.1.3
Additional Objectives 

To evaluate the effect of TAK-438 on subjective symptoms of erosive esophagitis (heartburn 
and regurgitation) and improvement in Health Related Quality of Life using the EuroQol 
(EQ-5D-5L).
5.2
Endpoints
5.2.1
Primary Endpoints 
The primary efficacy endpoint for this study is the rate of recurrence* of erosive esophagitis as 
confirmed on endoscopy during the 24-week Maintenance Phase.
*Recurrence: defined as subjects endoscopically confirmed to have erosive esophagitis (LA 
classification grades A to D) during the Maintenance Phase (24 weeks).
5.2.2
Secondary Endpoints 
The secondary efficacy endpoint for this study is the rate of recurrence* of erosive esophagitis 
during the first 12 weeks of treatment in the Maintenance Phase. Safety endpoints for this study 
include adverse events (AEs), clinical laboratory test results, ECG, vital signs, serum gastrin and 
pepsinogen I/II levels.
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*Recurrence: defined as subjects endoscopically confirmed to have erosive esophagitis (LA 
classification grades A to D) during the Maintenance Phase (12 weeks).
5.2.3
Additional Endpoints 
Other efficacy endpoints include subjective symptoms of erosive esophagitis (heartburn and 
regurgitation) as recorded in subject diaries and Health-Related Quality of Life measures.
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
6.1.1
Study Description
This is a phase 3, multicenter, randomized double-blind, parallel-group study to demonstrate the 
noninferiority of TAK-438 (10 mg or 20 mg) to Lansoprazole 15 mg in preventing the recurrence 
of erosive esophagitis in subjects with endoscopically confirmed healing of erosive esophagitis. 
This study also aims to determine the clinically recommended dose of TAK-438 for maintenance 
therapy of erosive esophagitis.
This study is comprised of 2 treatment periods: An open-label, single-arm period in which subjects 
receive Lansoprazole 30 mg for up to 8 weeks (Healing Phase), and a double-blind, parallel-group 
period in which subjects are randomized at a 1:1:1 ratio to TAK-438 10 mg, 20 mg or 
Lansoprazole 15 mg once daily for up to 24 weeks (Maintenance Phase). To enroll in the study 
subjects must have ongoing erosive esophagitis or have completed Study TAK-438_303. Subjects 
with ongoing erosive esophagitis are required to undergo the Healing Phase. Once erosive 
esophagitis healing is confirmed by endoscopy, these subjects may be randomized to 1 of 
3 treatments in the Maintenance Phase. Subjects with endoscopic-confirmed healing of erosive 
esophagitis following the completion of Study TAK-438_303 will be randomized into the 
Maintenance Phase without carrying out the open-label Healing Phase. Subjects who previously 
entered the study (prior to Protocol Amendment 06) after confirmation of healed erosive 
esophagitis following treatment with a proton pump inhibitor (termed “de novo” subjects) are no 
longer eligible to enter the study; any ongoing subjects may continue being treated in the 
Maintenance Phase. A schematic of the study design is included in Figure 6.a. A schedule of 
assessments is listed in Appendix A. 
If relapse of erosive esophagitis has been endoscopically confirmed in any subject, the subject will 
complete the study at that time point (to be construed as “complete cases in the Maintenance 
Phase”), regardless of the time point where relapse of disease is confirmed.
This study will be conducted at a total of around 70 sites across Asia with an estimated total of 
231 subjects randomized to each treatment group during the Maintenance Phase (totaling 
693 subjects entering the Maintenance Phase for the study).
The study will consist of a Screening Phase of up to 28 days duration (Visit 1), a Healing Phase 
(for those subjects with ongoing erosive esophagitis only) of 4 or 8 weeks duration (Visits 2HP and 
3HP), followed by a Maintenance Phase of up to 24 weeks (Visits 2-8), and a Follow-up Period of 
up to 14 days duration. With the exception of the Follow-up (which will be carried out by phone), 
all visits will occur at the clinic. The total duration of treatment is up to 6 months (24 weeks) in 
subjects entering from Study TAK-438_303, and up to 8 months (32 weeks) in subjects entering 
the study with ongoing erosive esophagitis.
Subjects with ongoing erosive esophagitis: Subjects who have ongoing erosive esophagitis will 
enter the Healing Phase and administration of Lansoprazole 30 mg once daily will commence 
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following the completion of all required assessments at Visit 2HP. Subjects will then undergo a visit 
at Week -4 (Visit 3HP), where the subject may undergo endoscopy to confirm healing of erosive 
esophagitis. This is an optional procedure where the decision to perform endoscopy is based on the 
investigator’s clinical judgment of a subject’s symptoms of healing. Subjects who do not show 
endoscopic healing at Visit 3HP may continue in the Healing Phase and undergo endoscopy at 
Day 1 (Visit 2). Subjects with endoscopically confirmed healing of erosive esophagitis at Week -4 
or at Day 1 will be eligible to enter the Maintenance Phase. Where the results from clinical 
laboratory tests confirming eligibility for the Maintenance Phase at Week -4 are not immediately 
available, subjects should continue to receive Lansoprazole 30 mg for up to 14 days. Subjects 
healed at Day 1 should be immediately randomized. Subjects who do not have 
endoscopic-confirmed healed erosive esophagitis after 8 weeks treatment (Healing Phase Failures) 
will not be randomized into the Maintenance Phase and should be treated using routine clinical 
care.
Subjects with healed erosive esophagitis: Subjects with healed erosive esophagitis will undergo a 
randomization visit (Visit 2), and dosing for the Maintenance Phase will commence following the 
completion of all required assessments on Day 1. Visits will then occur at 2 week intervals after the 
initiation of treatment in the Maintenance Phase. As a result of Protocol Amendment 06, subjects 
with healed erosive esophagitis following treatment with a proton pump inhibitor outside Study 
TAK-438_303 or the Healing Phase of the current study (de novo subjects) are no longer eligible 
to enter the study; any ongoing subjects may continue to be treated in the Maintenance Phase.
All subjects receiving TAK-438 must undergo a total of 8 weeks of LFT monitoring visits with 
visits occurring every 2 weeks. For subjects entering the Maintenance Phase of the current study 
within 7 days of completing Study TAK-438_303, the requirement for 8 weeks of monitoring can 
be totalled across the 2 studies. Further detail on the LFT monitoring requirements is available in 
Section 9.1.8.
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Figure 6.a
Schematic of Study Design
Subjects entering the study from Study TAK-438_303 with endoscopic-confirmed healing of erosive esophagitis (EE) 
will be immediately randomized into the double-blind Maintenance Phase. Prior to randomization into the 
Maintenance Phase, subjects with ongoing EE will receive open-label Lansoprazole 30 mg once daily for 4 or 8 weeks 
(the Healing Phase) until healing of EE is confirmed by endoscopy performed at either Week -4 and/or Day 1. 
Subjects who do not have endoscopic-confirmed healed EE after 8 Weeks treatment (Healing Phase Failures) will not 
be randomized and should be treated using routine clinical care. 
6.2
Justification for Study Design, Dose, and Endpoints
For the patient population studied
To evaluate the efficacy and safety of TAK-438 as maintenance therapy for healed erosive 
esophagitis, this study plans to enroll subjects who were confirmed on endoscopy to have erosive 
esophagitis (LA classification grades A to D) and in whom endoscopic healing of erosive 
esophagitis has been confirmed either after treatment with TAK-438 or Lansoprazole in the 
TAK-438_303 study, or following up to 8 weeks treatment with open-label Lansoprazole in the 
current study.
The LA classification system is used to confirm the severity of erosive esophagitis, as this is a 
widespread method of classification, as well as used during an earlier Phase 2 dose-ranging study 
of TAK-438 (TAK-438/CCT-001).
For study design and sample size used
1. Study design.
To evaluate the efficacy and safety of TAK-438 as maintenance therapy for healed erosive 
esophagitis, the present study was designed as a randomized, double-blind, parallel-group study 
comparing the efficacy and safety of TAK-438 10 mg and 20 mg versus the PPI Lansoprazole
15 mg, a drug of first choice for maintenance therapy for erosive esophagitis. 
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In light of the results of a phase 2 dose-ranging study of TAK-438 (TAK-438/CCT-001) 
demonstrating a lower rate of endoscopically confirmed healing in subjects with the baseline LA 
classification grades C/D than those with grades A/B; similarly, in maintenance therapy, relapse is 
expected to be more common among those with endoscopically confirmed severe disease. 
Therefore, the present study planned to stratify the subjects by baseline endoscopic findings 
(grades A/B or C/D) at the start of the Maintenance Phase for those who have participated in Study 
TAK-438_303, and prior to open-label Lansoprazole during the Healing Phase in those subjects 
who did not first complete Study TAK-438_303. Moreover, to ensure sufficient enrolment of 
subjects with severe disease and to perform subgroup analysis, at least 15% LA Grades C/D 
subjects should be enrolled in this study. 
For those subjects entering the study with ongoing erosive esophagitis, a treatment period of 4 or 
8 weeks has been selected as the duration of treatment for Lansoprazole 30 mg during the Healing 
Phase. Lansoprazole 30 mg once daily has been shown to heal erosive esophagitis in 92% of 
subjects within 4 weeks treatment (Study TAK 438/CCT-002). A treatment duration of up to 
8 weeks is consistent with the approved product label for Lansoprazole in Malaysia, China and 
Taiwan and a treatment duration of 8 weeks is recommended in Korea. 
2. Sample size.
For a description of the rationale for sample size determination, refer to Section 13.3.
For doses of the study medications used
In a phase 2 dose-ranging study of TAK-438 in subjects with erosive esophagitis 
(TAK-438/CCT-001), TAK-438 exhibited a dose-response efficacy, when given once daily at 
doses 5 mg, 10 mg, 20 mg, and 40 mg for 8 weeks, and demonstrated its noninferiority to 
Lansoprazole 30 mg at either of the doses examined, with no particular safety concerns identified. 
Additionally, given that the rate of endoscopic healing of erosive esophagitis in subjects with more 
severe disease (LA classification grades C/D) was 95% or higher with TAK-438 at doses 20 mg or 
higher compared to 87% with Lansoprazole 30 mg, the clinically recommended dose of TAK-438 
for erosive esophagitis was determined as 20 mg.
The proton pump inhibitors as the standard of care for erosive esophagitis have been approved for 
use at the same dose used in the treatment of erosive esophagitis or half the dose in the 
maintenance treatment of erosive esophagitis.
As TAK-438 is an anti-secretory agent similar to the proton pump inhibitor Lansoprazole, the dose 
strengths to be tested for maintenance treatment have been determined as the recommended dose 
of TAK-438 for treatment of erosive esophagitis (20 mg) and half that dose (10 mg).
For the open-label Healing Phase, Lansoprazole 30 mg has been selected as this is the indicated 
dose for the treatment of erosive esophagitis in all participating countries.
For the route of administration used
In a phase 1 single-dose study of TAK-438 in healthy male volunteers conducted in Japan, which 
evaluated the influence of diet on the pharmacokinetics of TAK-438 10 mg and 40 mg, the 
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AUC0-48 and the Cmax was shown to be increased by 1.32-fold (95% CI, 1.18 to 1.48) and by 
1.21-fold (95% CI, 0.951 to 1.54), respectively, with TAK-438 10 mg, and by 1.15-fold (95% CI, 
1.05 to 1.27) and by 1.08 (95% CI, 0.944 to 1.23), respectively, with TAK-438 40 mg, after meals 
compared to those seen under fasting conditions, demonstrating that the postprandial increases in 
AUC and Cmax with TAK-438 were modest. Again, pharmacological results from the same phase 1 
study demonstrated that once-daily dosing of TAK-438 exhibited adequate acid-inhibitory effects 
that were sustained over a 24-hour period, and Lansoprazole 15 mg has been approved for once 
daily dosing.
Based on these results, it was decided that TAK-438 would be given after breakfast as a once-daily 
regimen, as in the earlier phase 2 dose-ranging study of TAK-438 (TAK-438/CCT-001).
For the duration of treatment used
In a double-blind comparative study of Lansoprazole (AG-1749), a drug of first choice for erosive 
esophagitis, as maintenance therapy for erosive esophagitis (AG-1749/CCT-202: A study of 
Lansoprazole as maintenance therapy for erosive esophagitis), Lansoprazole, given 15 or 30 mg 
once daily for 24 weeks, has been shown to be efficacious in subjects in whom endoscopic healing 
of erosive esophagitis were confirmed after 8 weeks of treatment with Lansoprazole 30 mg orally 
given once daily. 
In this study, which aims to validate the noninferiority of TAK-438 10 mg and 20 mg to 
Lansoprazole as well as to determine the clinically recommended dose of TAK-438, the duration 
of maintenance treatment with TAK-438 has been determined as 24 weeks as was the case with 
Lansoprazole.
For the endpoints used
1. Primary endpoint.
The primary endpoint for this study was defined as the rate of endoscopic recurrence of erosive 
esophagitis during the 24 weeks of maintenance treatment with TAK-438, as in the 
above-mentioned study of Lansoprazole as maintenance therapy for erosive esophagitis, as the 
study aimed to validate the noninferiority of TAK-438 10 mg and 20 mg to Lansoprazole and to 
determine the clinically recommended dose of TAK-438.
2. Secondary endpoints
To compare early recurrence of erosive esophagitis with TAK-438 and Lansoprazole, the 
secondary endpoint for this study was defined as the rate of recurrence during the first 12 weeks of 
maintenance treatment with TAK-438 10 mg and 20 mg versus Lansoprazole 15 mg.
3. Additional endpoints.
Heartburn and gastric acid regurgitation are typical symptoms of erosive esophagitis which could impact the subject’s 
Health-Related Quality of Life. The severity and frequency of those symptoms are recorded via the daily diary by the 
subjects using the questionnaires outlined in Table 9.c and 
Table 9.d, which were also implemented in the Japanese clinical development program. The
HRQoL will be assessed by subjects completing validated questionnaires. The EQ-5D-5L index 
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score has been previously used to demonstrate that moderate to severe symptoms of GERD are 
associated with a significant impairment in HRQoL[2, 3]. Consequently those subjective 
symptoms and health-related quality of life using EQ-5D-5L are considered as additional 
endpoints in this study.
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures. 
3. The subject has been confirmed on endoscopy to have had erosive esophagitis (LA 
classification grades A to D) within 84 days of Day 1. At least 15% (104 subjects) of LA 
grades C/D subjects should be enrolled in this study to ensure sufficient enrollment of subjects 
with severe disease and to perform subgroup analysis. 
Note: The recruitment goal is to enroll subjects so that those with a history of LA classification 
grade C/D will account for more than 15% of all subjects (104/693) and those with a history of 
grade A/B will not be recruited further when they account for more than 85% (589/693) of all 
subjects.
4. If the subject is not rolled over from TAK-438_303 study, he/she has undergone an open-label 
PPI treatment (Lansoprazole 30 mg, once daily) of 4 or 8 weeks within the TAK-438_305 
protocol. 
5. The subject has been confirmed on endoscopy to have healing of erosive esophagitis. This 
endoscopy, if not part of the TAK-438_303 study, must have been within the last 14 days prior 
to randomization, otherwise the endoscopy must be repeated to confirm healing before 
randomization in the TAK-438_305 study.
6. The subject is aged 18 years old or older (or the local age of consent if that is older), male or 
female, at the time of signing an informed consent, and is being treated on an outpatient basis 
for erosive esophagitis, including those temporarily admitted for examination.
7. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
throughout the duration of the study and for 4 weeks after last dose of study medication.
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.9 Contraception and Pregnancy Avoidance Procedure and reporting 
responsibilities are defined in Section 9.1.10 Pregnancy.
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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 (other than study TAK-438_303) 
within 84 days prior to screening phase. 
2. The subject has received TAK-438 in a previous clinical study (other than study 
TAK-438_303) 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 the conduct of this study 
(eg, spouse, parent, child, sibling) or may consent under duress. 
4. The subject has, in the judgment of the investigator, clinically significant abnormal 
hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening.
5. The subject has a history or clinical manifestations of significant CNS, cardiovascular, 
pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, endocrine or hematological 
disease. 
6. The subject has a history of hypersensitivity or allergies to TAK-438 or to proton pump 
inhibitors (PPIs) including any associated excipients*.
* 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 start the screening phase. 
8. The subject is required to take excluded medications listed in Section 7.3.
9. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after participating in this study; or intending to donate ova during such time 
period. 
10. The subject has participated in another clinical study (other than study TAK-438_303) within 
the past 30 days prior to the screening phase. 
11. The subject has co-morbidities that could affect the esophagus (eosinophilic esophagitis, 
esophageal varices, scleroderma, viral or fungal infection, esophageal strictures), a history of 
radiotherapy or cryotherapy for the esophagus; those with corrosive or physiochemical injury 
(with the possible inclusion in the study of those with Schatzki’s ring or Barrett’s esophagus).
12. The subject has a history of surgical procedures that may affect the esophagus 
(eg, fundoplication and mechanical dilatation for esophageal strictures excluding Schatzki’s 
ring) or a history of gastric or duodenal surgery excluding endoscopic removal of benign 
polyps.
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13. The subject developed acute upper gastrointestinal bleeding, gastric ulcer (a mucosal defect 
with white coating) or duodenal ulcer (a mucosal defect with white coating), within 30 days 
before the start of the Screening Phase (Visit 1) (with the possible inclusion of those with 
gastric or duodenal erosion). The subjects requiring NSAIDs or aspirin treatment along with 
the concomitant PPI therapy to prevent GI bleeding should not be enrolled
14. The subject has Zollinger-Ellison syndrome or gastric acid hypersecretion or a history of 
gastric acid hypersecretion.
15. The subject is scheduled for surgery that requires hospitalization or requires surgical treatment 
during his/her participation in the study.
16. The subject has a history of malignancy or was treated for malignancy within 5 years before 
the start of the Screening Phase (visit 1) (the subject may be included in the study if he/she has 
cured cutaneous basal cell carcinoma or cervical carcinoma in situ). 
17. The subject has acquired immunodeficiency syndrome (AIDS) or hepatitis, including hepatitis 
virus carriers (HBs-antigen or HCV-antibody-positive) (the subject may be included in the 
study if he/she is HCV-antigen or HCV-RNA-negative).
18. Laboratory tests performed on visit 1 revealed any of the following abnormalities in the 
subject:
a) Creatinine levels: >2 mg/dL (>177 µmol/L).
b) ALT, AST or total bilirubin levels: > the upper limit of normal (ULN).
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.
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Table 7.a
Excluded Medications and Treatments
From 12 weeks prior to 
randomization to study 
completion 
From the start of 
the Healing Phase 
through to study 
completion
From 7 days prior to 
randomization 
through to study 
completion
From start of randomization to study 
completion
Other investigational 
drugs or drugs 
administered due to 
participation in another 
clinical trial
H. pylori eradication 
therapy (ie, PPI + 2 
antibiotics)
H2 antagonists 
(interfere with gastric 
acid secretion)
Other agents affecting digestive organs 
including: muscarinic M3 receptor 
antagonists, prokinetics, anticholinergic 
agents, prostaglandins, antacids, anti-gastrin 
agents or mucosal-protective agents. 
Non-study related PPIs.
Hormonal 
contraceptives
Atazanavir sulfates; Rilpivirine hydrochloride 
(contraindicated with TAK-438)
Surgical procedures that could affect gastric 
acid secretion (eg, upper gastrointestinal 
surgery, vagotomy) or for treatment of EE 
(fundoplication)
Bisphosphonates(*)
(*) Except subjects that were using these agents before signing the informed consent form at the screening visit and the 
dose and administration will not be changed during the study. Switching between once-daily and weekly regimens is 
allowed for drugs containing the same active ingredients. Also allowed are compliant subjects on a stable dose (in 
accordance with the package insert) at the time of signing consent that have no GI inflammation or history of such.
7.4
Diet, Fluid, Activity Control 
The principal investigator, the co-investigators, and the study collaborators are to explain, and give 
instructions on, the following before the start of the study or during the study, as well as to check to 
see if the subjects keep to the instructions at the time of their scheduled visits.

Every subject should keep to the scheduled visits, seek medical consultation, and undergo 
predetermined laboratory tests. 

With the exception of Lansoprazole 30 mg during the Healing Phase (where applicable), which 
should be administered according to the approved local package insert, the subject should 
ensure that all study medications are swallowed with 240 ml water soon after breakfast 
according to the administration, dose and dosing schedule. Subjects should be instructed 
according to Section 8.1.3.3 (Missed Doses) and Section 9.2 (Compliance). Details of any 
missed or forgotten doses should be reported to the investigator or designee at the subsequent 
study visit.

The subject should store all medications in a cool, dry, safe place which is out of reach at 
children and to bring all study supplies (empty / used / unused drug packets and diaries alike) 
to each study visit.

The subject should record his/her nighttime (during sleep) subjective symptoms and the 
previous daytimes subjective symptoms in his/her subject diary upon rising in the morning on 
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a daily basis. The subject should also record his/her study medication compliance status during 
the Maintenance Phase of the study. 

Subjects will be required to fast for at least 10 hours before each visit, where fasting blood 
draw will be taken and/or endoscopy will be performed, after the Informed Consent is signed. 
Fasting status means no food or nutritional drinks. Water is allowed. Any medication that 
needs to be taken with food, and study medications, should be held until after the fasting blood 
draw has been taken and/or endoscopy has been performed. Medication that does not need to 
be taken with food should be continued. Investigator must instruct the subject accordingly 
prior to visits in which serum gastrin and pepsinogen I/II levels will be measured, endoscopy 
will be performed.

If on any day between study visits the subject failed to eat breakfast, he/she should take the 
study medication at about the same time as he/she usually does.

When the subject is to be treated by physicians other than study investigators or taking other 
medications, such as over-the-counter drugs, beyond those prescribed, he/she should consult 
the study investigator or designee beforehand. When the subject was treated by a physician 
other than the investigator or when he/she took other medications such as over-the-counter 
drugs beyond those prescribed, he/she should report on the treatment received or the 
medications taken at the next study visit.

The subject should report on all subjective or objective symptoms experienced with regard to 
their details, day of onset, severity, outcome, and day of outcome at every visit. In case of 
emergency, such as occurrence of a serious AE, the subject or his/her family should contact the 
investigator as soon as possible.

The subject should use contraception without fail. (A female subject of childbearing potential 
from signing of informed consent throughout the duration of the study and 4 weeks after the 
final dose of the study medication). Pregnancy in a female subject, if found, should be reported 
immediately.

The subject should not donate blood during the study, and should report on any such donation 
immediately.

The subject should refrain from excessive drinking and eating, an extreme diet change 
(eg, change to an extremely high-fat diet) or excessive exercise throughout the study.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study should be 
recorded in the case report form (eCRF) using the following categories. For screen failure subjects, 
refer to Section 9.1.12.
1. Pretreatment event or AE. The subject has experienced a pretreatment event or AE that 
requires early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the pretreatment event or AE.
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
Liver Function Test Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any time 
during study medication treatment:
–
ALT, AST or total bilirubin >2 times of upper limit of normal (ULN).
2. Major protocol deviation. The discovery post-randomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE or lack of efficacy should not be recorded in the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10.
7. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject. 
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF, for example: 
non-compliance.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may terminate a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded. In 
addition, efforts should be made to perform all procedures scheduled for the Early Termination 
Visit. Discontinued or withdrawn subjects will not be replaced.
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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to TAK-438 (10 mg tablets, 20 mg tablets and 
their matching placebo tablets) and Lansoprazole (15 mg capsules and matching placebo capsules, 
as well as Lansoprazole 30 mg capsules/ tablets) defined below. Study medication will be 
packaged in a blinded fashion for the Maintenance Phase and in an open fashion for the Healing 
Phase.
8.1.1.1
Investigational Drug
The chemical name of TAK-438 is: 
1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrrol-3-yl]-N-methyl methanamine 
monofumarate. The code name is TAK-438. The International Nonproprietary Name (INN) is 
vonoprazan. Note that there is no generic name assigned at the time of writing this protocol. 
TAK-438 10 mg, 20 mg and their matching placebo investigational drug is manufactured by 
Takeda Pharmaceutical Company, Osaka, Japan and will be supplied as pale yellow and pale red 
respectively, film-coated tablets.
The chemical name of Lansoprazole (AG-1749) is:
(RS)-2-({[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridylmethyl]sulfinyl} benzimidazole. 
Lansoprazole 15 mg will have a dual supply chain. The Lansoprazole 15 mg and 30 mg for the 
study conducted in China is manufactured locally by Tianjin Takeda, Tianjin China. Lansoprazole
15 mg and 30 mg for all other countries and matching placebo for Lansoprazole 15 mg is 
manufactured by Takeda Pharmaceutical Company, Osaka, Japan. All Lansoprazole 15 mg and 
matching placebo will be supplied as a white colored capsule. Lansoprazole 30 mg will be 
supplied as a white colored capsule with the exception of the Malaysia marketed version where 
Lansoprazole 30 mg will be supplied as a white-to-yellowish white uncoated tablet with 
orange-to-dark brown speckles.
For the Healing Phase, Lansoprazole 30 mg will be foil/foil blistered packaged into 35-day 
(4 weeks plus 7 extra days) child-resistant blister cards for sites in Korea and Taiwan. The daily 
dose will be 1 capsule. The country-specific marketed version of Lansoprazole 30 mg will be 
supplied for sites in China and Malaysia respectively. These products will be labelled in an open 
fashion.
For the Maintenance Phase, TAK-438 and Lansoprazole investigational drug will be foil/foil 
blistered packaged into 20-day (2 weeks plus 6 extra days) child-resistant blister cards. Each 
blister card will include 20 TAK-438 10 mg or placebo tablets; 20 TAK-438 20 mg or placebo 
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tablets and 20 Lansoprazole 15 mg or placebo capsules. The daily dose will be 2 tablets and 
1 capsule. Each blister card will be labeled in a blinded fashion. For all investigational treatments, 
each blister card will be accompanied by a single panel or multi language booklet label appropriate 
to the countries in which it will be used. The labels will include pertinent study information and
country-specific regulatory caution statement. 
An Interactive Web Response System (IWRS) program will be used to manage inventory, assist 
the site in dispensing the proper investigational drug to the subjects, record accountability and 
support the return to sponsor or designee of these investigational drugs after study completion.
Table 8.a
Investigational Drug
Study medication form
Description
Manufacturer and Location
Healing Phase
Lansoprazole 30 mg 
capsule/tablet*
White capsule 
White to yellowish white with orange to 
dark brown speckles uncoated tablet *
Tianjin Takeda Pharmaceuticals Co., 
Ltd, China(for the study in China) / 
Takeda Pharmaceutical Company 
Limited, Osaka, Japan (for the study in 
countries except for China) 
Maintenance Phase
TAK-438 10 mg tablet
Pale yellow film-coated tablet
Takeda Pharmaceutical Company Ltd, 
Japan
TAK-438 10 mg matching 
placebo tablet
Pale yellow film-coated tablet
Takeda Pharmaceutical Company Ltd, 
Japan
TAK-438 20 mg tablet
Pale red film-coated tablets with score 
on both side
Takeda Pharmaceutical Company Ltd, 
Japan
TAK-438 20 mg matching 
placebo tablet
Pale red film-coated tablets with score 
on both side 
Takeda Pharmaceutical Company Ltd, 
Japan
Lansoprazole 15 mg capsule
White capsule 
Tianjin Takeda Pharmaceuticals Co., 
Ltd, China(for the study in China) / 
Takeda Pharmaceutical Company 
Limited, Osaka, Japan (for the study in 
countries except for China) 
Lansoprazole 15 mg matching 
placebo capsule
White capsule 
Takeda Pharmaceutical Company Ltd, 
Japan
*In Malaysia, marketed Lansoprazole 30 mg is supplied as a tablet.
All active medications and their matching placebo are difficult to distinguish from their 
appearance.
8.1.1.2
Ancillary Materials
Daily subject diaries will be dispensed to all subjects entering the study.
8.1.1.3
Sponsor-Supplied Drug
All drugs referenced in Section 8.1.1.1 of this protocol will be supplied by the sponsor.
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8.1.2
Storage
TAK-438, Lansoprazole 15 mg and each matching placebo investigational drug should be stored 
at 25°C; with excursions permitted 15°C to 30°C). Please follow the instruction on the marketed 
drug (Lansoprazole 30 mg) label. Protect from moisture and humidity. Study medication is to 
remain in the blister card until time of dosing.
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. All sponsor-supplied drugs must be stored 
under the conditions specified on the label, and remain in the original container until dispensed. A 
daily temperature log of the drug storage area must be maintained every working day.
Temperature excursion must be reported to the sponsor or designee.
8.1.3
Dose and Regimen
8.1.3.1
Healing Phase
The Healing Phase is not applicable for subjects rolled over from TAK-438_303 study. 
Subjects who have ongoing erosive esophagitis and meet all of the inclusion criteria and none of 
the exclusion criteria will receive open-label Lansoprazole 30 mg administered once daily. 
Subjects will receive Lansoprazole 30 mg for 4 or 8 weeks and will self-administer according to 
guidelines provided in the local package insert.
8.1.3.2
Maintenance Phase
Following endoscopic confirmation of healed erosive esophagitis, each subject who meets all the 
inclusion criteria and none of the exclusion criteria will be randomly assigned via the IWRS to 
receive daily TAK-438 10 mg, TAK-438 20 mg, or Lansoprazole 15 mg.
Blinding will be achieved using double-dummy, therefore at each dosing time-point subjects will 
take 2 tablets and 1 capsule, one will be active and the other two will be placebos. All subjects will 
self-administer the study medications at approximately the same time each morning after 
breakfast.
Subjects will receive study drug for up to 24 weeks, thereafter subjects will move into the 
follow-up phase. A follow-up phone call will be completed at 7-14 days after the last dose.
The subject will take the first dose of study medication at Visit 2 after completion of all 
assessments but before leaving the clinic. At all subsequent study visits during the Maintenance 
Phase (Weeks 2, 4, 6, 8, 12 and 24) the subject should be instructed to present to the clinic for study 
visits without taking the study medication. The daily dose of the study medication on those days 
will be taken by the subject after completion of assessments.
Table 8.b describes the dose and tablet/capsule count that will be provided to each group.
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Table 8.b
Sponsor-Supplied Drug During the Maintenance Phase
Treatment 
Group
Dose
Treatment Description
Active
Placebo
A
10 mg TAK-438 QD
One 10 mg TAK-438 tablet
One placebo tablet for TAK-438 20 mg 
plus one placebo for 15 mg 
Lansoprazole capsule
B
20 mg TAK-438 QD
One 20 mg TAK-438 tablet
One placebo tablet for TAK-438 10 mg 
plus one placebo for 15 mg 
Lansoprazole capsule
C
15 mg Lansoprazole QD
One 15 mg Lansoprazole 
capsule
One placebo for 20 mg TAK-438 tablet 
and one placebo for 10 mg TAK-438 
tablet
8.1.3.3
Missed Doses
Subjects should be instructed that all doses of study medication (TAK-438 or Lansoprazole) 
should be taken on time. Subjects should also be instructed that if any dose is missed inadvertently 
it is acceptable for that dose to be taken within 12 hours of the time that it was due. If longer than 
12 hours have passed since the dose was due, it should not be taken but noted instead in the 
subject’s diary that the dose was missed.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. AEs 
associated with an overdose will be documented on AE CRF(s) according to Section 10.0, 
Pretreatment Events and Adverse Events.
Serious adverse events (SAEs) of overdose should be reported according to the procedure outlined 
in Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose in the subject should treat the subject symptomatically. 
8.2
Investigational Drug Assignment and Dispensing Procedures
The investigator or investigator’s designee will access the IWRS at the Screening Visit after the 
subject provides informed consent in order to obtain a subject number. 
Healing Phase: The investigator or investigator’s designee will access IWRS in order to record the 
number of Lansoprazole cartons/wallet cards that will be dispensed at Week -8 and Week -4 in 
order to provide enough study medication to cover the duration until the next visit. Lansoprazole 
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30 mg provided for Healing Phase has a different count of capsules/tablets in a carton/wallet card 
depending on the country. Please refer to the IWRS manual on how many cartons/wallet cards will 
need to be dispensed.
Maintenance Phase: Following confirmation of healed erosive esophagitis and study eligibility at 
Visit 2, the investigator or the investigator’s designee will utilize the IWRS to randomize the 
subject into the study. During this contact, the investigator or designee will provide the necessary 
subject-identifying information, including the subject number assigned at screening. The Med ID 
number of the investigational drug to be dispensed will then be provided by the IWRS. 
If sponsor-supplied drug (TAK-438 10 mg and 20 mg tablet or their matching placebo tablet, 
Lansoprazole 15 mg capsule or matching placebo capsule) is lost or damaged, the site can request 
a replacement from IWRS. (Refer to IWRS manual provided separately.) The Med ID number will 
be entered onto the eCRF at each dispensing visit for the Maintenance Phase.
At subsequent drug-dispensing visits, the investigator or designee will again contact the IWRS to 
request additional investigational drug for a subject. The IWRS will provide 2 Med ID numbers for 
dispensing to subjects for a 4-week treatment duration at Visit 2, 4 Med ID numbers for an 8 week 
treatment duration at Visit 3, and 6 Med ID numbers for a 12 week treatment duration at Visit4.
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 Maintenance Phase of the study. All randomization information will be 
stored in a secured area, accessible only by authorized personnel.
Subjects will be assigned in a 1:1:1 ratio to TAK-438 10 mg, TAK-438 20 mg or Lansoprazole
15 mg treatment groups. Subject randomization will be stratified by LA classification grades A/B 
vs C/D at the time of erosive esophagitis diagnosis.
8.4
Investigational Drug Blind Maintenance 
The investigational drug blind will be maintained using the IWRS
8.5
Unblinding Procedure 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. In the 
event of a medical emergency, if possible, the medical monitor should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding.
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by 
accessing the IWRS.
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF.
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If any site personnel is unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study. 
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the approved protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug (TAK-438, Lansoprazole, or matching placebo), the 
investigator must maintain records of all sponsor-supplied drug delivery to the site, site inventory, 
dispensation and use by each subject, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct; and is in 
good condition. If quantity and conditions are acceptable, investigator or designee should 
acknowledge the receipt of the shipment by recording in IWRS. If there are any discrepancies 
between the packing list versus the actual product received, Takeda must be contacted to resolve 
the issue. The packing list should be filed in the investigator’s essential document file.
The investigator must maintain 100% accountability for all sponsor-supplied drugs received and 
dispensed during his or her entire participation in the study. Proper drug accountability includes, 
but is not limited to:

Continuously monitoring expiration dates (drug label).

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot (or Med ID or job number) used to prepare 
each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator must record the current inventory of all sponsor-supplied drugs on a 
sponsor-approved drug accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, description 
of sponsor-supplied drugs, expiry or retest date, date and amount dispensed including initials of 
the person dispensing the drug, and the date and amount returned to the site by the subject, 
including the initials of the person receiving the sponsor-supplied drug. The log should include all 
required information as a separate entry for each subject to whom sponsor-supplied drug is 
dispensed.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
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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 should be obtained including date of birth, sex, race as described by the 
subject, smoking status, and history of alcohol use and caffeine-containing drinks, history of 
H. pylori eradication therapy (eg, triple therapy with PPI + amoxycillin + clarithromycin) and date 
of completion of such therapy (within the past 1 year/more than 1 years) of the subject at 
Screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.7). Medical history will include the following:

Erosive esophagitis.

Other upper gastrointestinal diseases including gastric ulcer, duodenal ulcer, erosive 
esophagitis, non-erosive gastroesophageal reflux disease or procedures.
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 90 days prior to signing the ICF. 
Medication history will include the following:

PPIs.

Histamine H2 receptor antagonists.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the pretreatment assessment immediately prior to the 
start of investigational drug) will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; 
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(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.
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 Study Schedule (Appendix A).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw.
9.1.6
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF.
9.1.7
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, electrocardiogram 
(ECG), or physical examination abnormalities noted at screening (Visit 1) or baseline (Visit 2) 
examinations. The condition (ie, diagnosis) should be described.
9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Except for 
Hepatitis B and C analysis, all other samples will be analyzed at the designated central laboratory.
The maximum volume of blood to be collected at any single visit for central laboratory analysis is 
approximately 3.5 to 19.5 mL. Additionally, the volume of blood to be collected for Hepatitis B 
and C tests at the Screening visit is up to 10 mL and the approximate total volume of blood to be 
collected for the study is 79.5~96.0 mL for those subjects entering directly in to the Maintenance 
Period and 96.0~112.5 mL for those subjects entering the Healing Phase and Maintenance Phase. 
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Details of these procedures and required safety monitoring will be given in the central laboratory 
manual.
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cells
ALT(*)
Protein (qualitative)
White blood cells
ALP
Sugar (qualitative)
Hemoglobin
AST(*)
Hematocrit
GGT
Gastrin(*)
Pepsinogen I/II(*) ($)
Platelets
Total bilirubin(*)
Direct bilirubin(*)
Hepatitis B and C Analysis (#)
White blood cell fractions 
(neutrophils, eosinophils, basophils, 
monocytes, lymphocytes)
LDH
CK (CPK)
Albumin
Total protein
Creatinine
BUN
Uric acid
Total cholesterol
Triglycerides(*)
Glucose(*)
Potassium
Sodium
Magnesium
Calcium
Inorganic phosphorus
Chloride
Serum iron
Vitamin B12
HBsAg
HCV-antibody
HCV-antigen (+)
HCV-RNA(+)
Other: 
Serum
Urine
Female subjects if menopause is suspected only
–
Follicle-stimulating hormone (FSH)
Female subjects of child-bearing potential only
–
hCG (for pregnancy)
(*)To be measured under fasting conditions.
($) This includes pepsinogen I, pepsinogen II and pepsinogen I/II ratio.
(#) To be measured either at the central laboratory or the local laboratory depending on the site capability.
(+) HCV-antigen and HCV-RNA are optional.
The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The HBV and HCV tests can be done either at the local laboratory or the central 
laboratory depending on the site capability. The results of the central laboratory tests will be 
returned to the investigator, who is responsible for reviewing and filing these results.
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All subjects receiving TAK-438 must undergo a total of 8 weeks of LFT monitoring visits with 
visits occurring every 2 weeks. For subjects entering the Maintenance Phase of the current study 
within 7 days of completing Study TAK-438_303, the frequency of the LFT monitoring visits 
depends on when the subject was healed in Study TAK-438_303. For example, a subject healed at 
Week 2 of Study TAK-438_303 would complete LFT monitoring visits at Weeks 2, 4, and 6 of the 
current study, whereas a subject healed at Week 4 of Study TAK-438_303 would complete LFT 
monitoring visits at Weeks 2 and 4 of the current study. Subjects entering the Maintenance Phase 
of the current study more than 7 daysafter completing antecedent study TAK-438_303, as well as 
subjects entering the Maintenance Phase after completing the Healing Phase, and de novo subjects 
(an eligible route of entry prior to protocol amendment 6), will be required to complete LFT 
monitoring visits every 2 weeks from Day 1 (at Weeks 2, 4, 6, and 8).
If subjects experience an increase in any one of ALT, AST or total bilirubin >2 ×ULN, the study 
medication shall be stopped according to the discontinuation criteria. Follow-up laboratory tests 
(at a minimum, serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) to monitor 
recovery should be performed within a maximum of 7 days and preferably within 48-72 hours after 
the abnormality was found. Please refer to Section 7.5 for discontinuation criteria, and 
Section 10.2.3 for the appropriate guidance on Reporting of Abnormal Liver Function Tests.
Given the possibility that the use of TAK-438 or Lansoprazole may be associated with increases in 
serum gastrin and pepsinogen I/II levels, the subjects will be examined for gastrin and pepsinogen 
I/II levels to investigate the magnitude of these increases throughout all applicable treatment 
periods in the study.
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.
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An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are excluded, the only 
acceptable methods of contraception are:
Barrier methods (each time the subject has 
intercourse) where applicable*:
Intrauterine devices (IUDs):

Cap (plus spermicidal cream or jelly) PLUS 
male condom.

Diaphragm (plus spermicidal cream or jelly) 
PLUS male condom.

Copper T.
*Barrier methods is only applicable in countries where spermicide is commercially available.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy and donation of ova during the course of 
the study.
During the course of the study, regular urine human chorionic gonadotropin (hCG) pregnancy tests 
will be performed only for women of childbearing potential and subjects will receive continued 
guidance with respect to the avoidance of pregnancy as part of the study procedures (Appendix A). 
In addition to a negative urine hCG pregnancy test at Screening, subjects also must have a negative 
urine hCG pregnancy test at day 1, prior to receiving any dose of study medication.
9.1.10 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (TAK-438, Lansoprazole, matching placebo and antacid 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. 
Subjects randomized to placebo need not to be followed.
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time 
she became pregnant and provide details of treatment the subject received (blinded or unblinded, 
as applicable).
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.
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9.1.11 ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The time that 
the ECG was performed will be recorded. The following parameters will be recorded on the eCRF 
from the subject’s ECG trace: heart rate, RR interval, PR interval, QT interval, and QRS interval,. 
As ECG tracings on thermal paper fade over time, any such tracings should be completely 
photocopied and both the original tracing and the counter-signed copy should be filed in the 
subject’s medical record.
9.1.12 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible at this visit, the investigator should complete the eCRF. 
The IWRS should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

Healing Phase failure (for subjects enrolled in the open-label Lansoprazole 30 mg Healing 
Phase only, and who are not healed after 8 weeks of treatment).

Pretreatment event/AE.

Did not meet inclusion criteria or did meet exclusion criteria <specify reason>.

Major protocol deviation.

Lost to follow-up.

Voluntary withdrawal <specify reason>.

Study termination.

Other <specify reason>.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.13 Documentation of Study Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance/randomization into the Maintenance Phase.
If the subject is found to be not eligible for randomization/Maintenance Phase, the investigator 
should record the primary reason for failure on the applicable eCRF.
If the subject is found to be eligible the subject will be randomized to either TAK-438 10 mg, 
20 mg or Lansoprazole using the IWRS. Instructions on accessing and using the IWRS will be 
provided in a separate manual. Blinded details of subject treatment allocation (Med ID numbers) 
provided by the IWRS should be documented in the subject’s medical record and/or eCRF.
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9.1.14 Endoscopy 
Endoscopy should be performed while subjects are fasted and according to the usual practice of the 
institution (ie, in regards to pre-medications or concomitant therapies as long as they are not 
prohibited in Section 7.3 of this protocol). 
During endoscopy the investigator, or designee, should ensure that the gastric and esophageal 
mucosa is observed for a sufficient duration that the subject’s eligibility is confirmed and/or ensure 
that accurate classification of the grade of any erosive esophagitis, Barrett’s mucosa or esophageal 
hiatal hernia observed can be made. Digital images of any esophagus should be captured and 
stored at the investigational site and they should be available in the event of a future medical or 
data query, audit or inspection.
The investigator should classify any lesions seen based on the LA classification (Table 9.b), any 
Barrett’s mucosa in accordance with the following criteria:

At Screening Phase (Visit 1), Visit 3HP, and Day 1: present (3 cm or greater), present (less 
than 3 cm), absent, unknown.

Other time points for endoscopy: increased, unchanged, reduced, disappeared, unknown.
And any esophageal hiatal hernia in accordance with the following criteria:

At Screening Phase (Visit 1), Visit 3HP, and Day 1: present (2 cm or greater), present (less 
than 2 cm), absent, unknown.
After the endoscopy the investigator should promptly record any findings or observations in the 
subject’s medical record.
Table 9.b
Los Angeles (LA) classification for diagnosis and grading of erosive 
esophagitis
Mucosal break: area with white coating or erythema clearly distinguished from the surrounding mucosa
Grade
Description
Grade O
No mucosal breaks
Grade A
One or more mucosal breaks no longer than 5 mm, none of which extends between the tops of the 
mucosal folds
Grade B
One or more mucosal breaks more than 5 mm long, none of which extends between the tops of 
two mucosal folds
Grade C
Mucosal breaks that extend between the tops of two or more mucosal folds, but which involve 
less than 75% of esophageal circumference
Grade D
Mucosal breaks which involve at least 75% of esophageal circumference
The investigator (or designee) will record the results of endoscopy (including results of the LA 
classification and other gradings) in the subject’s medical record. For LA Grade O, the investigator 
is allowed to record the result as either “No mucosal breaks” and/or “Grade O”. This reflects the 
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clinical practice of recording ‘No mucosal breaks’ in medical records, as Grade O is not routinely 
used.
To ensure the accuracy of EE evaluation according to LA grading, a second review process of the 
endoscopy image 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 EE LA grading 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 
sub-investigator in this study.

In cases where the principal investigator is the first reviewer, a sub-investigator 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 sub-investigators) can be delegated as the 
second reviewer. 
If the LA grading by the two reviewers are consistent, this result becomes the final report. If not, 
the two reviewers will discuss their findings and reach a consensus which will then become the 
final report.
9.1.15 Diary for Gastrointestinal symptoms and Health-Related Quality of Life
Subjective symptoms of erosive esophagitis to be entered in the subject’s diary will include 
“heartburn”, and “regurgitation”. The subjective symptoms to be surveyed are described in 
Table 9.c and the severity in 
Table 9.d. Additionally, during all study visits ‘Health-Related Quality of Life’(EQ-5D-5L) 
questionnaire will be completed as the first priority of all procedures. The subject will be evaluated 
for HRQoL in the preceding week at every visit scheduled during the Maintenance Phase of the 
study. The subject diary and EQ-5D-5L questionnaire will be paper-based and provided to the 
subjects in their local languages. Site staffs are required to check the completeness of the HRQoL 
questionnaires and patient diaries before subjects leave the site in each visit. The data will be 
recorded onto the (e)CRFs and considered source data based on the subject’s completion of the 
paper questionnaires.
The subject will be instructed as to how to enter any subjective symptoms of erosive esophagitis 
he/she may experience in a subject diary and will be given a copy of the subject diary.
The subject must start entering the subject diary in the next morning (upon rising) after the start of 
the Screening Phase. Any subjective symptoms experienced should be entered on a once daily 
basis in accordance with the descriptions given in Table 9.c, throughout the study, describing in 
the diary the severity of all heartburns or acid regurgitations experienced during the previous 
daytime and nighttime periods (previous 24 hours), in the morning. The subject must also record 
the study medication taken on a daily basis in the diary during the Maintenance Phase. On study 
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visit days, the administration of study medication for that day should be entered into the diary 
before the diary is returned.
Documentation that subjects are appropriately instructed (and re-instructed as necessary) on how 
to correctly complete their diary and questionnaire should be completed in the subject’s medical 
record.
Table 9.c
Requirements for Subject Diary Entries Regarding Subjective Symptoms
Subjective symptom 
Description of symptom
Entry requirements
Heartburn
A burning feeling, pressure or 
pain in the chest, just behind the 
breast bone which may rise from 
the upper part of the stomach 
upwards towards the throat.
How bad was the heartburn when it was 
at its worst?
Regurgitation
Flow of sour or bitter fluid into 
the mouth.
How bad did regurgitation feel when it 
was at its worst?
Table 9.d
Severity of Subjective Symptoms
Subjective symptom 
Severity
Heartburn
Regurgitation
No symptoms
Mild
Moderate
Severe
* Please refer to Appendix E for definition of each ‘severity’ grade.
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study medication containers to each dispensing site visit. 
Investigators or designee should perform subject treatment compliance checks by reviewing the 
subject’s diary and returned medications.
If a subject is persistently noncompliant with the study medication (Lansoprazole 30 mg during the 
Healing Phase or TAK-438 10 mg, 20 mg or Lansoprazole 15 mg and their matching placebos 
during the Maintenance Phase) (eg, at more than 2 consecutive compliance checks to have taken 
less than 75% or more than 133% of the study medication), it may be appropriate to withdraw the 
subject from the study. 
At each applicable study visit it should be documented in the subject’s medical record that study 
medication was dispensed or collected, or checked for compliance. All subjects should be 
reinstructed about the dosing requirement during study contacts. The authorized study personnel 
conducting the re-education must document the process in the subject source records.
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9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Individual schedule of study-related procedures are presented separately for subjects entering the 
current study at the Healing Phase (Appendix A1), subjects entering the current study within 
7 days of completing Study TAK-438_303 (Appendix A2), and subjects entering the current study 
more than 7 days after completing Study TAK-438_303 (Appendix A3). Ongoing de novo
subjects (an eligible route of entry prior to protocol amendment 06), should follow the schedules 
outlined in Appendix A3. 
All assessments should be completed at the designated visit/time point(s). 
9.3.1
Visit 1: Screening Phase (Day -28 to Day -1)
Prior to any assessments being performed, all subjects will sign the ICF. The first procedure will 
be to access IWRS to obtain the subject number. Section 9.1.12 documents the procedures for 
screening failures, Healing Phase Failures, or randomization failures.
Subjects With Ongoing Erosive Esophagitis: All subjects with ongoing erosive esophagitis will 
undergo assessments for the Screening Phase within 28 days before the initiation of study 
medication as outlined in Appendix A1. 

Subjects will need to be in a fasted state for the Screening Visit. If fasting is not the routine 
clinical practice of the site, informed consent should be obtained prior to the request for fasting 
for the Screening Visit. If the subject comes to the site in an unfasted state, the following 
procedures will be performed at a second (fasting) Screening Visit.
–
Eligibility assessment (review inclusion/exclusion criteria).
–
Demographics, vital signs, medical and medication history.
–
Height and weight. BMI will be calculated during data analysis.
–
Physical examination including concurrent medical conditions and medications.
–
Concomitant medications assessment.
–
Hepatitis B and C analysis at the local laboratory (reliable, documented Hepatitis B and C 
results performed in a routine clinical setting within 14 days prior to signing the informed 
consent will be accepted).
–
ECG procedure (reliable, documented results available from an ECG performed in a 
routine clinical setting within 14 days prior to signing the informed consent will be 
accepted).
–
Fasting clinical laboratory tests: hematology, serum chemistry (excluding serum gastrin 
and pepsinogen I/II), urinalysis.
–
Urine pregnancy test (in females of childbearing potential only).
–
FSH (when menopause is suspected).
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–
Guidance on the avoidance of pregnancy and ova donation.
–
Endoscopy.
–
Pretreatment events assessment.
Subjects Entering the Current Study on the Same Day as Completing Study TAK-438_303 
Treatment: Screening procedures for these are outlined in Appendix A2. If the final study visit in 
the TAK-438_303 study coincides with the randomization visit (Visit 2) of the current study, these 
2 visits can be combined such that all of the overlapped examinations will be exempt from the 
screening and Day 1 procedures for the TAK-438_305 study. The overlapping examinations are 
comprised of clinical laboratory tests (hematology, serum chemistry, and urinalysis), serum 
gastrin and pepsinogen I/II levels, urine hCG, FSH, endoscopy, ECG, the subject diary, 
EQ-5D-5L, vital signs, and the physical examination. 
Laboratory test results from the TAK-438_303 study can be used for eligibility confirmation in the 
TAK-438_305 study, as long as they are within 28 days prior to randomization in the 
TAK-438_305 study. For these subjects, data obtained in the week when subjects were confirmed 
as healed in the TAK-438_303 study will be used as the baseline data for the current study, and 
data should be transcribed from the last visit in the TAK-438_303 study into the Visit 1 pages in 
the eCRF for the current study.
Subjects Entering the Current Study Within 7 Days of Completing Study TAK-438_303 Treatment:
Screening procedures for these subjects are outlined in Appendix A2. If the subjects are planned to 
be randomized into the current study within 7 days after completing the last visit in the 
TAK-438_303 study, Visit 1 and Visit 2 of the current study can be combined. Any overlapped 
procedures will be exempt from the screening procedures in the TAK-438_305 study. The 
overlapping examinations are comprised of clinical laboratory tests (hematology, serum 
chemistry, and urinalysis), serum gastrin and pepsinogen I/II levels, urine hCG, FSH, endoscopy, 
ECG, and the subject diary. However, EQ-5D-5L, vital signs, and the physical examination will 
have to be performed. 
For these subjects, data obtained in the week when subjects were confirmed as healed in the 
TAK-438_303 study will be used as the baseline data in the current study, and data should be 
transcribed from the last visit in the TAK-438_303 study into the Visit 1 pages in the eCRF for the 
current study.
Subjects Entering the Current Study More Than 7 Days After Completing Study TAK-438_303: 
Subjects planned to be randomized in to the current study more than 7 days after completing the 
last visit in the TAK-438_303 study, will follow screening period procedures outlined in 
Appendix A3. 
9.3.2
Visit 2HP: Healing Phase (Week -8)
This visit is only applicable for subjects undergoing the Healing Phase. Procedures to be 
completed at this visit include:
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
Dispense Healing Phase study medication (Lansoprazole 30 mg QD) and record number of 
cartons/wallets of study medication in the IWRS.

Guidance on the avoidance of pregnancy and ova donation.

AE/ Pretreatment Event assessment.

Concomitant medications assessment. 
9.3.3
Visit 3HP: Healing Phase (Week -4)
This visit is only applicable for subjects undergoing the Healing Phase. Procedures to be 
completed at this visit include:

Physical examination.

Vital signs.

Fasting clinical laboratory tests: hematology, serum chemistry (including serum gastrin and 
pepsinogen I/II), urinalysis.

Urine pregnancy test (in females of childbearing potential only).

ECG procedure.

Endoscopy. This is an optional procedure based on the investigator’s clinical judgment of a 
subject’s symptoms of healing. If the subject’s is endoscopically confirmed as healed, and the 
result of clinical laboratory tests at this visit from central laboratory re-confirms the subject’s 
eligibility, the subjects can be randomized within 14 days of this endoscopy date. During this 
period of waiting for randomization, subjects shall continue to take the newly dispensed 
Lansoprazole 30 mg QD. Subjects who do not show endoscopic healing at Visit 3HP may 
continue in the Healing Phase and undergo endoscopy at Day 1 (Visit 2).

Guidance on the avoidance of pregnancy and ova donation.

Study drug accountability and check treatment compliance, re-instruct the subject if necessary, 
dispense additional Healing Phase study medication (Lansoprazole 30 mg QD) and record the 
number of cartons/wallets of study medication in the IWRS.

AE assessment.

Concomitant medications assessment.
9.3.4
Visit 2: Randomization (Day 1)
Randomization will take place on Day 1 (Visit 2). The procedures followed during Visit 2 vary 
depending on the route of entry in to the Maintenance Phase. Individual schedule of study-related 
procedures are presented separately for subjects entering the current study at the Healing Phase 
(Appendix A1), subjects entering the current study within 7 days of completing treatment in 
antecedent Study TAK-438_303 (Appendix A2), and subjects entering the current study more 
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than 7 days of completing Study TAK-438_303 (Appendix A3). De novo subjects (an eligible 
route of entry prior to protocol amendment 6), should follow the schedules outlined in 
Appendix A3. 
In all cases, the EQ-5D-5L questionnaire is the first priority of all procedures in this visit. 

EQ-5D-5L.

Endoscopy (if the subject has not been confirmed healed after entering the Healing Phase). 

Physical examination.

Vital signs.

AE/ Pretreatment Event assessment.

Concomitant medications assessment. 

Urine pregnancy test (in females of childbearing potential only). This test is applicable only to 
subjects who are to be randomized more than 7 days after completing the Healing Phase 
Week -4 [Visit 3HP], or who are randomized more than7 days after completing TAK-438_303 
study treatment, or subjects who are not healed at Week -4 [Visit 3HP]).

Eligibility assessment (review inclusion/ exclusion criteria)

Collect study medication. This procedure is only applicable to subjects who have participated 
in the Healing Phase.

If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IWRS system, as described in 
Section 8.2. For eligible subjects the following should be completed:
–
Randomization via IWRS.
–
Fasting clinical laboratory tests: hematology, serum chemistry (including serum gastrin 
and pepsinogen I/II), urinalysis. This test is applicable only to subjects who are to be 
randomized more than 7 days after completing the Healing Phase Week -4 [Visit 3HP], or 
who are randomized more than 7 days after completing TAK-438_303 study treatment, or 
subjects who are not healed at Week -4 [Visit 3HP]).
–
Guidance on the avoidance of pregnancy and ova donation.
–
Dispense Maintenance Phase study medication (first daily dose to be taken before subject 
leaves the study site) and instruct the subject on correct self-administration for subsequent 
daily doses.
–
Dispense new subject diary for symptom and treatment compliance collection.
For ineligible subjects, the procedure for documenting Screening failures is provided in 
Section 9.1.12.
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9.3.5
Visit 3: Maintenance Phase (Day 15 / Week 2)

This visit is only applicable for subjects who have completed the Healing Phase, or for subjects 
who have rolled-over from the TAK-438_303 study and were confirmed as healed erosive 
esophagitis in the TAK-438_303 study at 2 or 4 weeks.
Procedures to be completed at this visit include:

Fasting liver function tests: ALT, AST, total bilirubin and direct bilirubin.

Guidance on the avoidance of pregnancy and ova donation.

AE assessment.

Concomitant medications assessment.
9.3.6
Visit 4: Maintenance Phase (Day 29 / Week 4)
Procedures to be completed at Visit 4 include:

EQ-5D-5L questionnaire. This shall be the first priority of all procedures in this visit.

Physical examination.

Vital signs.

Fasting clinical laboratory tests: hematology, serum chemistry (including serum gastrin and 
pepsinogen I/II), urinalysis. 

Urine pregnancy test (in females of childbearing potential only).

Collect completed diary since Visit 2, review completion compliance, and dispense new 
subject diary. On study visit days, allow the subject to record the administration of study 
medication for that day before the diary is returned.

Guidance on the avoidance of pregnancy and ova donation.

Review treatment compliance, re-instruct the subject if necessary and dispense Maintenance 
Phase investigational drugs via the IWRS.

AE assessment.

Concomitant medications assessment.
9.3.7
Visit 5: Maintenance Phase (Day 43 / Week 6)

This visit is only applicable for subjects who have completed the Healing Phase, or for subjects 
who have rolled-over from the TAK-438_303 study and confirmed as healed erosive 
esophagitis in the TAK-438_303 study at 2 weeks.
Procedures to be completed at this visit include:

Fasting liver function tests: ALT, AST, total bilirubin and direct bilirubin.
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
Guidance on the avoidance of pregnancy and ova donation.

AE assessment.

Concomitant medications assessment.
9.3.8
Visit 6: Maintenance Phase (Day 57/ Week 8)

This visit is only applicable for subjects who have completed the Healing Phase and de novo
subjects (an eligible route of entry prior to protocol amendment 6). Procedures to be completed 
at this visit include:
–
Fasting liver function tests: ALT, AST, total bilirubin and direct bilirubin.
–
Guidance on the avoidance of pregnancy and ova donation.
–
AE assessment.
–
Concomitant medications assessment.
9.3.9
Visit 7: Maintenance Phase (Day 85 / Week 12)
Procedures to be completed at Visit 7 include:

EQ-5D-5L questionnaire. This shall be the first priority of all procedures in this visit.

Physical examination.

Vital signs.

Collect completed diary since visit 4, review completion compliance, and dispense new 
subject diary (only if the subject’s EE has not relapsed).

Fasting clinical laboratory tests (hematology, chemistry including gastrin & pepsinogen I/II 
levels, urinalysis).

ECG procedure.

Endoscopy (Optional. Only if relapse of erosive esophagitis is suspected due to subjective 
symptoms or changes in clinical laboratory values).

Urine pregnancy test (in females of childbearing potential only).

Guidance on the avoidance of pregnancy and ova donation.

Review treatment compliance, re-instruct the subject if necessary.

AE assessment.

Concomitant medications assessment.

Dispense additional Maintenance Phase drug via the IWRS, or register as study completion if 
relapse is confirmed by endoscopy.
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
If relapse of erosive esophagitis has been endoscopically confirmed at this visit or any other 
time, the subject will complete the study at that time point and be considered as a completed 
case in the Maintenance Phase, regardless of the time point when relapse of disease is 
confirmed.

During the 12 weeks between Visit 7 and Visit 8, the site staff will follow their routine clinical 
practice to follow up with those subjects and make sure the subjects are in compliance of the 
study treatment and diary recording.
9.3.10 Visit 8: End of Treatment (Day 169 / Week 24) or Study Early Discontinuation Visit 
(within 14 days after final dose)
The following procedures should be performed and documented at the End of Treatment Visit 
(Visit 8: Day 169 / Week 24), or at the Study discontinuation visit:

EQ-5D-5L questionnaire. This shall be the first priority of all procedures in this visit.

Physical examination.

Vital signs.

Collect completed diary since Visit 7, review completion compliance.

Fasting clinical laboratory tests (hematology, chemistry including gastrin & pepsinogen I/II 
levels, urinalysis).

ECG procedure.

Endoscopy.

Urine pregnancy test (in females of childbearing potential only).

Guidance on the avoidance of pregnancy and ova donation.

Collect study medication and review treatment compliance.

AE assessment.

Concomitant medications assessment.

Register the subject study discontinuation or completion via IWRS.

For all randomized subjects, the investigator must complete the End of Study eCRF page.
9.3.11 Follow-up
The study site staff will follow up with a phone call between 7 and 14 days after the final dose of 
study medication. Any new AEs will be recorded in the eCRFs and subject’s source documents. 
Follow-up will begin the first day after the Final Visit/Early Termination and will continue until 
14 days post treatment. 
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9.3.12 Post Study Care
The study medication will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies as required.
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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.
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
If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
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worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
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 fulfill 1 or more of the serious criteria above are also to be considered as serious and 
should be reported and followed up in the same manner as SAEs (see Sections 10.2.2 and 10.3).
10.1.5 Special Interest AEs 
A Special Interest Adverse Event (serious or non-serious) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication by 
the investigator to Takeda may be appropriate. Such events may require further investigation in 
order to characterize and understand them and would be described in protocols and instructions 
provided for investigators as to how and when they should be reported to Takeda. There are no 
AEs of Special Interest.
10.1.6 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
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10.1.7 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Yes:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
No:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Yes if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as No.
10.1.9 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.10Stop 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.
10.1.11Frequency 
Episodic AEs/serious PTE (eg, vomiting) or those which occur repeatedly over a period of 
consecutive days are intermittent. All other events are continuous.
10.1.12Action Concerning Study Medication

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE.

Dose Increased – the dose was increased due to the particular AE.

Dose Reduced – the dose was reduced due to the particular AE
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
Dose Interrupted - The study medication was temporarily interrupted (discontinued) (including 
voluntary drug interruption by the subject) due to the particular AE, and resumed at a later 
date.
10.1.13Outcome 

Recovered/Resolved – Subject returned to first assessment status with respect to the 
AE/serious PTE.

Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/serious PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/serious PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/serious PTE but was left 
with permanent/significant impairment (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 – Subjects that did not participate in TAK-438_303
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication Visit 2) 
or until screen failure. For subjects who discontinue prior to study medication administration, 
PTEs are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication (Visit 2). Routine collection of AEs will continue until the Final Visit or Early 
Termination. A follow-up phase will be made to each subject 7-14 days following the last dose of 
study drug to collect any AEs that may have occurred. The stop date of the AE/serious PTE is the 
date at which the subject recovered, the event resolved but with sequelae or the subject died.
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10.2.1.2 AE Collection Period – Subjects that did participate in TAK-438_303
Collection of AEs will commence from the time the subject is first administered study medication 
for this study and continue until the Final Visit or Early Termination. A follow-up phase will be 
made to each subject 7-14 days following the last dose of study drug to collect any AEs that may 
have occurred. The stop date of the AE/serious AE is the date at which the subject recovered, the 
event resolved but with sequelae or the subject died.
10.2.1.3 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:

Event term.

Start and stop date.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (yes or no) (not completed for PTEs).

Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.

Action concerning study medication (not applicable for PTEs).

Outcome of event.

Seriousness.

Subject diary and questionnaire will not be used as a primary means to collect AEs. However, 
should the investigator become aware of a potential AE through the information collected with 
this instrument, proper follow-up with the patient for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been 
identified, normal reporting requirements should be applied.
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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 Liver Function Tests
If during the treatment or follow-up period a subject is noted to have ALT or AST >3 ×ULN and 
total bilirubin >2 ×ULN for which an alternative etiology has not been identified, the event should 
be recorded as an SAE and reported as per Section 10.2.2. The investigator must contact the 
Medical Monitor for discussion of the relevant subject details and possible alternative etiologies, 
such as acute viral hepatitis A or B or other acute liver disease. Follow-up laboratory tests as 
described in Section 9.1.8 must also be performed. In addition, a Liver Function Test Abnormality 
Form must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
If subjects experience an increase in any one of ALT, AST or total bilirubin >2 ×ULN, the study 
medication shall be stopped according to the discontinuation criteria. Follow-up laboratory tests 
(at a minimum, serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) to monitor 
recovery should be performed within a maximum of 7 days and preferably within 48-72 hours after 
the abnormality was found (see Section 9.1.8).
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 
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fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper should be 
copied and certified, source worksheets, all original signed and dated informed consent forms, 
subject authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. Furthermore, International Conference on Harmonisation (ICH) E6 Section 4.9.5 
requires the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 
2 years after the last approval of a marketing application for a specified drug indication being 
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investigated or, if an application is not approved, until at least 2 years after the investigation is 
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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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 un-blinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database.
13.1.1 Analysis Sets
Analysis of efficacy variables will be conducted in the Full Analysis Set defined as all randomized 
subjects who receive at least 1 dose of the Maintenance Phase drug and have at least 
1 post-baseline endoscopy, and will be based on the randomized treatment. The primary efficacy 
endpoint and the secondary efficacy endpoint will also be analyzed in the Per Protocol Set; subject 
evaluability criteria for the Per Protocol Set will be specified in the SAP. Analysis of safety 
variables will be conducted in the Safety Analysis Set defined as all subjects who take at least 
1 dose of the Maintenance Phase drug and will be based on the treatment received in the 
Maintenance Phase. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Baseline and demographic information will be listed and summarized by treatment group and 
overall. For continuous variables, the summary will consist of descriptive statistics (number of 
subjects, mean, standard deviation, minimum, median, and maximum). For categorical variables, 
the summary will consist of number and percentage of subjects in each category.
13.1.3 Efficacy Analysis
The following analyses will be provided using the Full Analysis Set.
For the primary efficacy endpoint of rate of endoscopic recurrence of erosive esophagitis during 
the 24-week Maintenance Phase, a 2-sided 95% confidence interval (CI) will be constructed for 
the difference between each TAK-438 group and Lansoprazole. The upper bound of this CI will be 
compared to 10%, the non-inferiority margin for TAK-438 relative to Lansoprazole. Rate of 
endoscopic recurrence of erosive esophagitis during the 24-week Maintenance Phase will also be 
analyzed in subgroups defined by LA classification grades A/B vs C/D at the time of erosive 
esophagitis diagnosis.
The secondary endpoint of rate of endoscopic recurrence of erosive esophagitis during the first 
12 weeks of treatment in the Maintenance Phase will be compared between each TAK-438 group 
and Lansoprazole by constructing a 2-sided 95% CI for the healing rate difference.
The additional endpoints related to GERD symptoms that occur during treatment in the 
Maintenance Phase will be compared between treatment groups using Wilcoxon rank-sum tests, 
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with treatment effects presented using Hodges-Lehmann estimator and 95% Moses CI. Analysis of 
HRQoL endpoints will be conducted with an Analysis of Covariance model with treatment and 
baseline EE grade (A/B vs C/D) as factors and baseline as a covariate.
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 and secondary efficacy endpoints in 
the following order under the closed testing procedure: 

The primary endpoint will be tested for non-inferiority between the TAK-438 20 mg group and 
Lansoprazole.

If the previous test is successful, the primary endpoint will be tested for non-inferiority 
between the TAK-438 10 mg group and Lansoprazole.

If the previous test is successful, the primary endpoint will be tested for superiority between 
the TAK-438 20 mg group and Lansoprazole. The upper bound of the CI of the difference 
between the TAK-438 20 mg group and Lansoprazole will be compared to 0%.

If the previous test is successful, the primary endpoint will be tested for superiority between 
the TAK-438 10 mg group and Lansoprazole.

If the previous test is successful, the secondary endpoint will be tested for superiority between 
the TAK-438 20 mg group and Lansoprazole.

If the previous test is successful, the secondary endpoint will be tested for superiority between 
the TAK-438 10 mg group and Lansoprazole.
13.1.4 Handling of Missing Data
For the primary efficacy endpoint of rate of endoscopic recurrence of erosive esophagitis during 
the 24-week Maintenance Phase, FAS subjects who have no endoscopy data obtained on Day 2 or 
after (where Day 1 is the date of first dose of the Maintenance Phase drug) and within 14 days after 
the date of last dose will be excluded from the analysis. FAS subjects assessed as LA classification 
of Grade A to D based on the endoscopy data obtained on Day 2 or after and within 14 days after 
the date of last dose will be considered as relapsed subjects. Other FAS subjects will be considered 
as ‘not relapsed’.
For the secondary endpoint of rate of endoscopic recurrence of erosive esophagitis during the first 
12 weeks of treatment in the Maintenance Phase, FAS subjects who have no endoscopy data 
during Day 2 to Day 127 and within 14 days after the date of last dose of the Maintenance Phase 
will be excluded from the analysis. FAS subjects assessed as LA classification of Grade A to D 
based on the endoscopy data obtained between Day 2 and Day 127 and within 14 days after the 
date of last dose will be considered relapsed subjects. Other FAS subjects will be considered ‘not 
relapsed’.
Further details will be described in the Statistical Analysis Plan.
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13.1.5 Safety Analysis
Safety analysis will be performed for the Maintenance Phase using the safety analysis set. 
The number and percentage of subjects with treatment-emergent AEs will be summarized by 
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class and Preferred Term 
overall, by severity, and by relationship to study drug for each treatment group. Separate 
summaries will also be generated for treatment-related AEs overall and by severity. Change from 
baseline in clinical laboratory tests (including serum gastrin and pepsinogen I/II), vital signs and 
quantitative ECG variables will be summarized by treatment group. For qualitative ECG 
assessments, post-baseline results will be tabulated against baseline. Subjects with markedly 
abnormal values for laboratory tests, vital signs, and ECG parameters will be tabulated. No 
statistical testing or inferential statistics will be generated.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
Assuming that the true Week 24 recurrence rate is 30.4% for Lansoprazole, 22.0% for TAK-438 
10 mg, and 13.6% for TAK-438 20 mg, and assuming that the dropout rate is approximately 30%, 
a sample size of 208 subjects per group will provide an overall power of 90% to establish 
noninferiority using a 2-sided 95% CI with a 10% noninferiority margin. 231 subjects per group 
will be included to allow adequate numbers for the regulatory requirements of various countries.
The assumption of the true recurrence rate is based on a phase 3 study that showed a Week 24 
recurrence rate of 30.4% for Lansoprazole 15 mg and 13.6% for Lansoprazole 30 mg.
Based on results from an earlier study of Lansoprazole as maintenance therapy for erosive 
esophagitis (AG-1747/CCT-202), the point estimate for the difference (Lansoprazole 15 mg 
group – famotidine group) was calculated as -57.6% with the upper limit of the confidence 
interval being -30.7%. Therefore, the noninferiority margin is specified as 10%. 
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the medical 
monitor (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospective approved deviation) from the inclusion or exclusion criteria.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (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 state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those US sites unwilling to provide names and titles of all members 
due to privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During the study, only the sponsor may make study information 
available to other study investigators or to regulatory agencies, except as required by law or 
regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, Takeda will, at a minimum register all 
clinical trials conducted in patients that it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before trial initiation. Takeda contact information, along with 
investigator’s city, state (for US investigators), country, and recruiting status will be registered and 
available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of this clinical trial, regardless of outcome, on ClinicalTrials.gov or 
other publicly accessible websites, as required by applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1. Fass R, Shapiro M, Swell J. Systematic review: proton-pump inhibitor failure in 
gastro-oesophageal reflux disease—where next? Aliment Pharmacol Ther. 2005;22:79-94.
2. Jones, R., Horbach, S., Sander, P., & Ryden-Bergsten, T. (2003). Heartburn in patients with 
gastro-oesophageal reflux disease in Germany and Sweden: a study on patients' burden of 
disease. [Research Support, Non-U.S. Gov't]. Pharmacoeconomics, 21(15), 1091-1102.
3. Mahadeva, S., Wee, H., L., Goh, K., & Thumboo, J. (2009). The EQ-5D (Euroqol) is a valid 
generic instrument for measuring quality of life in patients with dyspepsia. BMC 
Gastroenterology, 9. doi: http://dx.doi.org/10.1186/1471-230X-9-20.
4. Peter J, et al. A randomized, comparative study of three doses of AZD0865 and esomeprazole 
for healing of reflux esophagitis. Clin Gastroenterol Hepatol. 2007;5:12.
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Appendix A
Schedule of Study Procedures
Appendix A1 For Subjects With Ongoing Erosive Esophagitis Entering the Healing Phase.
Screening 
Phase
Healing 
Phase
Maintenance Phase
Follow-up 
Phase
Study Day/ Week
Weeks 
-12 to -8
Week 
-8
Week 
-4
Day 
1**
Week 
2 
(Day 
15)
Week 
4 
(Day 
29)
Week 
6 
(Day 
43)
Week 8 
(Day 
57)
Week 
12
(Day 
85)
Week 
24
(Day 
169)
Early 
Discontinuation 
Visit
Follow-
up phone 
call
Visit Windows (Days):
-
±3
±3
-
±3
±3
±3
±3
±3
±3
Within 14 days 
after final dose
7-14 days
after final 
dose
Visit Number
1
2HP
3HP
2 
3 (l)
4 
5
6
7 
8
-
Informed Consent
X
Inclusion/exclusion 
criteria
X
X
Concurrent medical 
conditions, medication 
and medical history
X
Demographics
X
Physical examination
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Height, weight and BMI
X
Concomitant medications
X
X
Fasting Clinical 
laboratory tests (a)
X
X
X*
X
X
X
X
Liver function test (k)
X
X
X
Serum gastrin/ 
pepsinogen I/II levels
X
X*
X
X
X
X
Guidance on avoidance of 
pregnancy and ova 
donation(b) 
X
X
X
X
X
X
X
X
X
X
X
FSH (c)
X
Urine pregnancy test 
(hCG) (d)
X
X
X*
X
X
X
X
Electrocardiogram (ECG)
X(o)
X
X
X
X
Hepatitis B and C tests (e)
X
Dispense/collect subject 
diary, review compliance 
(f)
X
X
X
X
X
EQ-5D-5L questionnaire
X
X
X
X
X
Endoscopy (g)
X
X(m)
X(n)
X(i)
X
X 
Obtain subject number 
via IWRS
X
Randomization via IWRS
X
Dispense investigational 
drug via IWRS
X(h)
X
X
Record investigational 
drug in IWRS
X
X
Collect study medication 
and review its compliance
X
X
X
X
X
X
Access IWRS for study 
screen failure, 
discontinuation or 
X
X
X
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Screening 
Phase
Healing 
Phase
Maintenance Phase
Follow-up 
Phase
Study Day/ Week
Weeks 
-12 to -8
Week 
-8
Week 
-4
Day 
1**
Week 
2 
(Day 
15)
Week 
4 
(Day 
29)
Week 
6 
(Day 
43)
Week 8 
(Day 
57)
Week 
12
(Day 
85)
Week 
24
(Day 
169)
Early 
Discontinuation 
Visit
Follow-
up phone 
call
Visit Windows (Days):
-
±3
±3
-
±3
±3
±3
±3
±3
±3
Within 14 days 
after final dose
7-14 days
after final 
dose
Visit Number
1
2HP
3HP
2 
3 (l)
4 
5
6
7 
8
-
completion(j)
AE/PTE assessment
X
X
Follow-up Phone call
X
*Only for subjects who are to be randomized more than 7 days after completing the Healing Phase Week -4 [Visit 3HP], 
or who are not healed at Week -4 [Visit 3HP]).
**The date of first investigational drug administration for Maintenance Phase is defined as Day 1.
(a) Hematology, serum chemistry, and urinalysis.
(b) Women of child-bearing potential.
(c) Only if menopause is suspected. 
(d) To be performed only in female subjects of childbearing potential.
(e) Hepatitis B and C analysis in accordance with Section 9.1.8 will be conducted either at the local laboratory or at the central 
laboratory depending on the site capability. However, any reliable, documented Hepatitis B and C results performed in a routine 
clinical setting within 14 days prior to Healing Phase (before signing of informed consent) will be accepted.
(f) On study visit days, allow the subject to record the administration of study medication for that day before the diary is returned.
(g) The endoscopy taken at Screening must be within 4 weeks prior to receiving open-label Lansoprazole. Considering the invasive 
nature of the endoscopy, any reliable, documented results available from an endoscopy performed in a routine clinical setting 
before signing of informed consent will be acceptable instead. Additionally, the endoscopy can be performed anytime during the 
treatment if recurrence is suspected.
(h) The subjects will be given the first daily dose of the study medication to before leaving the study site after completion visit 
assessments. 
(i) If relapse of erosive esophagitis is suspected in the subject due to subjective symptoms or changes in clinical laboratory values, 
he/she will undergo confirmatory endoscopy.
(j) At any time during the study, once the relapse is confirmed by endoscopy, the subject is considered “Completed”. If the subject 
is not randomized and withdrawn from the study, eg, failed during Healing Phase, the subject is considered “Screen Failed”. 
(k) Liver function tests include ALT, AST, total bilirubin and direct bilirubin. All subjects receiving TAK-438 must undergo a total 
of 8 weeks of LFT monitoring visits with visits occurring every 2 weeks (see Section 9.1.8 for further details on the timings of these 
tests).
(l) This visit is only applicable for subjects who have completed the Healing Phase.
(m) Optional. If EE healing is suspected at the investigators’ judgment, the endoscopy may be performed. Once the healing is 
endoscopically confirmed and eligibility re-confirmed including clinical laboratory test results, the subject may be randomized 
providing this occurs within 14 days of the endoscopy. The study medication Lansoprazole 30 mg QD shall be continued until the 
randomization. 
(n) Endoscopy is applicable only to those subjects who were not confirmed as healed at Week-4. 
(o) Any reliable, documented results available from an ECG performed in a routine clinical setting within 14 days prior to Healing 
Phase (before signing of informed consent) will be accepted.
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Appendix A2 For Subjects Entering the Current Study Within 7 Days of Completing Study 
TAK-438_303 Treatment 
Maintenance Phase
Follow-up 
Phase
Study Day/ Week
Screeni
ng/Day 
1**
Week 
2 (Day 
15)
Week 
4 
(Day 
29)
Week 6 
(Day 43)
Week 8 
(Day 57)
Week 12
(Day 85)
Week 24
(Day 
169)
Early 
Discontinua
tion Visit
Follow- up 
phone call
Visit Windows (Days):
±3
±3
±3
±3
±3
±3
Within14 
days after 
final dose
7-14 days 
after final 
dose
Visit Number
Visit 2
Visit 3 
(l)
Visit 4
Visit 5 
(m)
Visit 6 
(n)
Visit 7
Visit 8
-
Informed Consent
X
Inclusion/exclusion criteria
X
Concurrent medical 
conditions, medication and 
medical history
X
Demographics
X
Physical examination
X*
X
X
X
X
Vital signs 
X*
X
X
X
X
Height, weight and BMI
X
Concomitant medications
X
X
Clinical laboratory tests (a)
X
X
X
X
Liver function test (k)
X
X
Serum gastrin/ pepsinogen I/II 
levels
X
X
X
X
Guidance on avoidance of 
pregnancy and ova 
donation(b) 
X
X
X
X
X
X
X
FSH (c)
Urine pregnancy test (hCG) 
(d)
X
X
X
X
Electrocardiogram (ECG)
X
X
X
Hepatitis B and C tests (e)
Dispense/collect subject diary, 
review compliance (f)
X
X
X
X
X
EQ-5D-5L questionnaire
X*
X
X
X
X
Endoscopy (g)
X (i)
X
X 
Obtain subject number via 
IWRS
X
Randomization via IWRS
X
Dispense investigational drug 
via IWRS
X (h)
X
X
Collect study medication and 
review its compliance 
X
X
X
X
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Study No. TAK-438_305
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Protocol Incorporating Amendment No. 06
15 November 2016
Maintenance Phase
Follow-up 
Phase
Study Day/ Week
Screeni
ng/Day 
1**
Week 
2 (Day 
15)
Week 
4 
(Day 
29)
Week 6 
(Day 43)
Week 8 
(Day 57)
Week 12
(Day 85)
Week 24
(Day 
169)
Early 
Discontinua
tion Visit
Follow- up 
phone call
Visit Windows (Days):
±3
±3
±3
±3
±3
±3
Within14 
days after 
final dose
7-14 days 
after final 
dose
Visit Number
Visit 2
Visit 3 
(l)
Visit 4
Visit 5 
(m)
Visit 6 
(n)
Visit 7
Visit 8
-
Access IWRS for study 
discontinuation or 
completion(j)
X
X
AE/PTE assessment
X
X
Follow-up Phone call
X
* Only for the subject that his/her randomization visit in this study is not the same visit as the completion visit in the TAK-438_303 
study.
**The date of first investigational drug administration for the Maintenance Phase is defined as Day 1. All the procedures at the last
visit of TAK-438_303 should be performed according to TAK-438_303 protocol. Additional procedures at the Day 1 visit in 
TAK-438_305 should also be performed.
(a) Hematology, serum chemistry, and urinalysis.
(b) Women of child-bearing potential.
(c) Not required in this scenario. 
(d) To be performed only in female subjects of childbearing potential.
(e) Not required in this scenario. 
(f) The diary shall be dispensed to subjects for completion at least 3 days prior to randomization in order to provide baseline data. 
However, completion of the diary is not an inclusion/exclusion criterion. On study visit days, allow the subject to record the 
administration of study medication for that day before the diary is returned.
(g) Endoscopy confirmed healed in TAK-438_303 is considered the baseline endoscopy in this study. Additionally, the endoscopy 
can be performed anytime during the treatment if the recurrence is suspected.
(h) The subjects will be given the first daily dose of the study medication to be taken before leaving the study site after completion 
visit assessments. 
(i) If relapse of erosive esophagitis is suspected in the subject due to subjective symptoms or changes in clinical. laboratory values, 
he/she will undergo confirmatory endoscopy.
(j) At any time during the study, once the relapse is confirmed by endoscopy, the subject is considered “Completed”.
(k) Liver function tests include ALT, AST, total bilirubin and direct bilirubin. All subjects receiving TAK-438 must undergo a total 
of 8 weeks of LFT monitoring visits with visits occurring every 2 weeks (see Section 9.1.8 for further details on the timings of these 
tests).
(l) This visit is only applicable for subjects who have rolled-over from the TAK-438_303 study and confirmed as healed erosive 
esophagitis in the TAK-438_303 study at 2 or 4 weeks.
(m) This visit is only applicable for subjects who have rolled-over from the TAK-438_303 study and confirmed as healed erosive 
esophagitis in the TAK-438_303 study at 2 weeks.
(n) This visit is NOT applicable for roll-over subjects from TAK-438_303 study.
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Appendix A3 For Subjects Entering the Current Study More Than 7 Days After 
Completing Study TAK-438_303 and de Novo Subjects (where de novo was an 
eligible route of entry prior to Protocol Amendment 06).
Screen-
ing 
Phase
Maintenance Phase
Follow-up 
Phase
Study Day/ Week
Day 
-28 to 
Day -1
Day 
1**
Week 2 
(Day 
15)
Week 4 
(Day 
29)
Week 6 
(Day 
43)
Week 8 
(Day 
57)
Week 
12
(Day 
85)
Week 
24
(Day 
169)
Early 
Discontinu-
ation Visit
Follow-up 
phone call
Visit Windows (Days):
-
-
±3
±3
±3
±3
±3
±3
Within14 
days after 
final dose
7-14 days 
after final 
dose
Visit Number
Visit 1
Visit 
2
Visit 3 
(l)
Visit 4
Visit 5 
(m)
Visit 6 
(n)
Visit 7
Visit 8
-
Informed Consent
X
Inclusion/exclusion 
criteria
X
X
Concurrent medical 
conditions, medication 
and medical history
X
Demographics
X
Physical examination
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
Height, weight and BMI
X
Concomitant medications
X
X
Clinical laboratory tests 
(a)
X
X*
X
X
X
X
Liver function test (k)
X
X
X
Serum gastrin/ 
pepsinogen I/II levels
X
X
X
X
X
Guidance on avoidance of 
pregnancy and ova 
donation(b) 
X
X
X
X
X
X
X
X
X
FSH (c)
X
Urine pregnancy test 
(hCG) (d)
X
X*
X
X
X
X
Electrocardiogram (ECG)
X
X
X
X
Hepatitis B and C tests (e)
X
Dispense/collect subject 
diary, review compliance 
(f)
X
X
X
X
X
X
EQ-5D-5L questionnaire
X
X
X
X
X
X
Endoscopy (g)
X
X (i)
X
X 
Obtain subject number via 
IWRS
X
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Study No. TAK-438_305
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Screen-
ing 
Phase
Maintenance Phase
Follow-up 
Phase
Study Day/ Week
Day 
-28 to 
Day -1
Day 
1**
Week 2 
(Day 
15)
Week 4 
(Day 
29)
Week 6 
(Day 
43)
Week 8 
(Day 
57)
Week 
12
(Day 
85)
Week 
24
(Day 
169)
Early 
Discontinu-
ation Visit
Follow-up 
phone call
Visit Windows (Days):
-
-
±3
±3
±3
±3
±3
±3
Within14 
days after 
final dose
7-14 days 
after final 
dose
Visit Number
Visit 1
Visit 
2
Visit 3 
(l)
Visit 4
Visit 5 
(m)
Visit 6 
(n)
Visit 7
Visit 8
-
Randomization via IWRS
X
Dispense investigational 
drug via IWRS
X 
(h)
X
X
Collect study medication 
and review its compliance
X
X
X
X
Access IWRS for study 
discontinuation or 
completion(j)
X
X
AE/PTE assessment
X
X
Follow-up Phone call
X
* Only for subjects that had more than 7 days between Visit 1 and Visit 2.
**The date of first investigational drug administration for Maintenance Phase is defined as day 1.
(a) Hematology, serum chemistry, and urinalysis.
(b) Women of child-bearing potential.
(c) Only if menopause is suspected. 
(d) To be performed only in female subjects of childbearing potential.
(e) Hepatitis B and C analysis in accordance with Section 9.1.8 will be conducted either at the local laboratory or at the central 
laboratory depending on the site capability. 
(f) The diary shall be dispensed to subjects for completion at least 3 days prior to randomization in order to provide baseline data. 
But completeness of the diary is not an inclusion/exclusion criteria. On study visit days, allow the subject to record the 
administration of study medication for that day before the diary is returned.
(g) Endoscopy must be within 7 days prior to the randomization. Considering the invasive nature of the endoscopy, any reliable, 
documented results available from an endoscopy performed in a routine clinical setting within 7 days prior to randomization 
(Day 1) before signing of informed consent) will be acceptable instead. Additionally, the endoscopy can be performed anytime 
during the treatment if the recurrence is suspected.
(h) The subjects will be given the first daily dose of the study medication to before leaving the study site after completion visit 
assessments. 
(i) If relapse of erosive esophagitis is suspected in the subject due to subjective symptoms or changes in clinical laboratory values, 
he/she will undergo confirmatory endoscopy.
(j) At any time during the study, once the relapse is confirmed by endoscopy, the subject is considered “Completed”.
(k) Liver function tests include ALT, AST, total bilirubin and direct bilirubin. All subjects receiving TAK-438 must undergo a total 
of 8 weeks of LFT monitoring visits with visits occurring every 2 weeks (see Section 9.1.8 for further details on the timings of these 
tests).
(l) This visit is only applicable for de-novo subjects, and subjects who have rolled-over from the TAK-438_303 study and 
confirmed as healed erosive esophagitis in the TAK-438_303 study at 2 or 4 weeks.
(m) This visit is only applicable for de-novo subjects, and subjects who have rolled-over from the TAK-438_303 study and 
confirmed as healed erosive esophagitis in the TAK-438_303 study at 2 weeks.
(n) This visit is only applicable for de-novo subjects.
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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.
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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 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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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 
found to be pregnant during study, study medication will be discontinued and the investigator 
will offer the subject the choice to receive unblinded treatment information.
25. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix E
Definition of Heartburn/ Regurgitation Severity 
Definitions of Heartburn/Regurgitation Severity 
None 
No symptoms
Mild 
Occasional symptoms, can be ignored, does not influence daily routine
Moderate 
Symptoms cannot be ignored and/ or occasionally influence daily routine
Severe
Symptoms present most of the day and/ or regularly influence daily routine
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Appendix F
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 06 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Updated study team contacts and approvers.
The primary change occurs in Section 1.1 (Contacts) and Section 1.2 (Approval):
Description 
of change:
In Section 1.1, Asia Pacific contact details have been updated for :

Serious adverse event, pregnancy, and special interest adverse event reporting.

Medical Monitor.
In Section 1.2, the approver VP Head of Clinical Science GI TAU has been removed
Rationale for Change:
Updates made for alignment with template and standard operating process.
Change 2: Information from phase 3 clinical studies of TAK-438 has been added.
The primary change occurs in Section 4.1 Background:
Added text:TAK-438 has been studied in a number of acid-related diseases and 
noninferiority with Lansoprazole has been confirmed in several phase 3 studies 
including reflux esophagitis healing and prevention of recurrence studies, 
gastric/duodenal ulcer healing and for the prevention of recurrence of a gastric 
or duodenal ulcer during NSAID or aspirin administration and has subsequently 
been launched in Japan for these indications. All treatments were well-tolerated.
Rationale for Change:
New information describing the efficacy and safety of TAK-438 is available.
Change 3: Added a 4- or 8-week, open-label single-arm Lansoprazole 30 mg treatment period (the 
Healing Phase); new language to distinguish between the open-label Healing Phase and 
randomized, double-blind Maintenance Phase; defined Healing Phase Failures, and qualified that 
de novo subjects are no longer eligible to enroll.
The primary change occurs in Section 6.1.1 Study Description:
Initial 
wording:
All subjects who have been confirmed on endoscopy to have healing of erosive 
esophagitis will be randomized at a 1:1:1 ratio to oral TAK-438 10 mg, 20 mg or 
Lansoprazole 15 mg once daily given in the Maintenance Phase lasting 24 weeks. 
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If relapse of erosive esophagitis has been endoscopically confirmed in any subject, the 
subject will complete the study at that time point (to be construed as “complete cases 
in the Maintenance Phase”, regardless of the time point where relapse of disease is 
confirmed).
This study will be conducted at a total of around 60 sites across Asia with an estimated 
total of 231 subjects randomized to each treatment group totaling 693 for the study.
The study will consist of a Screening Phase of up to 28 days followed by a Treatment 
Phase of up to 24 weeks. There will be 8 subject visits scheduled: the start of the 
Screening Phase (Visit 1), the start of the Treatment Phase (Visit 2), 2 weeks after 
treatment (Visit 3), 4 weeks after of treatment (Visit 4), 6 weeks after treatment (Visit 
5), 8 weeks after treatment (Visit 6), 12 weeks after treatment (Visit 7), and 24 weeks 
after treatment (Visit 8), and a Follow-up phase. The LFT monitoring visits at Week 2, 
6 and 8 depend on whether the subjects have completed TAK-438_303 treatment or 
how long they have been in TAK-438_303 study. The biweekly LFT monitoring visits 
for blood draws is required for 8 weeks after subjects starts the study medication at 
TAK-438_303.
Dosing will commence on Day 1 after randomization at Visit 2 (after completion of all 
required assessments scheduled on the day 1). 
A schematic of the study design is included as 
Figure 6.a. A schedule of assessments is listed in Appendix A. 
Amended 
or new 
wording:
This study is comprised of 2 treatment periods: An open-label, single-arm period 
in which subjects receive Lansoprazole 30 mg for up to 8 weeks (Healing Phase), 
and a double-blind, parallel-group period in which subjects are randomized at a 
1:1:1 ratio to TAK-438 10 mg, 20 mg or Lansoprazole 15 mg once daily for up to 
24 weeks (Maintenance Phase). To enroll in the study subjects must have 
ongoing erosive esophagitis or have completed Study TAK-438_303. Subjects 
with ongoing erosive esophagitis are required to undergo the Healing Phase. 
Once erosive esophagitis healing is confirmed by endoscopy, these subjects may 
be randomized to 1 of 3 treatments in the Maintenance Phase. Subjects with 
endoscopic-confirmed healing of erosive esophagitis following the completion of 
Study TAK-438_303 will be randomized into the Maintenance Phase without 
carrying out the open-label Healing Phase. Subjects who previously entered the 
study (prior to Protocol Amendment 06) after confirmation of healed erosive 
esophagitis following treatment with a proton pump inhibitor (termed “de novo” 
subjects) are no longer eligible to enter the study; any ongoing subjects may 
continue being treated in the Maintenance Phase. A schematic of the study 
design is included in Figure 6.a. A schedule of assessments is listed in 
Appendix A. 
If relapse of erosive esophagitis has been endoscopically confirmed in any subject, the 
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subject will complete the study at that time point (to be construed as “complete cases 
in the Maintenance Phase”), regardless of the time point where relapse of disease is 
confirmed.
This study will be conducted at a total of around 70 sites across Asia with an 
estimated total of 231 subjects randomized to each treatment group during the 
Maintenance Phase (totaling 693 subjects entering the Maintenance Phase for 
the study).
The study will consist of a Screening Phase of up to 28 days duration (Visit 1), a 
Healing Phase (for those subjects with ongoing erosive esophagitis only) of 4 or 
8 weeks duration (Visits 2HP and 3HP), followed by a Maintenance Phase of up to 
24 weeks (Visits 2-8), and a Follow-up Period of up to 14 days duration. With the 
exception of the Follow-up (which will be carried out by phone), all visits will 
occur at the clinic. The total duration of treatment is up to 6 months (24 weeks) 
in subjects entering from Study TAK-438_303, and up to 8 months (32 weeks) in 
subjects entering the study with ongoing erosive esophagitis.
Subjects with ongoing erosive esophagitis: Subjects who have ongoing erosive 
esophagitis will enter the Healing Phase and administration of Lansoprazole 
30 mg once daily will commence following the completion of all required 
assessments at Visit 2HP. Subjects will then undergo a visit at Week -4 (Visit 3HP), 
where the subject may undergo endoscopy to confirm healing of erosive 
esophagitis. This is an optional procedure where the decision to perform 
endoscopy is based on the investigator’s clinical judgment of a subject’s 
symptoms of healing. Subjects who do not show endoscopic healing at Visit 3HP 
may continue in the Healing Phase and undergo endoscopy at Day 1 (Visit 2). 
Subjects with endoscopically confirmed healing of erosive esophagitis at Week -4 
or Day 1 will be eligible to enter the Maintenance Phase. Where the results from 
clinical laboratory tests confirming eligibility for the Maintenance Phase at 
Week -4 are not immediately available, subjects should continue to receive 
Lansoprazole 30 mg for up to 14 days. Subjects healed at Day 1 should be 
immediately randomized. Subjects who do not have endoscopic-confirmed 
healed erosive esophagitis after 8 weeks treatment (Healing Phase Failures) will 
not be randomized into the Maintenance Phase and should be treated using 
routine clinical care.
Subjects with healed erosive esophagitis: Subjects with healed erosive esophagitis 
will undergo a randomization visit (Visit 2), and dosing for the Maintenance 
Phase will commence following the completion of all required assessments on 
Day 1. Visits will then occur at 2 week intervals after the initiation of treatment 
in the Maintenance Phase. As a result of Protocol Amendment 06, subjects with 
healed erosive esophagitis following treatment with a proton pump inhibitor 
(de novo subjects) are no longer eligible to enter the study; any ongoing subjects 
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may continue to be treated in the Maintenance Phase.
All subjects receiving TAK-438 must undergo a total of 8 weeks of LFT 
monitoring visits with visits occurring every 2 weeks. For subjects entering the 
Maintenance Phase of the current study within 7 days of completing Study 
TAK-438_303, the requirement for 8 weeks of monitoring can be totalled across 
the 2 studies. Further detail on the LFT monitoring requirements is available in 
Section 9.1.8.
Rationale for Change:
To improve subject recruitment to the study, subjects with ongoing erosive esophagitis are 
permitted to enroll and first receive Lansoprazole 30 mg once daily for 4 or 8 weeks. To reduce the 
complexity of the study, subjects previously known as de novo subjects (subjects with healed 
erosive esophagitis following treatment with a proton pump inhibitor as per standard clinical 
practice) are no longer eligible to enter the study. 
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 4.2 Rationale for the Proposed Study

Section 6.2 Justification for Study Design, Dose, and Endpoints.

Section 9.1.12 Documentation of Screen Failure

Section 9.3.1 Visit 1: Screening Phase (Day -28 to Day -1).
Change 4: Added the Healing Phase to the Study Design Schematic.
The primary change occurs in Figure 6.a
Schematic of Study Design
Amended 
or new 
wording:
Figure 6.a Schematic of Study Design
[Figure changed to indicate that subjects with ongoing erosive esophagitis may enter 
the study and undergo a 4- or 8-week open-label Healing Phase.]
Rationale for Change:
To provide consistency with the revised text supporting the addition of a Healing Phase to the 
study design.
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Change 5: Clarified the primary and secondary objectives.
The primary change occurs in Section 5.1 Objectives
Initial 
wording:
Primary Objective(s)
To demonstrate the non-inferiority of TAK-438 to Lansoprazole in the reduction of 
relapse of erosive esophagitis in subjects in the Maintenance Phase (24 weeks) in 
whom endoscopic healing of erosive esophagitis has been confirmed after treatment 
with TAK-438 or a PPI, as well as to determine the clinically recommended dose of 
TAK-438 for maintenance therapy in erosive esophagitis.
Secondary Objectives
To evaluate the efficacy of TAK-438 during the 12-week treatment and the safety of 
TAK-438 versus Lansoprazole in subjects in the Maintenance Phase (24 weeks) in 
whom endoscopic healing of erosive esophagitis has been confirmed after treatment 
with TAK-438 or a PPI.
Amended 
or new 
wording:
Primary Objectives

To demonstrate the noninferiority of TAK-438 to Lansoprazole in the reduction of 
relapse of erosive esophagitis in subjects in the Maintenance Phase (24 weeks) in 
whom endoscopic healing of erosive esophagitis has been confirmed after 
treatment with TAK-438 or a PPI.

To determine the clinically recommended dose of TAK-438 for maintenance 
therapy in erosive esophagitis in whom endoscopic healing of erosive 
esophagitis has been confirmed after treatment with TAK-438 or a PPI.
Secondary Objectives

To evaluate the efficacy of TAK-438 during the first 12-weeks of treatment in the 
Maintenance Phase in subjects with endoscopically confirmed healed erosive 
esophagitis receiving TAK-438 or a PPI.

To evaluate the safety of TAK-438 versus Lansoprazole in subjects in the 
Maintenance Phase (24 weeks) in whom endoscopic healing of erosive 
esophagitis has been confirmed after treatment with TAK-438 or a PPI.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.
Rationale for Change:
To provide consistency with the revised text supporting the addition of a Healing Phase to the 
study design.
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Change 6: Changed the inclusion criteria.
The primary change occurs in Section 7.1: Inclusion Criteria
Initial 
wording:
4.
The subject has undergone PPI treatment if he/she is not rolled over from 
TAK-438_303 study. PPI treatment is defined as the treatment with at least 2 
weeks on a registered dose of a PPI combined with an endoscopy within 1 week of 
randomization confirming healing of the erosive esophagitis.
5.
The subject has been confirmed on endoscopy to have healing of erosive 
esophagitis. This endoscopy, if not part of the TAK-438_303 study, must have 
been within the last 1 week prior to randomization, otherwise the endoscopy must 
be repeated to confirm healing before randomization in the TAK-438_305 study.
Amended 
or new 
wording:
4. If the subject is not rolled over from TAK-438_303 study, he/she has 
undergone an open-label PPI treatment (Lansoprazole 30 mg, once daily) of 4 
or 8 weeks within the TAK-438_305 protocol. 
5. The subject has been confirmed on endoscopy to have healing of erosive 
esophagitis. This endoscopy, if not part of the TAK-438_303 study, must have 
been within the last 14 days prior to randomization, otherwise the endoscopy must 
be repeated to confirm healing before randomization in the TAK-438_305 study.
Rationale for Change:
To provide consistency with the revised text supporting the addition of a Healing Phase to the 
study design.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY
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Change 7: Updated the timings relating to excluded medications and treatments.
The primary change occurs in Table 7.a
Excluded Medications and Treatments:
Initial 
wording:
From 84 days prior to 
treatment to 
completion of the 
study
From 30 days 
prior to treatment 
through study 
completion
From 7 days 
prior to 
treatment
through study 
completion
From start of treatment to completion of the 
study
Amended 
or new 
wording:
From 12 weeks prior 
to randomization to 
study completion 
From the start of 
the Healing 
Phase to study 
completion
From 7 days prior 
to randomization 
to study completion
From start of randomization to study 
completion
Rationale for Change:
To provide consistency with the revised text supporting the addition of a Healing Phase to the 
study design.
Change 8: Stated the dosing instructions for Lansoprazole 30 mg.
The primary change occurs in Section 7.4 Diet, Fluid, Activity Control:
Amended 
or new 
wording:
With the exception of Lansoprazole 30 mg during the Healing Phase (where 
applicable), which should be administered according to the approved local 
package insert, the subject should ensure that all study medications are swallowed 
with 240 ml water soon after breakfast according to the administration, dose and 
dosing schedule. Subjects should be instructed according to Section 8.1.3.3 (Missed 
Doses) and Section 9.2 (Compliance). Details of any missed or forgotten doses should 
be reported to the Investigator or designee at the subsequent study visit.
Rationale for Change:
To provide consistency with the revised text supporting the addition of a Healing Phase to the 
study design.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 8.1.3.1 Healing Phase.
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Change 9: Stated dosage form, manufacturing, packaging, and labeling for Lansoprazole 30 mg.
The primary change occurs in Section 8.1.1.1 Investigational Drug:
Amended 
or new 
wording:
The chemical name of Lansoprazole (AG-1749) is:
(RS)-2-({[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridylmethyl]sulfinyl} 
benzimidazole. Lansoprazole 15 mg will have a dual supply chain. The Lansoprazole 
15 mg and 30 mg for the study conducted in China is manufactured locally by Tianjin 
Takeda, Tianjin China. Lansoprazole 15 mg and 30 mg for all other countries and 
matching placebo for Lansoprazole 15 mg is manufactured by Takeda Pharmaceutical 
Company, Osaka, Japan. All Lansoprazole 15 mg and matching placebo will be 
supplied as a white colored capsule. Lansoprazole 30 mg will be supplied as a white 
colored capsule with the exception of the Malaysia marketed version where 
Lansoprazole 30 mg will be supplied as a white-to-yellowish white uncoated 
tablet with orange-to-dark brown speckles.
For the Healing Phase, Lansoprazole 30 mg will be foil/foil blistered packaged 
into 35-day (4 weeks plus 7 extra days) child-resistant blister cards for sites in 
Korea and Taiwan. The daily dose will be 1 capsule. The country-specific 
marketed version of Lansoprazole 30 mg will be supplied for sites in China and 
Malaysia respectively. These products will be labelled in an open fashion.
For the Maintenance Phase, TAK-438 and Lansoprazole investigational drug will 
be foil/foil blistered packaged into 20-day (2 weeks plus 6 extra days) child-resistant 
blister cards. Each blister card will include 20 TAK-438 10 mg or placebo tablets; 20 
TAK-438 20 mg or placebo tablets and 20 Lansoprazole 15 mg or placebo capsules. 
The daily dose will be 2 tablets and 1 capsule. Each blister card will be labeled in a 
blinded fashion. For all investigational treatments, each blister card will be 
accompanied by 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. 
Rationale for Change:
To provide consistency with the revised text supporting the addition of a Healing Phase to the 
study design.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.
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Change 10: Clarified dispensing procedures during the Healing Phase.
The primary change occurs in Section 8.2 Investigational Drug Assignment and Dispensing 
Procedures:
Amended 
or new 
wording:
The investigator or investigator’s designee will access the IWRS at the Screening 
Visit after the subject provides informed consent in order to obtain a subject number. 
Healing Phase: The investigator or investigator’s designee will access IWRS in 
order to record the number of Lansoprazole cartons/ wallet cards that will be 
dispensed at Week -8 and Week -4 in order to provide enough study medication 
to cover the duration until the next visit. Lansoprazole 30 mg provided for 
Healing Phase has a different count of capsules/tablets in a carton/wallet card 
depending on the country. Please refer to the IWRS manual on how many 
cartons/wallet cards will need to be dispensed.
Maintenance Phase: Following confirmation of healed erosive esophagitis and
study eligibility at Visit 2, the investigator or the investigator’s designee will utilize 
the IWRS to randomize the subject into the study. During this contact, the investigator 
or designee will provide the necessary subject-identifying information, including the 
subject number assigned at screening. The Med ID number of the investigational drug 
to be dispensed will then be provided by the IWRS. 
Rationale for Change:
To provide consistency with the revised text supporting the addition of a Healing Phase to the 
study design.
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Change 11: Clarified the total volume of blood collected.
The primary change occurs in Section 9.1.8: Procedures for Clinical Laboratory Samples
Initial 
wording
The maximum volume of blood to be collected at any single visit for central laboratory 
analysis is approximately 3.5 - 19.5 mL (Visit 1, Visit 2, Visit 3, Visit 4, Visit 5, Visit 
6, Visit 7 and Visit 8/Early Discontinuation Visit). Additionally, the volume of blood 
to be collected for Hepatitis B and C tests at the Screening visit is up to 10 mL and the 
approximate total volume of blood to be collected for the study is 79.5~96.0 mL. 
Details of these procedures and required safety monitoring will be given in the central 
laboratory manual.
Amended 
or new 
wording:
The maximum volume of blood to be collected at any single visit for central laboratory 
analysis is approximately 3.5 to 19.5 mL. Additionally, the volume of blood to be 
collected for Hepatitis B and C tests at the Screening visit is up to 10 mL and the 
approximate total volume of blood to be collected for the study is 79.5~96.0 mL for 
those subjects entering directly in to the Maintenance Period and 96.0~112.5 mL 
for those subjects entering the Healing Phase and Maintenance Phase. Details of 
these procedures and required safety monitoring will be given in the central laboratory 
manual.
Rationale for Change:
To provide consistency with the revised text supporting the addition of a Healing Phase to the 
study design.
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Change 12: Further detailed the site visits for liver function tests.
The primary change occurs in Section 9.1.8 Procedures for Clinical Laboratory Samples:
Amended 
or new 
wording:
All subjects receiving TAK-438 must undergo a total of 8 weeks of LFT 
monitoring visits with visits occurring every 2 weeks. For subjects entering the 
Maintenance Phase of the current study within 7 days of completing Study 
TAK-438_303, the frequency of the LFT monitoring visits depends on when the 
subject was healed in Study TAK-438_303. For example, a subject healed at 
Week 2 of Study TAK-438_303 would complete LFT monitoring visits at 
Weeks 2, 4, and 6 of the current study, whereas a subject healed at Week 4 of 
Study TAK-438_303 would complete LFT monitoring visits at Weeks 2 and 4 of 
the current study. Subjects entering the Maintenance Phase of the current study 
more than 7 days after completing antecedent study TAK-438_303, as well as 
subjects entering the Maintenance Phase after completing the Healing Phase, 
and de novo subjects (an eligible route of entry prior to protocol amendment 6), 
will be required to complete LFT monitoring visits every 2 weeks from Day 1 (at 
Weeks 2, 4, 6, and 8).
The following sections also contain this change:

Appendix A1, Appendix A2, and Appendix A3, footnote K.
Rationale for Change:
To clarify the frequency in site visits for liver function tests.
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Change 13: Clarified the classification of endoscopy.
The primary change occurs in Section 9.1.14 Endoscopy:
Amended 
or new 
wording:
The investigator should classify any lesions seen based on the LA classification 
(Table 9.b), any Barrett’s mucosa in accordance with the following criteria:

At Screening Phase (Visit 1), Visit 3HP, and Day 1: present (3 cm or greater), 
present (less than 3 cm), absent, unknown.

Other time points for endoscopy: increased, unchanged, reduced, disappeared, 
unknown.
And any esophageal hiatal hernia in accordance with the following criteria:

At Screening Phase (Visit 1), Visit 3HP and Day 1: present (2 cm or greater), 
present (less than 2 cm), absent, unknown.
After the endoscopy the investigator should promptly record any findings or 
observations in the subject’s medical record.
. . .
The investigator (or designee) will record the results of endoscopy (including 
results of the LA classification and other gradings) in the subject’s medical 
record. For LA Grade O, the investigator is allowed to record the result as either 
“No mucosal breaks” and/or Grade O. This reflects the clinical practice of 
recording ‘No mucosal breaks’ in medical records, as Grade O is not routinely 
used.
Rationale for Change:
Addition of endoscopy procedures during the Healing Phase has been included to provide 
consistency with the revised text supporting the addition of the Healing Phase to the study design.
Addition of LA classification grading O has been included to reflect routine clinical practice.
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Change 14: Clarified procedures around diary collection on study visit days.
The primary change occurs in Section 9.1.15 Diary for Gastrointestinal symptoms and 
Health-Related Quality of Life:
Amended 
or new 
wording:
The subject must start entering the subject diary in the next morning (upon rising) after 
the start of the Screening Phase. Any subjective symptoms experienced should be 
entered on a once daily basis in accordance with the descriptions given in Table 9.c, 
throughout the study, describing in the diary the severity of all heartburns or acid 
regurgitations experienced during the previous daytime and nighttime periods 
(previous 24 hours), in the morning. The subject must also record the study medication 
taken on a daily basis in the diary during the Maintenance Phase. On study visit 
days, the administration of study medication for that day should be entered into 
the diary before the diary is returned.
The following sections also contain this change:

Appendix A1, Appendix A2, and Appendix A3, footnote F.
Rationale for Change:
To ensure compliance is accurately reported, investigators are requested to ensure the subject has 
completed the diary for the study visit day indicating that study medication has been taken before 
the diaries are collected.
Change 15: Updated compliance instructions to include treatment during the Healing Phase.
The primary change occurs in Section 9.2 Monitoring Subject Treatment Compliance:
Amended 
or new 
wording:
If a subject is persistently noncompliant with the study medication (Lansoprazole 
30 mg during the Healing Phase or TAK-438 10 mg, 20 mg or Lansoprazole 15 mg 
and their matching placebos during the Maintenance Phase) (eg, at more than 
2 consecutive compliance checks to have taken less than 75% or more than 133% of 
the study medication), it may be appropriate to withdraw the subject from the study. 
Rationale for Change:
To provide consistency with the revised text supporting the addition of a Healing Phase to the 
study design.
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Change 16: Clarified that 3 schedules of study-related procedures are included in Appendix A.
The primary change occurs in Section 9.3 Schedule of Observations and Procedures:
Amended 
or new 
wording:
The schedule for all study-related procedures for all evaluations is shown in 
Appendix A. Individual schedule of study-related procedures are presented 
separately for subjects entering the current study at the Healing Phase 
(Appendix A1), subjects entering the current study within 7 days of completing 
Study TAK-438_303 (Appendix A2), and subjects entering the current study 
more than 7 days after completing Study TAK-438_303 (Appendix A3). Ongoing 
de novo subjects (an eligible route of entry prior to protocol amendment 06), 
should follow the schedules outlined in Appendix A3.
All assessments should be completed at the designated visit/time point(s). 
Rationale for Change:
To provide consistency with the revised text supporting this change to the study design.
The following sections also contain this change:

Section 9.3.4 Visit 2: Randomization (Day 1).

Appendix A1, Appendix A2, and Appendix A3.
Change 17: Clarified the study-related procedures to be conducted during the Screening Phase 
(Visit 1)
The primary change occurs in Section 9.3.1 Visit 1: Screening Phase (Day -28 to Day -1):
Initial 
wording:
All subjects will be assessed for the following within 28 days before the start of the 
study medication for the Treatment Phase (Visit 2). Only those subjects that did not 
participate in TAK-438_303 or who had more than 7 days between finishing that study 
and starting this one will be examined for eligibility. See Section 9.1.12 for procedures 
for documenting screening or randomization failures.
For subjects who participated in TAK-438_303:
If the final study visit in the 303 study coincides with the first (randomization) visit in 
the 305 study, these 2 visits can be combined together. All of the overlapped 
examinations, i.e. laboratory procedures including hematology, urine analysis, serum 
chemistry, gastrin and pepsinogen I/II levels, urine hCG, FSH, and ECG, endoscopy 
in the 305 study will be exempted. It is also not required to repeat EQ-5D-5L, vital 
signs, the physical examination and subject diary completion. The data taken from the 
last visit in the 303 study can be used as the baseline data for the 305 study. Laboratory 
test results from the 303 study can be used for eligibility confirmation in the 305 study, 
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Study No. TAK-438_305
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as long as they are within 28 days prior to randomization in the 305 study. 
If the subjects are planned to be randomized in the 305 study within 7 days after 
completing the last visit in the 303 study, Visit 1 and Visit 2 of the 305 study can be 
combined together. The overlapped procedures, i.e. safety laboratory tests including 
hematology, urine analysis, serum chemistry, gastrin and pepsinogen I/II levels, urine 
hCG, FSH, endoscopy, ECG and diary completion in the 305 study will be exempted. 
However, EQ-5D-5L, vital signs, and the physical examination will have to be 
performed. The baseline clinical safety data of those subjects in this study will be the 
same data as obtained when subjects were confirmed healed either at Week 2, Week 4 
or Week 8 in the previous TAK-438_303 study.
For the above two cases, the data should be transcribed from the last visit in the 303 
study into the Visit 1 pages in the eCRF in the 305 study to comprise the baseline data 
in this study.
If the subjects are planned to be randomized in the 305 study after 7 days of 
completing the last visit in the 303 study, these subjects will follow the same 
procedures as the de novo subjects. 
A clear procedure instruction can be found in Appendix A. 
Procedures to be completed at Visit 1 include:

Informed consent (will be obtained from the subjects within 28 days before the 
start of the Treatment Phase (Visit 2).

Access IWRS to obtain subject number.

If fasting is not normal, routine clinical practice of the site, informed consent 
should be obtained prior to the request for fasting for the Screening Visit. The 
following procedures will be performed at a second (fasting) Screening date.

EQ-5D-5L questionnaire. It shall be completed as the first priority of all 
procedures except obtaining the ICF and access IWRS.

Eligibility assessment (review Inclusion/exclusion criteria).

Demographics, vital signs, medical and medication history.

Height and weight. BMI will be calculated during data analysis.

Physical examination including concurrent medical conditions and medications.

Concomitant medications assessment.

Hepatitis B and C analysis at the local laboratory*

ECG procedure*

Fasting clinical laboratory examination (urinalysis, hematology, serum chemistry 
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but excluding gastrin & pepsinogen I/II,)*

Urine pregnancy test (in females of childbearing potential only)*

FSH (when menopause is suspected)*

Guidance on the avoidance of pregnancy and ova donation.

Subject diary dispensed (to collect heartburn and acid reflux symptoms). 

Endoscopy *

Pretreatment events assessment.
*: Only for subjects that did not participate in TAK-438_303 or who had more than 7 days between 
finishing that study treatment and starting this one.
Amended 
or new 
wording:
Prior to any assessments being performed, all subjects will sign the ICF. The 
first procedure will be to access IWRS to obtain the subject number. 
Section 9.1.12 documents the procedures for screening, Healing Phase Failures, 
or randomization failures.
Subjects With Ongoing Erosive Esophagitis: All subjects with ongoing erosive 
esophagitis will undergo assessments for the Screening Phase within 28 days 
before the initiation of study medication as outlined in Appendix A1. 

Subjects will need to be in a fasted state for the Screening Visit. If fasting is 
not the routine clinical practice of the site, informed consent should be 
obtained prior to the request for fasting for the Screening visit. If the subject 
comes to the site in an unfasted state, the following procedures will be 
performed at a second (fasting) Screening Visit.
–
Eligibility assessment (review inclusion/exclusion criteria).
–
Demographics, vital signs, medical and medication history.
–
Height and weight. BMI will be calculated during data analysis.
–
Physical examination including concurrent medical conditions and 
medications.
–
Concomitant medications assessment.
–
Hepatitis B and C analysis at the local laboratory (reliable, documented 
Hepatitis B and C results performed in a routine clinical setting within 14 
days prior to signing the informed consent will be accepted).
–
ECG procedure (reliable, documented results available from an ECG 
performed in a routine clinical setting within 14 days prior to signing the 
informed consent will be accepted).
–
Fasting clinical laboratory tests: hematology, serum chemistry (excluding
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Study No. TAK-438_305
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serum gastrin and pepsinogen I/II), urinalysis.
–
Urine pregnancy test (in females of childbearing potential only).
–
FSH (when menopause is suspected).
–
Guidance on the avoidance of pregnancy and ova donation.
–
Endoscopy 
–
Pretreatment events assessment.
Subjects Entering the Current Study on the Same Day as Completing Study 
TAK-438_303 Treatment: Screening procedures for these are outlined in 
Appendix A2. If the final study visit in Study TAK-438_303 study coincides with 
the randomization visit (Visit 2) of the current study, these 2 visits can be 
combined such that all of the overlapped examinations will be exempt from the 
screening and Day 1 procedures for the TAK-438_305 study. The overlapping 
examinations are comprised of clinical laboratory tests (hematology, serum 
chemistry, and urinalysis), serum gastrin and pepsinogen I/II levels, urine hCG, 
FSH, endoscopy, ECG, the subject diary, EQ-5D-5L, vital signs, and the physical 
examination. 
Laboratory test results from the TAK-438_303 study can be used for eligibility 
confirmation in the TAK-438_305 study, as long as they are within 28 days prior 
to randomization in the TAK-438_305 study. For these subjects, data obtained in 
the week when subjects were confirmed as healed in the TAK-438_303 study will 
be used as the baseline data for the current study, and data should be 
transcribed from the last visit in the TAK-438_303 study into the Visit 1 pages in 
the eCRF for the current study.
Subjects Entering the Current Study Within 7 Days of Completing Study 
TAK-438_303 Treatment: Screening procedures for these subjects are outlined in 
Appendix A2. If the subjects are planned to be randomized into the current 
study within 7 days after completing the last visit in the TAK-438_303 study, 
Visit 1 and Visit 2 of the current study can be combined. Any overlapped 
procedures will be exempt from the screening procedures in the TAK-438_305 
study. The overlapping examinations are comprised of clinical laboratory tests 
(hematology, serum chemistry, and urinalysis), serum gastrin and pepsinogen 
I/II levels, urine hCG, FSH, endoscopy, ECG, and the subject diary. However, 
EQ-5D-5L, vital signs, and the physical examination will have to be performed. 
For these subjects, data obtained in the week when subjects were confirmed as 
healed in the TAK-438_303 study will be used as the baseline data in the current 
study, and data should be transcribed from the last visit in the TAK-438_303 
study into the Visit 1 pages in the eCRF for the current study.
Subjects Entering the Current Study More than7 Days After Completing Study 
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Protocol Incorporating Amendment No. 06
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TAK-438_303: Subjects planned to be randomized in to the current study more 
than 7 days after completing the last visit in the TAK-438_303 study, will follow 
screening period procedures outlined in Appendix A3.
Rationale for Change:
To provide consistency with the revised text supporting the addition of a Healing Phase to the 
study design.
The following sections also contain this change:
Appendix A
Schedule of Study Procedures.
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Change 18: Added a description of study procedures during Healing Phase visits.
The primary change occurs in Section 9.3.2 Visit 2HP: Healing Phase (Week -8) and Section 9.3.3
Visit 3HP: Healing Phase (Week -4):
Amended 
or new 
wording:
Section 9.3.2 Visit 2HP: Healing Phase (Week -8)
This visit is only applicable for subjects undergoing the Healing Phase. 
Procedures to be completed at this visit include:

Dispense Healing Phase study medication (Lansoprazole 30 mg QD) and 
record number of cartons/wallets of study medication in the IWRS.

Guidance on the avoidance of pregnancy and ova donation.

AE/ Pretreatment Event assessment.

Concomitant medications assessment. 
Section 9.3.3 Visit 3HP: Healing Phase (Week -4)
This visit is only applicable for subjects undergoing the Healing Phase. 
Procedures to be completed at this visit include:

Physical examination.

Vital signs.

Fasting clinical laboratory tests: hematology, serum chemistry (including 
serum gastrin and pepsinogen I/II), urinalysis.

Urine pregnancy test (in females of childbearing potential only).

ECG procedure.

Endoscopy. This is an optional procedure based on the investigator’s clinical 
judgment of a subject’s symptoms of healing. If the subject’s is 
endoscopically confirmed as healed, and the result of clinical laboratory tests 
at this visit from central laboratory re-confirms the subject’s eligibility, the 
subjects can be randomized within 14 days of this endoscopy date. During 
this period of waiting for randomization, subjects shall continue to take the 
newly dispensed Lansoprazole 30 mg QD. Subjects who do not show 
endoscopic healing at Visit 3HP may continue in the Healing Phase and 
undergo endoscopy at Day 1 (Visit 2).

Guidance on the avoidance of pregnancy and ova donation.

Study drug accountability and check treatment compliance, re-instruct the 
subject if necessary, dispense additional Healing Phase study medication 
(Lansoprazole 30 mg QD) and record the number of cartons/wallets of study 
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15 November 2016
medication in the IWRS.

AE assessment.

Concomitant medications assessment.
Rationale for Change:
To provide consistency with the revised text supporting this change to the study design.
Change 19: Repeated the discontinuation criteria for liver function abnormalities.
The primary change occurs in Section 10.2.3 Reporting of Abnormal Liver Function Tests:
Added text:If subject experience an increase in any one of ALT, AST or total bilirubin 
>2 ×ULN, the study medication shall be stopped according to the discontinuation 
criteria. Follow-up laboratory tests (at a minimum, serum alkaline phosphatase, 
ALT, AST, total bilirubin, GGT, and INR) to monitor recovery should be 
performed within a maximum of 7 days and preferably within 48-72 hours after 
the abnormality was found (see Section 9.1.8).
Rationale for Change:
To ensure all information pertaining to liver function abnormalities is consistent throughout the 
document.
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Change 20: Confirmed that the questionnaires used to rate a subject’s symptoms and severity of 
symptoms are the same as that used in the Japanese clinical development program.Repeated the 
discontinuation criteria for liver function abnormalities.Information from phase 3 clinical studies 
of TAK-438 has been added.
The primary change occurs in Section 6.2 Justification for Study Design, Dose, and 
EndpointsBackground:
Added text:3 Additional endpoints
Heartburn and gastric acid regurgitation are typical symptoms of erosive esophagitis 
which could impact the subject’s Health-Related Quality of Life. The severity and 
frequency of those symptoms are recorded via the daily diary by the subjects using the 
questionnaires outlined in Table 9.c and Table 9.d, which were also implemented 
in the Japanese clinical development program. while The HRQoL will be assessed 
by subjects completing validated questionnaires. The EQ-5D-5L index score has been 
previously used to demonstrate that moderate to severe symptoms of GERD are 
associated with a significant impairment in HRQoL[2, 3]. Consequently those 
subjective symptoms and health-related quality of life using EQ-5D-5L are considered 
as additional endpoints in this study.
Rationale for Change:
Clarification purposes.
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d6804e130f
Amendment 6 to A Randomized, Double-Blind, Double-Dummy, Parallel-group Phase 3 Study to Evaluate the
Efficacy and Safety of Oral Once-Daily Administration of TAK-438 10 or 20 mg Compared to Lansoprazole 15
mg in the Maintenance Treatment of Subjects With Endoscopic Healing of Erosive Esophagitis
Biostatistics Approval
24-Nov-2016 15:03 UTC
Clinical Approval
25-Nov-2016 01:22 UTC
Medical Monitor Approval
25-Nov-2016 03:38 UTC
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

SAP_000.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, Parallel-group Phase 3 Study to Evaluate 
the Efficacy and Safety of Oral Once-Daily Administration of TAK-438 10 or 20 mg Compared 
to Lansoprazole 15 mg in the Maintenance Treatment of Subjects With Endoscopic Healing of 
Erosive Esophagitis
NCT Number: NCT02388737
SAP Approve Date: 08 January 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.


TAK-438_305 Statistical Analysis Plan Version 2
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TAKEDA DEVELOPMENT CENTER
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-438_305
A Randomized, Double-Blind, Double-Dummy, Parallel-group Phase 3 Study to Evaluate
the Efficacy and Safety of Oral Once-Daily Administration of TAK-438 10 or 20 mg
Compared to Lansoprazole 15 mg in the Maintenance Treatment of Subjects With
Endoscopic Healing of Erosive Esophagitis
PHASE 3
Version: 2
Date: 08 January 2019
Prepared by:
PPD
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o
Date
ate: 08
0
n-commercial use only and subject to the applicable Terms of Use
Phase 3 
Phase 3
on of
n of TA
T
f
ce Treat
e Trea
ive Esop
ve Eso
E 3
Versi
Ver
For non
erty o


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1.0
APPROVAL SIGNATURES
Electronic signatures can be found on the last page of this document.
Study Title:
A Randomized, Double-Blind, Double-Dummy, Parallel-group Phase 3 
Study to Evaluate the Efficacy and Safety of Oral Once-Daily
Administration of TAK-438 10 or 20 mg Compared to Lansoprazole 15 mg 
in the Maintenance Treatment of Subjects With Endoscopic Healing of 
Erosive Esophagitis
TDC Approvals:
PPD
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up Phase
Phas
aily
ily
Lansopra
ansop
oscopi
opic H
c
non-commercial use only and subjec


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2.0
TABLE OF CONTENTS
1.0
APPROVAL SIGNATURES ..................................................................................................................2
2.0
TABLE OF CONTENTS........................................................................................................................3
3.0
LIST OF ABBREVIATIONS .................................................................................................................6
4.0
OBJECTIVES.........................................................................................................................................7
4.1
PRIMARY OBJECTIVES....................................................................................................................... 7
4.2
SECONDARY OBJECTIVES................................................................................................................. 7
4.3
ADDITIONAL OBJECTIVES ................................................................................................................ 7
4.4
STUDY DESIGN.................................................................................................................................... 7
5.0
ANALYSIS ENDPOINTS.......................................................................................................................9
Primary Endpoint....................................................................................................................................9
Secondary Endpoint ................................................................................................................................9
Additional Endpoints...............................................................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE............................................................................................. 10
7.0
METHODS OF ANALYSIS AND PRESENTATION ......................................................................... 11
7.1
GENERAL CONSIDERATIONS.......................................................................................................... 11
7.1.1
DEFINITIONS...................................................................................................................................... 11
7.1.2
ANALYSIS SETS................................................................................................................................. 11
7.1.3
HANDLING OF RATE OF ENDOSCOPIC RECURRENCE OF EROSIVE ESOPHAGITIS................ 12
7.1.3.1
Rate of Endoscopic Recurrence of Erosive Esophagitis During the first 12 Weeks of Treatment in the 
Maintenance Phase............................................................................................................................ 12
7.1.3.2
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-Week Maintenance Phase ............ 12
7.1.4
HANDLING OF DATA WHEN CALCULATING MEAN SEVERITY ACCORDING TO SUBJECT 
DIARY ................................................................................................................................................. 12
7.1.5
HRQOL (EQ-5D-5L) ............................................................................................................................ 13
7.1.6
HANDLING OF OTHER ENDPOINTS................................................................................................ 14
7.2
STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS ............... 16
7.2.1
DISPOSITION OF SUBJECTS............................................................................................................. 16
7.2.1.1
Study Information.................................................................................................................................. 16
7.2.1.2
Screen Failures ...................................................................................................................................... 16
7.2.1.3
Subject Eligibility.................................................................................................................................. 16
7.2.1.4
Number of Subjects Randomized by Country, Site, and Treatment Group............................................... 17
7.2.1.5
Disposition of Subjects........................................................................................................................... 17
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7.2.1.6
Protocol Deviations and Analysis Sets.................................................................................................... 18
Protocol Deviations............................................................................................................................... 18
Analysis Sets......................................................................................................................................... 18
7.2.2
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS.................................................. 18
7.2.2.1
Summary of Demographics and Other Baseline Characteristics............................................................... 18
7.2.2.2
Medical History and Concurrent Medical Conditions.............................................................................. 19
7.2.2.3
Medication History and Concomitant Medications.................................................................................. 20
7.2.3
TREATMENT COMPLIANCE............................................................................................................. 20
7.2.3.1
Study Drug Exposure and Compliance ................................................................................................... 20
7.3
EFFICACY ANALYSIS....................................................................................................................... 21
7.3.1
PRIMARY EFFICACY ENDPOINT..................................................................................................... 21
7.3.1.1
Primary Analysis.................................................................................................................................... 21
7.3.1.2
Secondary Analysis................................................................................................................................ 21
7.3.2
SECONDARY EFFICACY ENDPOINT............................................................................................... 21
7.3.2.1
Rate of Endoscopic Recurrence of Erosive Esophagitis During the First 12 Weeks of Treatment in the 
Maintenance Phase............................................................................................................................ 21
7.3.2.2
Sensitivity Analysis................................................................................................................................ 22
7.3.3
ADDITIONAL EFFICACY ENDPOINTS ............................................................................................ 22
7.3.3.1
Gastrointestinal Symptoms Based on Subject Diary................................................................................ 22
Heartburn Symptoms............................................................................................................................. 22
Gastric Acid Regurgitation.................................................................................................................... 22
7.3.3.2
HRQoL (EQ-5D-5L).............................................................................................................................. 23
EQ-5D-5L Index Value......................................................................................................................... 23
EQ VAS Score...................................................................................................................................... 24
7.3.3.3
Barrett's Mucosa .................................................................................................................................... 24
7.3.4
STATISTICAL/ANALYTICAL ISSUES.............................................................................................. 24
7.3.4.1
Adjustments for Covariates .................................................................................................................... 24
7.3.4.2
Handling of Dropouts or Missing Data ................................................................................................... 24
7.3.4.3
Interim Analyses and Data Monitoring................................................................................................... 25
7.3.4.4
Multicenter Studies................................................................................................................................ 25
7.3.4.5
Multiple Comparison/Multiplicity .......................................................................................................... 25
7.3.4.6
Use of an "Efficacy Subset" of Subjects.................................................................................................. 26
7.3.4.7
Active-Control Studies Intended to Show Equivalence or Non-Inferiority............................................... 26
7.3.4.8
Subgroup Analysis................................................................................................................................. 26
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7.4
SAFETY ANALYSIS........................................................................................................................... 27
7.4.1
TREATMENT-EMERGENT ADVERSE EVENTS .............................................................................. 27
7.4.1.1
Overview of Treatment-Emergent Adverse Events.................................................................................. 27
7.4.1.2
Displays of Treatment-Emergent Adverse Events ................................................................................... 28
7.4.2
PRETREATMENT EVENTS AND ADVERSE EVENTS IN THE HEALING PHASE......................... 30
7.4.2.1
Displays of Pretreatment Events............................................................................................................. 30
7.4.2.2
Displays of Adverse Events in the Healing Phase.................................................................................... 30
7.4.3
LABORATORY AND OTHER SAFETY DATA.................................................................................. 31
7.4.3.1
Laboratory Test Results.......................................................................................................................... 31
Hematology and Serum Chemistry ........................................................................................................ 31
Urinalysis.............................................................................................................................................. 32
Serum Gastrin, Pepsinogen I/II.............................................................................................................. 32
7.4.4
VITAL SIGNS, PHYSICAL FINDINGS, AND OTHER OBSERVATIONS RELATED TO SAFETY.. 33
Vital Signs............................................................................................................................................ 33
12-lead ECG......................................................................................................................................... 33
7.4.5
SUBGROUP ANALYSIS FOR CHINA................................................................................................ 34
7.4.6
SUBGROUP ANALYSIS FOR TAIWAN............................................................................................. 34
7.4.7
SUBGROUP ANALYSIS FOR SAFETY ANALYSIS SET EXCLUDING ACCIDENTALLY 
UNBLINDED SUBJECTS.................................................................................................................... 34
7.4.8
SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT........................................................... 34
7.4.9
CHANGES IN THE STATISTICAL ANALYSIS PLAN....................................................................... 35
8.0
REFERENCES ..................................................................................................................................... 54
9.0
APPENDIX ........................................................................................................................................... 55
9.1
CRITERIA FOR MARKEDLY ABNORMAL VALUES ...................................................................... 55
9.1.1
HEMATOLOGY, SERUM CHEMISTRY, URINALYSIS, VITAL SIGNS, AND 12-LEAD ECG 
(EXCEPT UPPER MAV CRITERIA OF QTCF INTERVAL)............................................................... 55
9.1.2
12-LEAD ECG (UPPER MAV CRITERIA OF QTCF INTERVAL)...................................................... 56
9.2
CRITERIA FOR ELEVATED LIVER ENZYME.................................................................................. 57
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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BMI
body mass index
BUN
blood urea nitrogen
CMH
Cochran-Mantel-Haenszel
CPK
creatine phosphokinase
ECG
electrocardiogram
EQ-5D-5L
the 5-level version of the EuroQOL five dimensions questionnaire
FAS
full analysis set
GGT
-glutamyl transferase
H. pylori
Helicobacter pylori
HRQoL
Health-Related Quality of Life
LA classification
Los Angeles classification
LDH
lactate dehydrogenase
LLN
lower limit of normal
LS means
least square means
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model repeated measures analysis
PPI
proton pump inhibitor
PPS
per protocol set
QOL
quality-of-life
QTcF
Fridericia's corrected QT
SAP
statistical analysis plan
Tbili
total bilirubin
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WHO Drug
World Health Organization Drug Dictionary
WMWodds
Wilcoxon-Mann-Whitney odds
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OBJECTIVES
4.1
PRIMARY OBJECTIVES
・
To demonstrate the non-inferiority of TAK-438 to Lansoprazole in the reduction of relapse of erosive 
esophagitis in subjects in the Maintenance Phase (24 weeks) in whom endoscopic healing of erosive 
esophagitis has been confirmed after treatment with TAK-438 or a PPI. 
・
To determine the clinically recommended dose of TAK-438 for maintenance therapy in erosive esophagitis in 
whom endoscopic healing of erosive esophagitis has been confirmed after treatment with TAK-438 or a PPI.
4.2
SECONDARY OBJECTIVES
・
To evaluate the efficacy of TAK-438 during the first 12-weeks of treatment in the Maintenance Phase in 
subjects with endoscopically confirmed healed erosive esophagitis receiving TAK-438 or a PPI.
・
To evaluate the safety of TAK-438 versus Lansoprazole in subjects in the Maintenance Phase (24 weeks) in 
whom endoscopic healing of erosive esophagitis has been confirmed after treatment with TAK-438 or a PPI.
4.3
ADDITIONAL OBJECTIVES
・
To evaluate the effect of TAK-438 on subjective symptoms of erosive esophagitis (heartburn and regurgitation) 
and improvement in Health Related Quality of Life using the EuroQol (EQ-5D-5L).
4.4
STUDY DESIGN
This is a phase 3, multicenter, randomized double-blind, parallel-group study to demonstrate the non-inferiority of 
TAK-438 (10 mg or 20 mg) to Lansoprazole 15 mg in preventing the recurrence of erosive esophagitis in subjects 
with endoscopically confirmed healing of erosive esophagitis. This study also aims to determine the clinically 
recommended dose of TAK-438 for maintenance therapy of erosive esophagitis.
This study is comprised of 2 treatment periods: An open-label, single-arm period in which subjects receive 
Lansoprazole 30 mg for up to 8 weeks (Healing Phase), and a double-blind, parallel-group period in which subjects 
are randomized at a 1:1:1 ratio to TAK-438 10 mg, 20 mg or Lansoprazole 15 mg once daily for up to 24 weeks 
(Maintenance Phase). To enroll in the study subjects must have ongoing erosive esophagitis or have completed 
Study TAK-438_303. Subjects with ongoing erosive esophagitis are required to undergo the Healing Phase. Once 
erosive esophagitis healing is confirmed by endoscopy, these subjects may be randomized to 1 of 3 treatments in the 
Maintenance Phase. Subjects with endoscopic-confirmed healing of erosive esophagitis following the completion of 
Study TAK-438_303 will be randomized into the Maintenance Phase without carrying out the open-label Healing 
Phase. Subjects who previously entered the study (prior to Protocol Amendment 06) after confirmation of healed 
erosive esophagitis following treatment with a proton pump inhibitor (termed “de novo” subjects) are no longer 
eligible to enter the study; any ongoing subjects may continue being treated in the Maintenance Phase. A schematic 
of the study design is included in Figure 4.a.
If relapse of erosive esophagitis has been endoscopically confirmed in any subject, the subject will complete the 
study at that time point (to be construed as “complete cases in the Maintenance Phase”), regardless of the time point 
where relapse of disease is confirmed.
This study will be conducted at a total of around 70 sites across Asia with an estimated total of 231 subjects 
randomized to each treatment group during the Maintenance Phase (totaling 693 subjects entering the Maintenance 
Phase for the study).
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The study will consist of a Screening Phase of up to 28 days duration (Visit 1), a Healing Phase (for those subjects 
with ongoing erosive esophagitis only) of 4 or 8 weeks duration (Visits 2HP and 3HP), followed by a Maintenance 
Phase of up to 24 weeks (Visits 2-8), and a Follow-up Period of up to 14 days duration. With the exception of the 
Follow-up (which will be carried out by phone), all visits will occur at the clinic. The total duration of treatment is 
up to 6 months (24 weeks) in subjects entering from Study TAK-438_303, and up to 8 months (32 weeks) in 
subjects entering the study with ongoing erosive esophagitis.
Subjects with ongoing erosive esophagitis: Subjects who have ongoing erosive esophagitis will enter the Healing 
Phase and administration of Lansoprazole 30 mg once daily will commence following the completion of all required 
assessments at Visit 2HP. Subjects will then undergo a visit at Week -4 (Visit 3HP), where the subject may undergo 
endoscopy to confirm healing of erosive esophagitis. This is an optional procedure where the decision to perform 
endoscopy is based on the investigator’s clinical judgment of a subject’s symptoms of healing. Subjects who do not 
show endoscopic healing at Visit 3HP may continue in the Healing Phase and undergo endoscopy at Day 1 (Visit 2). 
Subjects with endoscopically confirmed healing of erosive esophagitis at Week -4 or at Day 1 will be eligible to 
enter the Maintenance Phase. Where the results from clinical laboratory tests confirming eligibility for the 
Maintenance Phase at Week -4 are not immediately available, subjects should continue to receive Lansoprazole 30 
mg for up to 14 days. Subjects healed at Day 1 should be immediately randomized. Subjects who do not have 
endoscopic-confirmed healed erosive esophagitis after 8 weeks treatment (Healing Phase Failures) will not be 
randomized into the Maintenance Phase and should be treated using routine clinical care.
Subjects with healed erosive esophagitis: Subjects with healed erosive esophagitis will undergo a randomization 
visit (Visit 2), and dosing for the Maintenance Phase will commence following the completion of all required 
assessments on Day 1. Visits will then occur at 2 week intervals after the initiation of treatment in the Maintenance 
Phase. As a result of Protocol Amendment 06, subjects with healed erosive esophagitis following treatment with a 
proton pump inhibitor outside Study TAK-438_303 or the Healing Phase of the current study (de novo subjects) are 
no longer eligible to enter the study; any ongoing subjects may continue to be treated in the Maintenance Phase.
All subjects receiving TAK-438 must undergo a total of 8 weeks of LFT monitoring visits with visits occurring 
every 2 weeks. For subjects entering the Maintenance Phase of the current study within 7 days of completing Study 
TAK-438_303, the requirement for 8 weeks of monitoring can be totalled across the 2 studies. 
Figure 4.a Schematic of Study Design
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5.0
ANALYSIS ENDPOINTS
Primary Endpoint
The primary efficacy endpoint for this study is the rate of recurrence* of erosive esophagitis as confirmed on 
endoscopy during the 24-week Maintenance Phase.
*Recurrence: defined as subjects endoscopically confirmed to have erosive esophagitis (LA classification grades A 
to D) during the Maintenance Phase (24 weeks).
Secondary Endpoint
The secondary efficacy endpoint for this study is the rate of recurrence* of erosive esophagitis during the first 12 
weeks of treatment in the Maintenance Phase. Safety endpoints for this study include adverse events (AEs), clinical 
laboratory test results, ECG, vital signs, serum gastrin and pepsinogen I/II levels.
*Recurrence: defined as subjects endoscopically confirmed to have erosive esophagitis (LA classification grades A 
to D) during the Maintenance Phase (12 weeks).
Additional Endpoints
Other efficacy endpoints include subjective symptoms of erosive esophagitis (heartburn and regurgitation) as 
recorded in subject diaries and Health-Related Quality of Life measures.
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6.0
DETERMINATION OF SAMPLE SIZE
Assuming that the true Week 24 recurrence rate is 30.4% for Lansoprazole, 22.0% for TAK-438 10 mg, and 13.6% 
for TAK-438 20 mg, and assuming that the dropout rate is approximately 30%, a sample size of 208 subjects per 
group will provide an overall power of 90% to establish non-inferiority using a 2-sided 95% CI with a 10% 
non-inferiority margin. 231 subjects per group will be included to allow adequate numbers for the regulatory 
requirements of various countries.
The assumption of the true recurrence rate is based on a phase 3 study that showed a Week 24 recurrence rate of 
30.4% for Lansoprazole 15 mg and 13.6% for Lansoprazole 30 mg.
Based on results from an earlier study of Lansoprazole as maintenance therapy for erosive esophagitis 
(AG-1749/CCT-202), the point estimate for the difference (Lansoprazole 15 mg group – famotidine group) was 
calculated as -57.6% with the upper limit of the confidence interval being -30.7%. Therefore, the non-inferiority
margin is specified as 10%.
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
GENERAL CONSIDERATIONS
7.1.1
Definitions
The following definitions and calculation formulas will be used.
- TEAE: An adverse event whose date of onset occurs on or after the start of the Maintenance Phase drug. A 
TEAE whose relationship to the Maintenance Phase drug is missing will be considered drug-related. A TEAE 
whose intensity is missing will be considered severe.
- Descriptive statistics: number of subjects, mean, standard deviation, maximum, minimum, and quartiles
- Study Day: The day before the first dose of the Maintenance Phase drug will be defined as Study Day -1 and 
the day of the first dose will be defined as Study Day 1. Other study days are defined relative to Study Day 1, 
eg, the day prior to Study Day 1 is Day -1 and the day after Study Day 1 is Day 2.
- Follow-up Day: The day after the last dose of the Maintenance Phase drug will be defined as Follow-up Day 1. 
Other follow-up days are defined relative to Follow-up Day 1.
- Duration of exposure to study drug (days): date of last dose of Maintenance Phase drug - date of first dose of
Maintenance Phase drug + 1.
- Study drug compliance (%): (number of days the subject answered "Yes" in the subject diary to the question 
"Study medication taken?") / duration of exposure to study drug * 100 (rounded to 1 decimal place).
- Age (years): The following only applies to subjects from countries other than Korea. If the date informed 
consent obtained or the date of birth is missing, then age will be missing. If the month and the day of the date 
informed consent obtained is before the month and the day of the date of birth, then age will be calculated as 
follows: the year of the date informed consent obtained - the year of the date of birth - 1. For all others, age will 
be calculated as follows: the year of the date informed consent obtained - the year of the date of birth.
- BMI (kg/m2): weight (kg) / (height (m))2 (rounded to 1 decimal place).
-
Pepsinogen I/II Ratio: Pepsinogen I (μg/L) / Pepsinogen II (μg/L) (rounded to 1 decimal place).
- QTcF interval (msec): QT interval (msec) / (RR interval (sec))0.33 (rounded to the nearest whole number).
- Confidence interval for one sample proportion: Exact (Clopper-Pearson) confidence interval will be used.
- Confidence interval for two sample proportion difference: Wald confidence interval will be used.
-
Significant TEAE: Any TEAE (not including serious TEAEs) that led to an intervention, including withdrawal 
of drug treatment, dose increase, dose reduction, or significant additional concomitant therapy.
7.1.2
Analysis Sets
Analysis of efficacy variables will be conducted in the full analysis set (FAS) defined as all randomized subjects 
who receive at least 1 dose of the Maintenance Phase drug and have at least 1 post-baseline endoscopy, and will be 
based on the randomized treatment. Randomized subjects who were accidentally unblinded due to IWRS system 
error will be excluded.
The primary efficacy endpoint and the secondary efficacy endpoint will also be analyzed in the per protocol set
defined as all FAS subjects who did not have any of the major protocol deviations listed below. Analyses will be 
based on the randomized treatment.
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- Subjects who did not meet inclusion criteria #3 or #4
- Subjects who met exclusion criteria #8, #11, #12, #13, or #14
- Subjects with study drug 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 the Maintenance Phase drug and will be based on the treatment received in the Maintenance Phase.
7.1.3
Handling of Rate of Endoscopic Recurrence of Erosive Esophagitis
7.1.3.1 Rate of Endoscopic Recurrence of Erosive Esophagitis During the first 
12 Weeks of Treatment in the Maintenance Phase
A subject who is diagnosed as LA classification grade A, B, C, or D from endoscopy tests performed between Study 
Day 2 and Study Day 127 (up to and including Follow-up Day 14) will be considered as a relapsed subject. Subjects 
who do not have any endoscopy data during this period will be treated as missing. Subjects who do not meet this 
requirement will be considered as 'not relapsed'. Recurrence rate will be calculated from the relapsed and not 
relapsed subjects, however, any subjects diagnosed as LA classification grade A, B, C, or D from endoscopy tests 
performed before the Maintenance Phase drug administration will be excluded from the analysis.
7.1.3.2 Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-Week 
Maintenance Phase
A subject who is diagnosed as LA classification grade A, B, C, or D from endoscopy tests performed after Study 
Day 2 (up to and including Follow-up Day 14) will be considered as a relapsed subject. Subjects who do not have 
any endoscopy data during this period will be treated as missing. Subjects who do not meet this requirement will be 
considered as 'not relapsed'. Recurrence rate will be calculated from the relapsed and not relapsed subjects, however, 
any subjects diagnosed as LA classification grade A, B, C, or D from endoscopy tests performed before the 
Maintenance Phase drug administration will be excluded from the analysis.
7.1.4
Handling of Data When Calculating Mean Severity According to Subject 
Diary
Each subjective symptom of erosive esophagitis as recorded in subject diaries (ie, heartburn, gastric acid 
regurgitation) will be handled as below.
Severity will be scored as follows. None: 0, Mild: 1, Moderate: 2, Severe: 3.
For each subject, the mean severity will be calculated as follows at each visit. If the denominator is missing, then the 
calculated result should also be missing.
Mean severity = (total score of the severity recorded for the visit) / (number of days the severity of symptom is 
recorded) (rounded to 2 decimal places)
(Note: Severity recorded as "Not Completed" will be treated as missing.)
The following visits will be used.
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Visit
Time Interval (days)
Study Day
Follow-up Day
Baseline*
Day -6 – Day 1
Week 4
Day 2 – Day 29
up to and including Follow-up Day 1
Week 8
Day 30 – Day 57
up to and including Follow-up Day 1
Week 12
Day 58 – Day 85
up to and including Follow-up Day 1
Week 16
Day 86 – Day 113
up to and including Follow-up Day 1
Week 20
Day 114 – Day 141
up to and including Follow-up Day 1
Week 24
Day 142 – Day 169
up to and including Follow-up Day 1
*: Will not be included in the analysis, however, data will be created.
7.1.5
HRQoL (EQ-5D-5L)
All evaluable data (ie, non-missing) obtained in the corresponding time interval will be used in evaluating the 
EQ-5D-5L index value and EQ VAS score. If more than one observation lies within the same visit window, the 
observation with the closest Study Day to the scheduled Study Day will be used. If there are two observations 
equidistant to the scheduled Study Day, the later observation will be used.
The EQ-5D-5L index values will be calculated from the EQ-5D-5L descriptive system scores based on the 
EQ-5D-5L Crosswalk value sets. If any of the questions are not answered, the EQ-5D-5L index value of the day will 
be treated as missing.
The following visits will be used.
Visit
Scheduled Study Day
(days) 
Time Interval (days) 
Study Day
Follow-up Day
Baseline
Study Day:
1
-28 – 1
Week 4
Study Day:
29
2 – 57
up to and including Follow-up Day 14
Week 12
Study Day:
85
58 – 127
up to and including Follow-up Day 14
Week 24
Study Day:
169
128 – 211
up to and including Follow-up Day 14
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7.1.6
Handling of Other Endpoints
For each visit, all evaluable observation (ie, non-missing) obtained in the corresponding time interval will be used. If 
more than one observation lies within the same visit window, the observation with the closest Study Day to the 
scheduled Study Day will be used. If there are two observations equidistant to the scheduled Study Day, the later 
observation will be used.
The following visits will be used.
Weight, BMI, Endoscopy (esophageal hiatal hernia)
Visit
Scheduled Study Day
(days) 
Time Interval (days) 
Study Day
Follow-up Day
Baseline 
Study Day:
1
up to and 
including Study 
Day 1
Endoscopy (Barrett's mucosa), 12-lead ECG
Visit
Scheduled Study Day
(days) 
Time Interval (days) 
Study Day
Follow-up Day
Baseline
Study Day:
1
up to and 
including Study 
Day 1
Week 12
Study Day:
85
2 – 127
up to and including 
Follow-up Day 14
Week 24
Study Day:
169
128 – 211
up to and including 
Follow-up Day 14
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Clinical laboratory tests (ALT, AST, total bilirubin, and direct bilirubin)
Visit
Scheduled Study Day
(days) 
Time Interval (days) 
Study Day
Follow-up Day
Baseline*
Study Day:
1
-28 – 1
Week 2
Study Day:
15
2 – 22
up to and including 
Follow-up Day 14
Week 4
Study Day
29
23 – 36
up to and including 
Follow-up Day 14
Week 6
Study Day:
43
37 – 50
up to and including 
Follow-up Day 14
Week 8
Study Day:
57
51 - 71
up to and including 
Follow-up Day 14
Week 12
Study Day:
85
72 – 127
up to and including 
Follow-up Day 14
Week 24
Study Day:
169
128 – 211
up to and including 
Follow-up Day 14
*: For the clinical laboratory tests of the subjects who participated in the TAK-438_303 study, if the last 
study visit coincides with the first visit in the 305 study or if the subject was randomized in the 305 study 
within 7 days after completing the last visit in the 303 study, then the data obtained at the last visit can be 
used as the baseline data for the 305 study.
Clinical laboratory tests (other than ALT, AST, total bilirubin, and direct bilirubin), Gastrin, Pepsinogen I/II, 
Vital signs
Visit
Scheduled Study Day
(days) 
Time Interval (days) 
Study Day
Follow-up Day
Baseline*
Study Day:
1
-28 – 1 
Week 4
Study Day
29
2 – 57
up to and including 
Follow-up Day 14
Week 12
Study Day:
85
58 – 127
up to and including 
Follow-up Day 14
Week 24
Study Day:
169
128 – 211
up to and including 
Follow-up Day 14
*: For the clinical laboratory tests, gastrin, and pepsinogen I/II of the subjects who participated in the 
TAK-438_303 study, if the last study visit coincides with the first visit in the 305 study or if the subject was 
randomized in the 305 study within 7 days after completing the last visit in the 303 study, then the data 
obtained at the last visit can be used as the baseline data for the 305 study.
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7.2
STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS
7.2.1
Disposition of Subjects
7.2.1.1 Study Information
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables:
Date First Subject Signed Informed Consent Form
Date of Last Subject’s Last Visit/Contact
MedDRA Version
WHO Drug Version
SAS Version Used for Creating the Datasets
Analytical Methods:
(1) Study Information
Study information shown in the analysis variables section will be provided.
7.2.1.2 Screen Failures
Analysis Set:
All Subjects Who Were Not Randomized
Analysis Variables:
Age (years) 
[Min<= - <65, 65<= - <75, 75<= - <=Max]
Gender
[Male, Female]
Race
[American Indian or Alaska Native, Asian, Black or African American,
Native Hawaiian or Other Pacific Islander, White, Multiple]
Analytical Methods:
(1) Screen Failures
Frequency distributions for categorical variables and descriptive statistics for continuous 
variables will be provided.
7.2.1.3 Subject Eligibility
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables:
Eligibility Status
[Yes, No]
Primary Reason for Subject Not Being Eligible
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, 
Lost to Follow-Up, 
Voluntary Withdrawal, 
Study Termination, 
Did Not Meet Entrance Criteria, 
Healing Phase Failure,
Other]
Analytical Methods:
(1) Eligibility for Randomization
Frequency distributions will be provided. When calculating the percentages for the 
primary reasons for subject not being eligible, the total number of ineligible subjects will 
be used as the denominator.
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7.2.1.4 Number of Subjects Randomized by Country, Site, and Treatment Group
Analysis Set:
Randomized Set
Analysis Variables:
Randomization Status
[Yes]
Stratum:
Country
[China, Malaysia, South Korea, Taiwan]
Site
[Site numbers will be used as categories]
Analytical Methods:
(1) Number of Subjects Randomized by Country, Site, and Treatment Group
Frequency distribution will be provided for each stratum by treatment group and overall.
7.2.1.5 Disposition of Subjects
Analysis Set:
Randomized Set
Analysis Variables:
Maintenance Phase Drug Administration 
Status
[No]
Reason for Not Being Treated
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to Follow-Up,
Voluntary Withdrawal, Study Termination,
Pregnancy, Lack of Efficacy, Other]
Maintenance Phase Drug Completion Status [Completed Maintenance Phase Drug, 
Prematurely Discontinued Maintenance Phase
Drug]
Reason for Discontinuation of Maintenance 
Phase Drug
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to Follow-Up, 
Voluntary Withdrawal, Study Termination, 
Pregnancy, Lack of Efficacy, Other]
Analytical Methods:
(1) Disposition of Subjects
Frequency distributions will be provided for each treatment group and overall. When 
calculating percentages for the reasons for not being treated, the total number of subjects 
not treated by the maintenance phase drug will be used as the denominator. When 
calculating percentages for the reasons for discontinuation of maintenance phase drug, 
the total number of subjects who prematurely discontinued the maintenance phase drug
will be used as the denominator.
(2) Flow Chart of Subject Distribution
Flow chart will be provided.
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7.2.1.6 Protocol Deviations and Analysis Sets
Protocol Deviations
Analysis Set:
Randomized Set
Analysis Variables:
Protocol Deviation
[Entry Criteria, Concomitant Medication, 
Procedure Not Performed Per Protocol,
Study Medication, Withdrawal Criteria]
Analytical Methods:
(1) Protocol Deviations
Frequency distribution will be provided by treatment group and overall for each deviation 
category. A subject who has several deviations will be counted once in each appropriate 
category. A subject who has several deviations that can be classified into the same 
category will be counted only once.
Analysis Sets
Analysis Set:
Randomized Set
Analysis Variables:
Analysis Sets
Full Analysis Set
Per Protocol Set
Safety Analysis Set
[Included]
[Included]
[Included]
Analytical Methods:
(1) Analysis Sets
Frequency distributions will be provided by treatment group and overall.
7.2.2
Demographics and Other Baseline Characteristics
7.2.2.1 Summary of Demographics and Other Baseline Characteristics
Analysis Set:
Randomized Set
Full Analysis Set
Analysis Variables:
Country
[China, Malaysia, South Korea, Taiwan]
Participation in TAK-438_303 Study
[Yes, No]
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, Multiple]
Height (cm)
[Min<= - <150, 150<= - <160, 
160<= - <170, 170<= - <=Max]
Weight (kg) (Baseline)
[Min<= - <50.0, 50.0<= - <60.0, 
60.0<= - <70.0, 70.0<= - <80.0, 
80.0<= - <=Max]
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BMI (kg/m2) (Baseline)
[Min<= - <18.5, 18.5<= - <25.0, 
25.0<= - <=Max]
Smoking Classification
[The Subject Has Never Smoked, 
The Subject Is a Current Smoker, 
The Subject Is an Ex-smoker]
Consumption of Alcohol
[Drink Everyday, 
Drink a Couple of Days Per Week,
Drink a Couple of Days Per Month, 
Never Drink]
Consumption of Caffeine
[Yes, No]
History of H. pylori Eradication
Therapy
[Yes (End of Treatment: Within the Past 1 Year), 
Yes (End of Treatment: More than 1 Year), No]
LA Classification (Time of Diagnosis)
[Grade A, Grade B, Grade C, Grade D]
[Grade A/B, Grade C/D]
Barrett's Mucosa (Baseline)
[Present (3 cm or Greater), 
Present (Less than 3 cm), Absent, Unknown]
Esophageal Hiatal Hernia (Baseline)
[Present (2 cm or Greater), 
Present (Less than 2 cm), Absent, Unknown]
HRQoL (EQ-5D-5L)
EQ-5D-5L Index Value (Baseline)
EQ VAS Score (Baseline)
Analytical Methods:
(1) Summary of Demographics and Other Baseline Characteristics
Frequency distributions for categorical variables and descriptive statistics for continuous 
variables will be provided by treatment group and overall.
7.2.2.2 Medical History and Concurrent Medical Conditions
Analysis Set:
Safety Analysis Set
Analysis Variables:
Medical History
Concurrent Medical Conditions
Analytical Methods:
(1) Medical History by System Organ Class and Preferred Term
(2) Concurrent Medical Conditions by System Organ Class and Preferred Term
Frequency distributions will be provided for each treatment group. MedDRA dictionary 
will be used for coding. Summaries will be provided using SOC and PT, where SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency. 
A subject with multiple occurrences of medical history or concurrent medical condition 
within a SOC will be counted only once in that SOC. A subject with multiple 
occurrences of medical history or concurrent medical condition within a PT will be 
counted only once in that PT.
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7.2.2.3 Medication History and Concomitant Medications
Analysis Set:
Safety Analysis Set
Analysis Variables:
Medication History
Concomitant Medications
Analytical Methods:
(1) Medication History by Preferred Medication Name
(2) Concomitant Medications That Started Prior to and Were Ongoing at Baseline as 
well as Those That Started After Baseline by Preferred Medication Name
Frequency distributions will be provided for each treatment group. WHO Drug 
dictionary will be used for coding. Summaries will be provided using preferred 
medication names and sorted in decreasing frequency based on the number of reports. 
A subject who has been administered several medications with the same preferred 
medication name will be counted only once for that preferred medication name.
7.2.3
Treatment Compliance
7.2.3.1 Study Drug Exposure and Compliance
Analysis Set:
Safety Analysis Set
Full Analysis Set
Analysis Variables:
Duration of Exposure to Study Drug (days) [1<= - <=84, 85<= - <=168,
169<= - <=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 in Maintenance Phase
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided by treatment group and overall.
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7.3
EFFICACY ANALYSIS
The full analysis set will be the main analysis set used. The per protocol set will be used for analyses performed 
secondarily on the primary efficacy endpoint and secondary efficacy endpoints in order to examine the robustness of 
the results.
7.3.1
Primary Efficacy Endpoint
7.3.1.1 Primary Analysis
Analysis Set:
Full Analysis Set
Analysis Variable:
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-week Maintenance 
Phase (%)
Analytical Methods:
(1) Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-week
Maintenance Phase
Frequency distributions will be provided by treatment group along with rates and the 
two-sided 95% confidence intervals. The differences in the rates between each TAK-438
group and the Lansoprazole group (each TAK-438 group – the Lansoprazole group) and 
the two-sided 95% confidence intervals using the Wald method will be provided. The 
non-inferiority margin will be set to 10%. Details concerning interpretation are described 
in section 7.3.4.5.
7.3.1.2 Secondary Analysis
Analysis Set:
Per Protocol Set
Analysis Variable:
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-week Maintenance 
Phase (%)
Analytical Methods:
(1) Sensitivity Analysis
To check the robustness of the results, the same analyses as those in section 7.3.1.1 will 
be performed using the per protocol set.
7.3.2
Secondary Efficacy Endpoint
7.3.2.1 Rate of Endoscopic Recurrence of Erosive Esophagitis During the First 12
Weeks of Treatment in the Maintenance Phase
Analysis Set:
Full Analysis Set
Analysis Variable:
Rate of Endoscopic Recurrence of Erosive Esophagitis During the First 12 Weeks of 
Treatment in the Maintenance Phase (%)
Analytical Methods:
(1) Rate of Endoscopic Recurrence of Erosive Esophagitis During the First 12 Weeks of 
Treatment in the Maintenance Phase
Frequency distributions will be provided by treatment group along with rates and the 
two-sided 95% confidence intervals. The differences in the rates between each TAK-438
group and the Lansoprazole group (each TAK-438 group – the Lansoprazole group) and 
the two-sided 95% confidence intervals will also be provided.
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7.3.2.2 Sensitivity Analysis
Analysis Set:
Per Protocol Set
Analysis Variable:
Rate of Endoscopic Recurrence of Erosive Esophagitis During the First 12 Weeks of 
Treatment in the Maintenance Phase (%)
Analytical Methods:
(1) Sensitivity Analysis
To check the robustness of the results, the same analyses as section 7.3.2.1 will be 
performed using the per protocol set.
7.3.3
Additional Efficacy Endpoints
7.3.3.1 Gastrointestinal Symptoms Based on Subject Diary
Heartburn Symptoms
Analysis Set:
Full Analysis Set
Analysis Variables:
Mean Severity of Symptoms
Subgroups:
Barrett's Mucosa (Baseline)
[Present, Absent]
Visit:
Week 4, Week 8, Week 12, Week 16, Week 20, Week 24
Analytical Methods:
The following summaries will be provided for each treatment group.
i)
Descriptive statistics will be provided for each visit.
ii)
The difference in the medians between each TAK-438 group and the Lansoprazole
group (each TAK-438 group – the Lansoprazole group) and the two-sided 95% 
confidence intervals will be provided for each visit using the Hodges-Lehmann 
estimator. Wilcoxon rank-sum tests will be used to test for treatment differences at each
visit.
iii)
WMWodds of each TAK-438 group to the Lansoprazole group and the two-sided 95% 
confidence intervals will be provided for each visit based on Wilcoxon-Mann-Whitney 
test statistics.
Subgroup Analysis (Baseline Barrett's Mucosa)
・
The same analyses as all of the above will be conducted for the defined subgroups.
Gastric Acid Regurgitation
Analysis Set:
Full Analysis Set
Analytical Methods:
The same analyses as those in section 7.3.3.1 "Heartburn Symptoms" will be conducted for 
the gastric acid regurgitation.
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7.3.3.2 HRQoL (EQ-5D-5L)
EQ-5D-5L Index Value
Analysis Set:
Full Analysis Set
Analysis Variables:
EQ-5D-5L Index Value
Covariates:
LA Classification (Time of Diagnosis)
[Grade A/B, Grade C/D]
EQ-5D-5L Index Value (Baseline)
Visit:
Baseline, Week 4, Week 12, Week 24
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 each TAK-
438 group and the Lansoprazole group (each TAK-438 group – the Lansoprazole group) 
and the two-sided 95% confidence intervals 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 LA classification at the 
time of diagnosis 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% confidence intervals will be provided for each treatment group. The difference 
in the LS means between each TAK-438 group and the Lansoprazole group (each TAK-
438 group – the Lansoprazole group) and the two-sided 95% confidence interval will be 
provided. The difference in the LS means will be tested for treatment differences.
(3) MMRM
The changes from baseline (each post baseline visit – baseline) in the analysis variable 
will be analyzed using a mixed model repeated measures analysis (MMRM) model with 
the changes from baseline in the analysis variable as the response, and treatment, LA 
classification at the time of diagnosis, baseline value of the analysis variable, visit, 
treatment-by-visit interaction, baseline-by-visit interaction, and LA grade-by-visit
interaction as fixed effects. LS means and the two-sided 95% confidence intervals will be 
provided by visit for each treatment group. The differences in the LS means between 
each TAK-438 group and the Lansoprazole group (each TAK-438 group - the 
Lansoprazole group) and the two-sided 95% confidence intervals will be provided for 
each visit. The differences in the LS means will be tested for treatment differences. An 
unstructured variance-covariance matrix will be used to model the within-subject errors 
and Satterthwaite's method will be used to approximate the degrees of freedom.
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EQ VAS Score
Analysis Set:
Full Analysis Set
Analysis Variables:
EQ VAS Score
Covariates:
LA Classification (Time of Diagnosis)
[Grade A/B, Grade C/D]
EQ VAS Score (Baseline)
Analytical Methods:
The same analyses as those in section 7.3.3.2 "EQ-5D-5L Index Value" will be conducted for 
the EQ VAS score.
7.3.3.3 Barrett's Mucosa
Analysis Set:
Full Analysis Set
Analysis Variables:
Barrett's Mucosa (Change)
[Increased, Unchanged, Reduced, Disappeared, Unknown]
Subgroups:
Barrett's Mucosa (Baseline)
[Present (3 cm or Greater), Present (Less than 3 cm), Absent, 
Unknown]
Visit:
Week 12, Week 24
Analytical Methods:
(1) Frequency distribution of Barrett's Mucosa (Change) by Baseline Barrett's Mucosa
Frequency distribution will be provided for each subgroup and visit by treatment group.
7.3.4
Statistical/Analytical Issues
7.3.4.1 Adjustments for Covariates
Analysis Set:
Full Analysis Set
Analysis Variable:
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-week Maintenance 
Phase (%)
Rate of Endoscopic Recurrence of Erosive Esophagitis During the First 12 Weeks of
Treatment in the Maintenance Phase (%)
Stratified Variable:
LA Classification (Time of Diagnosis)
[Grade A/B, Grade C/D]
Analytical Methods:
(1) CMH Test for the Rate of Endoscopic Recurrence of Erosive Esophagitis During the 
24-week Maintenance Phase
(2) CMH Test for the Rate of Endoscopic Recurrence of Erosive Esophagitis During the 
First 12 Weeks of Treatment in the Maintenance Phase
A CMH test with LA Classification at the time of diagnosis as a stratification factor will 
be used to compare the above analysis variable between each TAK-438 group and the 
Lansoprazole group for treatment differences. Mantel-Haenszel estimate of risk 
difference between each TAK-438 group and the Lansoprazole group (each TAK-438 
group – the Lansoprazole group) and the two-sided 95% confidence interval using the 
Wald method will also be provided.
7.3.4.2 Handling of Dropouts or Missing Data
For the primary endpoint "rate of endoscopic recurrence of erosive esophagitis during the 24-week maintenance 
phase" and the secondary efficacy endpoint "rate of endoscopic recurrence of erosive esophagitis during the first 12
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weeks of treatment in the maintenance phase", missing data will be handled according to the details described in 
section 7.1.3.
Values below the lower limit of quantification will be treated as zero when calculating the descriptive statistics.
Values above the upper limit of quantification will be treated as the upper limit values when calculating the 
descriptive statistics.
7.3.4.3 Interim Analyses and Data Monitoring
No interim analysis is planned in this study.
7.3.4.4 Multicenter Studies
Treatment-by-center interaction will not be explored in this study.
7.3.4.5 Multiple Comparison/Multiplicity
Adjustment for multiplicity will be performed for the primary endpoint "rate of endoscopic recurrence of erosive 
esophagitis during the 24-week maintenance phase" and the secondary efficacy endpoint "rate of endoscopic 
recurrence of erosive esophagitis during the first 12 weeks of treatment in the maintenance phase" in the following 
order under the closed testing procedure and the analysis will be conducted using the full analysis set.
•
The primary endpoint "rate of endoscopic recurrence of erosive esophagitis during the 24-week 
maintenance phase" will be tested for non-inferiority between the TAK-438 20 mg group and the 
Lansoprazole group. In other words, if the upper bound of the 95% confidence interval of the treatment 
difference (the TAK-438 20 mg group – the Lansoprazole group) is ≤10%, the non-inferiority for TAK-438 
20 mg relative to Lansoprazole will be declared.
•
If the previous test is successful, the primary endpoint will be tested for non-inferiority between the 
TAK-438 10 mg group and the Lansoprazole group. In other words, if the upper bound of the 95% 
confidence interval of the treatment difference (the TAK-438 10 mg group – the Lansoprazole group) is 
≤10%, the non-inferiority for TAK-438 10 mg relative to Lansoprazole will be declared.
•
If the previous test is successful, the primary endpoint will be tested for superiority between the TAK-438 
20 mg group and the Lansoprazole group. The upper bound of the 95% confidence interval of the treatment 
difference (the TAK-438 20 mg group -the Lansoprazole group) will be compared to 0%.
•
If the previous test is successful, the primary endpoint will be tested for superiority between the TAK-438 
10 mg group and the Lansoprazole group.
•
If the previous test is successful, the secondary endpoint "rate of endoscopic recurrence of erosive 
esophagitis during the first 12 weeks of treatment in the maintenance phase" will be tested for superiority 
between the TAK-438 20 mg group and the Lansoprazole group.
•
If the previous test is successful, the secondary endpoint will be tested for superiority between the TAK-438 
10 mg group and the Lansoprazole group.
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Other analyses in this study will be done only for exploratory purposes and multiplicity adjustments will not be 
made.
7.3.4.6 Use of an "Efficacy Subset" of Subjects
In addition to analyses on the primary and secondary efficacy endpoints using the full analysis set, sensitivity 
analyses will also be performed using the per protocol set to examine the robustness of the results.
7.3.4.7 Active-Control Studies Intended to Show Equivalence or Non-Inferiority
For the primary efficacy endpoint, non-inferiority for each TAK-438 group relative to the Lansoprazole group will 
be confirmed in the full analysis set using a non-inferiority margin of 10%.
7.3.4.8 Subgroup Analysis
Analysis Set:
Full Analysis Set
Analysis Variable:
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-week Maintenance 
Phase (%)
Rate of Endoscopic Recurrence of Erosive Esophagitis During the First 12 Weeks of
Treatment in the Maintenance Phase (%)
Subgroups:
Age (years)
[Min<= - <65, 65<= - <75, 75<= - <=Max]
Gender
[Male, Female]
BMI (kg/m2) (Baseline)
[Min<= - <18.5, 18.5<= - <25.0, 25.0<= - <=Max]
LA Classification (Time of Diagnosis)
[Grade A/B, Grade C/D]
Barrett's Mucosa (Baseline)
[Present, Absent]
Esophageal Hiatal Hernia (Baseline)
[Present (2 cm or Greater), 
Present (Less than 2 cm), Absent, Unknown]
Analytical Methods:
(1)
Subgroup Analysis for the Rate of Endoscopic Recurrence of Erosive Esophagitis 
During the 24-week Maintenance Phase
(2)
Subgroup Analysis for the Rate of Endoscopic Recurrence of Erosive Esophagitis
During the First 12 Weeks of Treatment in the Maintenance Phase
The same analyses as those in section 7.3.1.1 will be performed for each of the above
subgroups, except for non-inferiority testing.
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7.4
SAFETY ANALYSIS
7.4.1
Treatment-Emergent Adverse Events
7.4.1.1 Overview of Treatment-Emergent Adverse Events
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Relationship to Study Drug
[Related, Not Related]
Intensity
[Mild, Moderate, Severe]
Analytical Methods: The following summaries will be provided for each treatment group.
(1) Overview of Treatment-Emergent Adverse Events
1) All Treatment-Emergent Adverse Events (number of events, number and percentage of 
subjects) 
2) Relationship of Treatment-Emergent Adverse Events to Study Drug (number of events, 
number and percentage of subjects) 
3) Intensity of Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects) 
4) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation (number 
of events, number and percentage of subjects) 
5) Relationship to Study Drug of Treatment-Emergent Adverse Events Leading to Study 
Drug Discontinuation (number of events, number and percentage of subjects) 
6) Serious Treatment-Emergent Adverse Events (number of events, number and percentage 
of subjects)
7) Relationship of Serious Treatment-Emergent Adverse Events to Study Drug (number of 
events, number and percentage of subjects) 
8) Serious Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
(number of events, number and percentage of subjects) 
9) Treatment-Emergent Adverse Events Resulting in Death (number of events, number and 
percentage of subjects) 
10) Treatment-Emergent Adverse Events Corresponding to Liver Function Test 
Abnormalities (number of events, number and percentage of subjects)
11) Significant Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)
TEAEs will be counted according to the rules below.
Number of subjects
・
Summaries for 2), 5), and 7)
A subject with occurrences of TEAE in both categories (ie, Related and Not Related) will 
be counted once in the Related category.
・
Summary for 3)
A subject with multiple occurrences of TEAE will be counted once for the TEAE with 
the maximum intensity.
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・
Summaries other than 2), 3), 5), and 7)
A subject with multiple occurrences of TEAE will be counted only once.
Number of events
For each summary, the total number of events will be calculated.
7.4.1.2 Displays of Treatment-Emergent Adverse Events
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Intensity
[Mild, Moderate, Severe]
Time of Onset (day)
[1<= - <=84, 85<= - <=168, 169<= - <=Max]
Analytical Methods: The following summaries will be provided using frequency distribution for each treatment 
group. 
TEAEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency for tables provided 
by SOC and PT. SOC and PT will be sorted in decreasing frequency for tables provided by 
SOC only or PT only.
(1) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
(2) Treatment-Emergent Adverse Events by System Organ Class
(3) Treatment-Emergent Adverse Events by Preferred Term
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(5) Intensity of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class, and Preferred Term
(7) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term
(8) Drug-Related Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term
(9) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term
(10) Serious Drug-Related Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term
(11) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Over Time
(12) Most Frequent Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(13) Treatment-Emergent Adverse Events Corresponding to Liver Function Test 
Abnormalities by System Organ Class and Preferred Term
(14) Drug-Related Treatment-Emergent Adverse Events Corresponding to Liver 
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Function Test Abnormalities by System Organ Class and Preferred Term
(15) Significant Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(16) Drug-Related Significant Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term
(17) Most Frequent Non Serious Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term
The frequency distribution will be provided according to the rules below.
Number of subjects
・
Summary tables other than (5), (6) and (11)
A subject with multiple occurrences of TEAE within a SOC will be counted only once in 
that SOC. A subject with multiple occurrences of TEAE within a PT will be counted 
only once in that PT. Percentages will be based on the number of subjects in the safety 
analysis set.
・
Summary tables for (5) and (6)
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted only 
once for the TEAE with the maximum intensity. Percentages will be based on the 
number of subjects in the safety analysis set.
・
Summary table for (11)
A subject with a TEAE that occurs in more than one interval is counted in all the 
intervals that the TEAE occurs. For each time interval, a subject with multiple 
occurrences of TEAE within a SOC or a PT will be counted only once in that SOC or PT.
When calculating percentages for each time interval, the number of subjects at risk 
(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)
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 calculating the percentages for 
"Subjects With Any TEAEs", the number of subjects with at least one of these most 
frequent non-serious TEAEs will be used as the numerator.
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7.4.2
Pretreatment Events and Adverse Events in the Healing Phase
7.4.2.1 Displays of Pretreatment Events
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables: PTE
Analytical Methods: The following summaries will be provided using frequency distribution.
PTEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC will 
be sorted alphabetically and PT will be sorted in decreasing frequency.
(1) Pretreatment Events by System Organ Class and Preferred Term
(2) Serious Pretreatment Events by System Organ Class and Preferred Term
The frequency distribution will be provided according to the rules below.
Number of subjects
A subject with multiple occurrences of PTE within a SOC will be counted only once in that 
SOC. A subject with multiple occurrences of PTE within a PT will be counted only once in 
that PT.
7.4.2.2 Displays of Adverse Events in the Healing Phase
Analysis Set:
All Subjects Who Entered the Healing Phase
Analysis Variables: AE in the Healing Phase
Analytical Methods: The following summaries will be provided using frequency distribution.
AEs 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) Adverse Events in the Healing Phase by System Organ Class and Preferred Term
(2) Serious Adverse Events in the Healing Phase 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 AE within a SOC will be counted only once in that 
SOC. A subject with multiple occurrences of AE within a PT will be counted only once in that 
PT.
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7.4.3
Laboratory and Other Safety Data
7.4.3.1 Laboratory Test Results
Hematology and Serum Chemistry
Analysis Set:
Safety Analysis Set
Analysis Variables : Hematology
Red Blood Cells (×1012/L)
White Blood Cells (×109/L)
Hemoglobin (g/L)
Hematocrit (%)
Platelets (×109/L)
White Blood Cell Fractions (Neutrophils (%), Eosinophils (%), Basophils (%), 
Monocytes (%), Lymphocytes (%)) 
Serum Chemistry
ALT (U/L)
ALP (U/L)
AST (U/L)
GGT (U/L)
Total Bilirubin (μmol/L)
Direct Bilirubin (μmol/L)
LDH (U/L)
CK (CPK) (U/L)
Albumin (g/L)
Total Protein (g/L)
Creatinine (μmol/L)
BUN (mmol/L)
Uric Acid (mmol/L)
Total Cholesterol (mmol/L)
Triglycerides (mmol/L)
Glucose (mmol/L)
Potassium (mmol/L)
Sodium (mmol/L)
Magnesium (mmol/L)
Calcium (mmol/L)
Inorganic Phosphorus (mmol/L)
Chloride (mmol/L)
Serum Iron (μmol/L)
Vitamin B12 (pmol/L)
Visit:
ALT, AST, Total Bilirubin, and Direct Bilirubin:
Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 24
Variables other than ALT, AST, Total Bilirubin, and Direct Bilirubin:
Baseline, Week 4, Week 12, Week 24
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 maintenance phase will be provided. If a 
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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 maintenance phase
will be provided. Further details are given in Appendix.
Urinalysis
Analysis Set:
Safety Analysis Set
Analysis Variables : Protein
[Neg, Trace, 30 mg/dL, 100 mg/dL, 300 mg/dL, >=2000 mg/dL]
Sugar
[Neg, 100 mg/dL, 250 mg/dL, 500 mg/dL, 1000 mg/dL, >=2000 mg/dL]
Visit:
Baseline, Week 4, Week 12, Week 24
Analytical Methods: The following summaries will be provided for each treatment group. 
(1) Summary of Shifts of Urine Laboratory Test Results
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided.
Serum Gastrin, Pepsinogen I/II
Analysis Set:
Safety Analysis Set
Analysis Variables : Serum Gastrin (pmol/L)
Pepsinogen I (μg/L)
Pepsinogen II (μg/L)
Pepsinogen I/II Ratio
Visit:
Baseline, Week 4, Week 12, Week 24
Analytical Methods: The following summaries will be provided for each treatment group. 
(1) Summary of Serum Gastrin and Pepsinogen I/II Results
For each visit, descriptive statistics for observed values and changes from baseline (each 
post-baseline visit - baseline) will be provided.
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7.4.4
Vital Signs, Physical Findings, and Other Observations Related to Safety
Vital Signs
Analysis Set:
Safety Analysis Set
Analysis Variables: Body Temperature (C)
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Pulse (bpm)
Visit:
Baseline, Week 4, Week 12, Week 24
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 maintenance phase will be provided. If a 
vital sign parameter has both lower and upper MAV criteria, analysis will be performed for 
each. Further details are given in Appendix.
12-lead ECG
Analysis Set:
Safety Analysis Set
Analysis Variables: Heart Rate (bpm)
RR Interval (msec)
PR Interval (msec)
QT Interval (msec)
QTcF Interval (msec)
QRS Interval (msec)
Interpretation
["Within Normal Limits",
"Abnormal, Not Clinically Significant",
"Abnormal, Clinically Significant"]
Visit:
Baseline, Week 12, Week 24
Analytical Methods: For each variable other than interpretation, 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 maintenance phase will be provided. If an 
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ECG laboratory parameter has both lower and upper MAV criteria, analysis will be 
performed for each. Further details are given in Appendix.
(3) Summary of Shifts of ECG Parameters
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided.
7.4.5
Subgroup Analysis for China
Analysis Population: Subjects in China
Subjects in Countries other than China
Analytical Methods: (1) The same analyses as those in section 7.2 to 7.4.4 will be conducted for the subjects in 
China.
(2) The same analyses as those in section 7.2 to 7.4.4 will be conducted for the subjects in 
countries other than China.
7.4.6
Subgroup Analysis for Taiwan
Analysis Population: Subjects in Taiwan
Analytical Methods: (1) The same analyses as those in section 7.2 to 7.4.4 will be conducted for the subjects in 
Taiwan.
7.4.7
Subgroup Analysis for Safety Analysis Set Excluding Accidentally 
Unblinded Subjects
Analysis Population: Safety Analysis Set Excluding the Accidentally Unblinded Subjects
Safety Analysis Set Excluding the Accidentally Unblinded Subjects in China
Safety Analysis Set Excluding the Accidentally Unblinded Subjects in Countries other than 
China
Safety Analysis Set Excluding the Accidentally Unblinded Subjects in Taiwan
Analytical Methods: The same analyses as those in sections 7.4.1.1 and 7.4.1.2 ((1), (4) to (17)) will be conducted 
in the safety analysis set that excludes subjects who were accidentally unblinded due to IWRS 
system error.
The same analyses will be conducted for the subjects in China and countries other than China.
The same analyses will be conducted for the subjects in Taiwan.
7.4.8
Significance Level and Confidence Coefficient
・
Significance level: 5% (two-sided test)
・
Confidence coefficient: 95% (two-sided)
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7.4.9
Changes in the Statistical Analysis Plan
The changes from the original SAP (Version: 1, Date: 20 November 2015) to the amended SAP were described 
below with a rationale for changes provided.
Page 1, TITLE PAGE
Existing Text
Revised Text
Rationale for Amendment
The responsible person has been changed.
Page 2, Section 1.0 APPROVAL SIGNATURES
Existing Text
Revised Text
Rationale for Amendment
The Responsible persons have been changed for Biostatistics and Clinical Science. The Responsible person has not 
been needed for Pharmacovigilance.
Page 7, Section 4.1 PRIMARY OBJECTIVES
Existing Text
To demonstrate the non-inferiority of TAK-438 to Lansoprazole in the reduction of relapse of erosive esophagitis in 
subjects in the Maintenance Phase (24 weeks) in whom endoscopic healing of erosive esophagitis has been 
PPD
PPD
PPD
PPD
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confirmed after treatment with TAK-438 or a PPI, as well as to determine the clinically recommended dose of TAK-
438 for maintenance therapy in erosive esophagitis.
Revised Text
・
To demonstrate the non-inferiority of TAK-438 to Lansoprazole in the reduction of relapse of erosive 
esophagitis in subjects in the Maintenance Phase (24 weeks) in whom endoscopic healing of erosive 
esophagitis has been confirmed after treatment with TAK-438 or a PPI. 
・
To determine the clinically recommended dose of TAK-438 for maintenance therapy in erosive esophagitis in 
whom endoscopic healing of erosive esophagitis has been confirmed after treatment with TAK-438 or a PPI.
Rationale for Amendment
The description has been revised in the protocol.
Page 7, Section 4.2 SECONDARY OBJECTIVES
Existing Text
To evaluate the efficacy of TAK-438 during the 12-week treatment and the safety of TAK-438 versus Lansoprazole 
in subjects in the Maintenance Phase (24 weeks) in whom endoscopic healing of erosive esophagitis has been 
confirmed after treatment with TAK-438 or a PPI.
Revised Text
・
To evaluate the efficacy of TAK-438 during the first 12-weeks of treatment in the Maintenance Phase in 
subjects with endoscopically confirmed healed erosive esophagitis receiving TAK-438 or a PPI.
・
To evaluate the safety of TAK-438 versus Lansoprazole in subjects in the Maintenance Phase (24 weeks) in 
whom endoscopic healing of erosive esophagitis has been confirmed after treatment with TAK-438 or a PPI.
Rationale for Amendment
The description has been revised in the protocol.
Page 7~8, Section 4.4 STUDY DESIGN
Existing Text
This is a phase III, multicenter, double-blind, parallel-group comparative study of TAK-438 (10 mg or 20 mg) in 
subjects in whom endoscopic healing of erosive esophagitis has been confirmed with TAK-438 or following proton 
pump inhibitor (PPI) treatment, to demonstrate the non-inferiority of TAK-438 to Lansoprazole in their maintenance 
treatment (6 months or 24 weeks) as well as to determine the clinically recommended dose for TAK-438 for 
maintenance therapy in erosive esophagitis.
All subjects who have been confirmed on endoscopy to have healing of erosive esophagitis will be randomized at a 
1:1:1 ratio to oral TAK-438 10 mg, 20 mg or Lansoprazole 15 mg once daily given in the Maintenance Phase lasting 
24 weeks.
If relapse of erosive esophagitis has been endoscopically confirmed in any subject, the subject will complete the 
study at that time point (to be construed as “complete cases in the Maintenance Phase”, regardless of the time point 
where relapse of disease is confirmed).
This study will be conducted at a total of around 60 sites across Asia with an estimated total of 200 subjects 
randomized to each treatment group totaling 600 for the study.
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The study will consist of a Screening Phase of up to 28 days followed by a Treatment Phase of up to 24 weeks. 
There will be 5 subject visits scheduled: the start of the Screening Phase (Visit 1), the start of the Treatment Phase 
(Visit 2), after 4 weeks of treatment (Visit 3), after 12 weeks of treatment (Visit 4), after 24 weeks of treatment 
(Visit 5), and a Follow-up phase.
Dosing will commence on Day 1 after randomization at Visit 2 (after completion of all required assessments 
scheduled on the day 1).
Revised Text
This is a phase 3, multicenter, randomized double-blind, parallel-group study to demonstrate the non-inferiority of 
TAK-438 (10 mg or 20 mg) to Lansoprazole 15 mg in preventing the recurrence of erosive esophagitis in subjects 
with endoscopically confirmed healing of erosive esophagitis. This study also aims to determine the clinically 
recommended dose of TAK-438 for maintenance therapy of erosive esophagitis.
This study is comprised of 2 treatment periods: An open-label, single-arm period in which subjects receive 
Lansoprazole 30 mg for up to 8 weeks (Healing Phase), and a double-blind, parallel-group period in which subjects 
are randomized at a 1:1:1 ratio to TAK-438 10 mg, 20 mg or Lansoprazole 15 mg once daily for up to 24 weeks 
(Maintenance Phase). To enroll in the study subjects must have ongoing erosive esophagitis or have completed 
Study TAK-438_303. Subjects with ongoing erosive esophagitis are required to undergo the Healing Phase. Once 
erosive esophagitis healing is confirmed by endoscopy, these subjects may be randomized to 1 of 3 treatments in the 
Maintenance Phase. Subjects with endoscopic-confirmed healing of erosive esophagitis following the completion of 
Study TAK-438_303 will be randomized into the Maintenance Phase without carrying out the open-label Healing 
Phase. Subjects who previously entered the study (prior to Protocol Amendment 06) after confirmation of healed 
erosive esophagitis following treatment with a proton pump inhibitor (termed “de novo” subjects) are no longer 
eligible to enter the study; any ongoing subjects may continue being treated in the Maintenance Phase. A schematic 
of the study design is included in Figure 4.a.
If relapse of erosive esophagitis has been endoscopically confirmed in any subject, the subject will complete the 
study at that time point (to be construed as “complete cases in the Maintenance Phase”), regardless of the time point 
where relapse of disease is confirmed.
This study will be conducted at a total of around 70 sites across Asia with an estimated total of 231 subjects 
randomized to each treatment group during the Maintenance Phase (totaling 693 subjects entering the Maintenance 
Phase for the study).
The study will consist of a Screening Phase of up to 28 days duration (Visit 1), a Healing Phase (for those subjects 
with ongoing erosive esophagitis only) of 4 or 8 weeks duration (Visits 2HP and 3HP), followed by a Maintenance 
Phase of up to 24 weeks (Visits 2-8), and a Follow-up Period of up to 14 days duration. With the exception of the 
Follow-up (which will be carried out by phone), all visits will occur at the clinic. The total duration of treatment is 
up to 6 months (24 weeks) in subjects entering from Study TAK-438_303, and up to 8 months (32 weeks) in 
subjects entering the study with ongoing erosive esophagitis.
Subjects with ongoing erosive esophagitis: Subjects who have ongoing erosive esophagitis will enter the Healing 
Phase and administration of Lansoprazole 30 mg once daily will commence following the completion of all required 
assessments at Visit 2HP. Subjects will then undergo a visit at Week -4 (Visit 3HP), where the subject may undergo 
endoscopy to confirm healing of erosive esophagitis. This is an optional procedure where the decision to perform 
endoscopy is based on the investigator’s clinical judgment of a subject’s symptoms of healing. Subjects who do not 
show endoscopic healing at Visit 3HP may continue in the Healing Phase and undergo endoscopy at Day 1 (Visit 2). 
Subjects with endoscopically confirmed healing of erosive esophagitis at Week -4 or at Day 1 will be eligible to 
enter the Maintenance Phase. Where the results from clinical laboratory tests confirming eligibility for the 
Maintenance Phase at Week -4 are not immediately available, subjects should continue to receive Lansoprazole 30 
mg for up to 14 days. Subjects healed at Day 1 should be immediately randomized. Subjects who do not have 
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endoscopic-confirmed healed erosive esophagitis after 8 weeks treatment (Healing Phase Failures) will not be 
randomized into the Maintenance Phase and should be treated using routine clinical care.
Subjects with healed erosive esophagitis: Subjects with healed erosive esophagitis will undergo a randomization 
visit (Visit 2), and dosing for the Maintenance Phase will commence following the completion of all required 
assessments on Day 1. Visits will then occur at 2 week intervals after the initiation of treatment in the Maintenance 
Phase. As a result of Protocol Amendment 06, subjects with healed erosive esophagitis following treatment with a 
proton pump inhibitor outside Study TAK-438_303 or the Healing Phase of the current study (de novo subjects) are 
no longer eligible to enter the study; any ongoing subjects may continue to be treated in the Maintenance Phase.
All subjects receiving TAK-438 must undergo a total of 8 weeks of LFT monitoring visits with visits occurring 
every 2 weeks. For subjects entering the Maintenance Phase of the current study within 7 days of completing Study 
TAK-438_303, the requirement for 8 weeks of monitoring can be totalled across the 2 studies.
Rationale for Amendment
The descriptions have been revised in the protocol.
Page 8, Section 4.4 STUDY DESIGN
Existing Figure
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Revised Figure
Rationale for Amendment
The figure (Figure 4.a) has been revised in the protocol.
Page 9, Section 5.0 ANALYSIS ENDPOINTS
Existing Text
The secondary efficacy endpoint for this study is the rate of recurrence* of erosive esophagitis during the 12 weeks 
of treatment in the Maintenance Phase. Safety endpoints for this study include adverse events, clinical laboratory 
test results, ECG, vital signs, serum gastrin and pepsinogen I/II levels.
Revised Text
The secondary efficacy endpoint for this study is the rate of recurrence* of erosive esophagitis during the first 12 
weeks of treatment in the Maintenance Phase. Safety endpoints for this study include adverse events (AEs), clinical 
laboratory test results, ECG, vital signs, serum gastrin and pepsinogen I/II levels.
Rationale for Amendment
The description has been revised in the protocol.
Page 10, Section 6.0 DETERMINATION OF SAMPLE SIZE
Existing Text
Assuming that the true Week 24 recurrence rate is 30.4% for lansoprazole, 22.0% for TAK-438 10 mg, and 13.6% 
for TAK-438 20 mg, and assuming that the dropout rate is up to 20%, a sample size of 185 subjects per group will 
provide an overall power of 90% to establish non-inferiority using a 2-sided 95% CI with a 10% non-inferiority 
margin. 200 subjects per group will be included to allow adequate numbers for the regulatory requirements of 
various countries.
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The assumption of the true recurrence rate is based on a Phase 3 study that showed a Week 24 recurrence rate of 
30.4% for lansoprazole 15 mg and 13.6% for lansoprazole 30 mg.
Based on results from an earlier study of Lansoprazole as maintenance therapy for erosive esophagitis (AG-
1749/CCT-202), the point estimate for the difference (Lansoprazole 15 mg group – Famotidine group) was 
calculated as -57.6% with the upper limit of the confidence interval being -30.7%. Therefore, the non-inferiority 
margin is specified as 10%.
Revised Text
Assuming that the true Week 24 recurrence rate is 30.4% for Lansoprazole, 22.0% for TAK-438 10 mg, and 13.6% 
for TAK-438 20 mg, and assuming that the dropout rate is approximately 30%, a sample size of 208 subjects per 
group will provide an overall power of 90% to establish non-inferiority using a 2-sided 95% CI with a 10% non-
inferiority margin. 231 subjects per group will be included to allow adequate numbers for the regulatory 
requirements of various countries.
The assumption of the true recurrence rate is based on a phase 3 study that showed a Week 24 recurrence rate of 
30.4% for Lansoprazole 15 mg and 13.6% for Lansoprazole 30 mg.
Based on results from an earlier study of Lansoprazole as maintenance therapy for erosive esophagitis (AG-
1749/CCT-202), the point estimate for the difference (Lansoprazole 15 mg group – famotidine group) was 
calculated as -57.6% with the upper limit of the confidence interval being -30.7%. Therefore, the non-inferiority
margin is specified as 10%.
Rationale for Amendment
The description with the targeted sample size has been revised in the protocol.
Page 11, Section 7.1.1 Definitions
Existing Text
TEAE: An adverse event whose date of onset occurs on or after the start of study drug.
Revised Text
TEAE: An adverse event whose date of onset occurs on or after the start of the Maintenance Phase drug. A TEAE 
whose relationship to the Maintenance Phase drug is missing will be considered drug-related. A TEAE whose 
intensity is missing will be considered severe.
Rationale for Amendment
The Maintenance Phase has been added in the protocol, and the handling rules for missing data for TEAE have been 
added.
Page 11, Section 7.1.1 Definitions
Existing Text
-
Study Day: The day before the first dose of the study medication will be defined as Study Day -1 and the day 
of the first dose will be defined as Study Day 1. Other study days are defined relative to Study Day 1, eg, the 
day prior to Study Day 1 is Day -1 and the day after Study Day 1 is Day 2.
-
Follow-up Day: The day after the last dose of the study medication will be defined as Follow-up Day 1. Other 
follow-up days are defined relative to Follow-up Day 1.
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-
Duration of exposure to study drug (days): date of last dose of study drug - date of first dose of study drug + 1
Revised Text
-
Study Day: The day before the first dose of the Maintenance Phase drug will be defined as Study Day -1 and 
the day of the first dose will be defined as Study Day 1. Other study days are defined relative to Study Day 1, 
eg, the day prior to Study Day 1 is Day -1 and the day after Study Day 1 is Day 2.
-
Follow-up Day: The day after the last dose of the Maintenance Phase drug will be defined as Follow-up Day 1. 
Other follow-up days are defined relative to Follow-up Day 1.
-
Duration of exposure to study drug (days): date of last dose of Maintenance Phase drug - date of first dose of
Maintenance Phase drug + 1
Rationale for Amendment
The Maintenance Phase has been added in the protocol.
Page 11, Section 7.1.1 Definitions
Added Text
Pepsinogen I/II Ratio: Pepsinogen I (μg/L) / Pepsinogen II (μg/L) (rounded to 1 decimal place)
Significant TEAE: Any TEAE (not including serious TEAEs) that led to an intervention, including withdrawal of 
drug treatment, dose increase, dose reduction or significant additional concomitant therapy.
Rationale for Amendment
The calculation formula for the above variable has been added with the number of decimal places. The significant 
TEAE should be analyzed and the definition of this type of TEAE has been added.
Page 11~12, Section 7.1.2 Analysis Sets
Existing Text
Analysis of efficacy variables will be conducted in the full analysis set (FAS) defined as all randomized subjects 
who receive at least 1 dose of study medication and have at least 1 post-baseline endoscopy, and will be based on 
the randomized treatment.
The primary efficacy endpoint and the secondary efficacy endpoint will also be analyzed in the per protocol set
defined as all FAS subjects who did not have any of the major protocol deviations listed below. Analyses will be 
based on the randomized treatment.
- Subjects who did not meet inclusion criteria #3 or #4
- Subjects who met exclusion criteria #8, #11, #12, #13, or #14
- Subjects with study medication compliance of less than 70%
- Subjects who have been unblinded prior to database lock
- Subjects who have violated the rules specified in section 7.3 of the protocol
Analysis of safety variables will be conducted in the safety analysis set defined as all subjects who take at least 1 
dose of study medication and will be based on the treatment received.
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Revised Text
Analysis of efficacy variables will be conducted in the full analysis set (FAS) defined as all randomized subjects 
who receive at least 1 dose of the Maintenance Phase drug and have at least 1 post-baseline endoscopy, and will be 
based on the randomized treatment. Randomized subjects who were accidentally unblinded due to IWRS system 
error will be excluded.
The primary efficacy endpoint and the secondary efficacy endpoint will also be analyzed in the per protocol set
defined as all FAS subjects who did not have any of the major protocol deviations listed below. Analyses will be 
based on the randomized treatment.
- Subjects who did not meet inclusion criteria #3 or #4
- Subjects who met exclusion criteria #8, #11, #12, #13, or #14
- Subjects with study drug 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 the Maintenance Phase drug and will be based on the treatment received in the Maintenance Phase.
Rationale for Amendment
The Maintenance Phase has been added in the protocol. Accidental unblinding was identified in the study on Dec 16, 
2015. It was confirmed that the treatment details of 93 subjects randomized in the study were accidentally unblinded 
to the site investigators, clinical project managers, and the CRA team through the IWRS subject visit notification 
emails. The accidental unblinding was caused by an IWRS system error. The randomized subjects who were 
accidentally unblinded due to IWRS system error should be excluded from the FAS and the PPS.
Page 12, Section 7.1.3 Handling of Rate of Endoscopic Recurrence of Erosive Esophagitis
Existing Text
7.1.3.1
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 12-Week Treatment
A subject who is diagnosed as LA classification grade A, B, C, or D from endoscopy tests performed between Study 
Day 2 and Study Day 127 (up to and including Follow-up Day 14) will be considered as a relapsed subject. Subjects 
who do not have any endoscopy data during this period will be treated as missing. Subjects who do not meet this 
requirement will be considered as 'not relapsed'. Recurrence rate will be calculated from the relapsed and not 
relapsed subjects, however, any subjects diagnosed as LA classification grade A, B, C, or D from endoscopy tests 
performed before the study medication administration will be excluded from the analysis. 
7.1.3.2
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-Week Treatment
A subject who is diagnosed as LA classification grade A, B, C, or D from endoscopy tests performed after Study 
Day 2 (up to and including Follow-up Day 14) will be considered as a relapsed subject. Subjects who do not have 
any endoscopy data during this period will be treated as missing. Subjects who do not meet this requirement will be 
considered as 'not relapsed'. Recurrence rate will be calculated from the relapsed and not relapsed subjects, however, 
any subjects diagnosed as LA classification grade A, B, C, or D from endoscopy tests performed before the study 
medication administration will be excluded from the analysis.
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Revised Text
7.1.3.1
Rate of Endoscopic Recurrence of Erosive Esophagitis During the first 12 Weeks of Treatment in the 
Maintenance Phase
A subject who is diagnosed as LA classification grade A, B, C, or D from endoscopy tests performed between Study 
Day 2 and Study Day 127 (up to and including Follow-up Day 14) will be considered as a relapsed subject. Subjects 
who do not have any endoscopy data during this period will be treated as missing. Subjects who do not meet this 
requirement will be considered as 'not relapsed'. Recurrence rate will be calculated from the relapsed and not 
relapsed subjects, however, any subjects diagnosed as LA classification grade A, B, C, or D from endoscopy tests 
performed before the Maintenance Phase drug administration will be excluded from the analysis.
7.1.3.2
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-Week Maintenance Phase
A subject who is diagnosed as LA classification grade A, B, C, or D from endoscopy tests performed after Study 
Day 2 (up to and including Follow-up Day 14) will be considered as a relapsed subject. Subjects who do not have 
any endoscopy data during this period will be treated as missing. Subjects who do not meet this requirement will be 
considered as 'not relapsed'. Recurrence rate will be calculated from the relapsed and not relapsed subjects, however, 
any subjects diagnosed as LA classification grade A, B, C, or D from endoscopy tests performed before the 
Maintenance Phase drug administration will be excluded from the analysis.
Rationale for Amendment
The Maintenance Phase has been added, and the description has been revised in the protocol.
Page 12, Section 7.1.4 Handling of Data When Calculating Mean Severity According to Subject Diary
Existing Text
Mean severity = (total score of the severity recorded for the visit) / (number of days the severity of symptom is 
recorded) * 100 (rounded to 2 decimal places)
Revised Text
Mean severity = (total score of the severity recorded for the visit) / (number of days the severity of symptom is 
recorded) (rounded to 2 decimal places)
Rationale for Amendment
The expression "* 100" has been deleted because of clerical error.
Page 14, Section 7.1.6 Handling of Other Endpoints
Existing Text
Study Day: -28 – 1 (2 places)
Revised Text
Study Day: up to and including Study Day 1 (2 places)
Rationale for Amendment
The time intervals should be changed because the Healing Phase has been added in the protocol.
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Page 15, Section 7.1.6 Handling of Other Endpoints
Existing Text
Clinical laboratory tests, Gastrin, Pepsinogen I/II, Vital signs
Revised Text
Clinical laboratory tests (ALT, AST, total bilirubin, and direct bilirubin)
Visit
Scheduled Study Day
(days) 
Time Interval (days) 
Study Day
Follow-up Day
Baseline*
Study Day:
1
-28 – 1
Week 2
Study Day:
15
2 – 22
up to and including 
Follow-up Day 14
Week 4
Study Day
29
23 – 36
up to and including 
Follow-up Day 14
Week 6
Study Day:
43
37 – 50
up to and including 
Follow-up Day 14
Week 8
Study Day:
57
51 - 71
up to and including 
Follow-up Day 14
Week 12
Study Day:
85
72 – 127
up to and including 
Follow-up Day 14
Week 24
Study Day:
169
128 – 211
up to and including 
Follow-up Day 14
*: For the clinical laboratory tests of the subjects who participated in the TAK-438_303 study, if the last 
study visit coincides with the first visit in the 305 study or if the subject was randomized in the 305 study 
within 7 days after completing the last visit in the 303 study, then the data obtained at the last visit can be 
used as the baseline data for the 305 study.
Clinical laboratory tests (other than ALT, AST, total bilirubin, and direct bilirubin), Gastrin, Pepsinogen I/II, Vital 
signs
Rationale for Amendment
Visit 3 (Week 2), Visit 5 (Week 6) and Visit 6 (Week 8) has been added in the protocol for evaluating liver function 
tests (ALT, AST, total bilirubin, and direct bilirubin).
Page 15, Section 7.1.6 Handling of Other Endpoints
Existing Text
For the clinical laboratory tests, gastrin and pepsinogen I/II, for the subjects who participated in the TAK-438_303 
study
Revised Text
For the clinical laboratory tests, gastrin, and pepsinogen I/II of the subjects who participated in the TAK-438_303 
study
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Rationale for Amendment
The expression has been revised.
Page 16, Section 7.2.1.2 Screen Failures
Existing Text
Race [American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific 
Islander, White]
Revised Text
Race [American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific 
Islander, White, Multiple]
Rationale for Amendment
There have been subjects whose race were "Multiple".
Page 16, Section 7.2.1.3 Subject Eligibility
Existing Text
Primary Reason for Subject Not Being Eligible [Pretreatment Event/Adverse Event, Major Protocol Deviation, Lost 
to Follow-Up, Voluntary Withdrawal, Study Termination, Did Not Meet Entrance Criteria, Other]
Revised Text
Primary Reason for Subject Not Being Eligible [Pretreatment Event/Adverse Event, Major Protocol Deviation, Lost 
to Follow-Up, Voluntary Withdrawal, Study Termination, Did Not Meet Entrance Criteria, Healing Phase Failure, 
Other]
Rationale for Amendment
The category "Healing Phase Failure" has been added.
Page 17, Section 7.2.1.5 Disposition of Subjects
Existing Text
Study Drug (5 places)
Revised Text
Maintenance Phase Drug (5 places)
Rationale for Amendment
The Maintenance Phase has been added in the protocol.
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Page 17, Section 7.2.1.5 Disposition of Subjects
Existing Text
(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.
Revised Text
(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 maintenance phase drug will be used as 
the denominator. When calculating percentages for the reasons for discontinuation of maintenance phase drug, the 
total number of subjects who prematurely discontinued the maintenance phase drug will be used as the denominator.
(2) Flow Chart of Subject Distribution
Flow chart will be provided.
Rationale for Amendment
The Maintenance Phase has been added in the protocol. The analysis for providing a flow chart has been added in 
this SAP.
Page 18, Section 7.2.2.1 Summary of Demographics and Other Baseline Characteristics
Existing Text
Analysis Set: Randomized Set
Revised Text
Analysis Set: Randomized Set, Full Analysis Set
Rationale for Amendment
The analysis for the full analysis set has been added.
Page 18, Section 7.2.2.1 Summary of Demographics and Other Baseline Characteristics
Existing Text
Race [American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific 
Islander, White]
Revised Text
Race [American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific 
Islander, White, Multiple]
Rationale for Amendment
There have been subjects whose race were "Multiple".
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Page 20, Section 7.2.3.1 Study Drug Exposure and Compliance
Existing Text
Analysis Set: Safety Analysis Set
Revised Text
Analysis Set: Safety Analysis Set, Full Analysis Set
Rationale for Amendment
The analysis for the full analysis set has been added.
Page 20, Section 7.2.3.1 Study Drug Exposure and Compliance
Existing Text
(1) Study Drug Exposure and Compliance
Revised Text
(1) Study Drug Exposure and Compliance in Maintenance Phase
Rationale for Amendment
The Maintenance Phase has been added in the protocol.
Page 21, Section 7.3.1 Primary Efficacy Endpoint
Existing Text
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-week Treatment (3 places)
Revised Text
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-week Maintenance Phase (3 places)
Rationale for Amendment
The Maintenance Phase has been added in the protocol.
Page 21~22, Section 7.3.2 Secondary Efficacy Endpoint
Existing Text
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 12-week Treatment (4 places)
Revised Text
Rate of Endoscopic Recurrence of Erosive Esophagitis During the First 12 Weeks of Treatment in the Maintenance 
Phase (4 places)
Rationale for Amendment
The Maintenance Phase has been added in the protocol and the description has been revised in the protocol.
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Page 24, Section 7.3.3.3 Barrett's Mucosa
Existing Text
Present (3 cm or greater)
Revised Text
Present (3 cm or Greater)
Rationale for Amendment
The expression "greater" has been replaced with "Greater" because of clerical error.
Page 24~26, Section 7.3.4 Statistical/Analytical Issues
Existing Text
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-week Treatment (7 places)
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 12-week Treatment (7 places)
Revised Text
Rate of Endoscopic Recurrence of Erosive Esophagitis During the 24-week Maintenance Phase (7 places)
Rate of Endoscopic Recurrence of Erosive Esophagitis During the First 12 Weeks of Treatment in the Maintenance 
Phase (7 places)
Rationale for Amendment
The Maintenance Phase has been added in the protocol and the description has been revised in the protocol.
Page 25, Section 7.3.4.2 Handling of Dropouts or Missing Data
Added Text
Values below the lower limit of quantification will be treated as zero when calculating the descriptive statistics. 
Values above the upper limit of quantification will be treated as the upper limit values when calculating the 
descriptive statistics.
Rationale for Amendment
The handling rules of values below the lower or upper limit values for calculating the descriptive statistics have been 
added.
Page 27, Section 7.4.1.1 Overview of Treatment-Emergent Adverse Events
Added Text
5) Relationship to Study Drug of Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
(number of events, number and percentage of subjects)
11) Significant Treatment-Emergent Adverse Events (number of events, number and percentage of subjects)
Rationale for Amendment
The analyses for these types of TEAEs have been added.
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Page 28, Section 7.4.1.2 Displays of Treatment-Emergent Adverse Events
Existing Text
System Organ Class
Revised Text
SOC
Rationale for Amendment
The expression "System Organ Class" has been replaced with "SOC" for expression consistency.
Page 28~29, Section 7.4.1.2 Displays of Treatment-Emergent Adverse Events
Added Text
(8) Drug-Related Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by System Organ 
Class and Preferred Term
(10) Serious Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
(15) Significant Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
(16) Drug-Related Significant Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
(17) Most Frequent Non Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
Summary table for (17)
Most frequent non-serious TEAEs refer to PTs that are not serious whose percentages are at least 5% in any one of 
the treatment groups. If there are no PTs whose percentages exceed 5%, the threshold is lowered to 2%. When 
calculating the percentages for "Subjects With Any TEAEs", the number of subjects with at least one of these most 
frequent non-serious TEAEs will be used as the numerator.
Rationale for Amendment
The analyses for these types of TEAEs has been added.
Page 30, Section 7.4.2 Pretreatment Events and Adverse Events in the Healing Phase
Existing Text
7.4.2 Pretreatment Events
Revised Text
7.4.2 Pretreatment Events and Adverse Events in the Healing Phase
(omitted)
7.4.2.2 Displays of Adverse Events in the Healing Phase
Analysis Set:
All Subjects Who Entered the Healing Phase
Analysis Variables: AE in the Healing Phase
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Analytical Methods: The following summaries will be provided using frequency distribution.
AEs 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) Adverse Events in the Healing Phase by System Organ Class and Preferred Term
(2) Serious Adverse Events in the Healing Phase 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 AE within a SOC will be counted only once in that 
SOC. A subject with multiple occurrences of AE within a PT will be counted only once in that 
PT.
Rationale for Amendment
The Healing Phase has been added in the protocol and the analyses for adverse events in the Healing Phase have
been added in this SAP.
Page 31~33, Section 7.4.3 Laboratory and Other Safety Data, Section 7.4.4 Vital Signs, Physical Findings, and 
Other Observations Related to Safety
Existing Text
treatment phase (4 places)
Revised Text
maintenance phase (4 places)
Rationale for Amendment
The Maintenance Phase has been added in the protocol.
Page 31, Section 7.4.3.1 Laboratory Test Results
Existing Text
Visit:
Baseline, Week 4, Week 12, Week 24
Revised Text
Visit:
ALT, AST, Total Bilirubin, and Direct Bilirubin:
Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 24
Variables other than ALT, AST, Total Bilirubin, and Direct Bilirubin:
Baseline, Week 4, Week 12, Week 24
Rationale for Amendment
Visit 3 (Week 2), Visit 5 (Week 6) and Visit 6 (Week 8) has been added in the protocol for evaluating liver function 
tests (ALT, AST, total bilirubin, and direct bilirubin).
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Page 32, Section 7.4.3.1 Laboratory Test Results (Serum Gastrin, Pepsinogen I/II)
Existing Text
Pepsinogen I (mcg/L), Pepsinogen II (mcg/L)
Revised Text
Pepsinogen I (μg/L), Pepsinogen II (μg/L)
Rationale for Amendment
The expression "mcg" has been replaced with "μg" for using more suitable expression.
Page 33, Section 7.4.4 Vital Signs, Physical Findings, and Other Observations Related to Safety (Vital Signs)
Existing Text
Body Temperature (°C)
Revised Text
Body Temperature (C)
Rationale for Amendment
The expression "°C" has been replaced with "C" for using more suitable expression.
Page 33, Section 7.4.4 Vital Signs, Physical Findings, and Other Observations Related to Safety (12-lead 
ECG)
Existing Text
12-lead ECG interpretations (3 places)
Revised Text
interpretations (3 places)
Rationale for Amendment
The expression "12-lead ECG" has been deleted for expression consistency with TFLs.
Page 34, Section 7.4.5 Subgroup Analysis for China
Existing Text
Analysis Population: Subjects in China
Analytical Methods: The same analyses as those in section 7.2 to 7.4 will be conducted for the subjects in China.
Revised Text
Analysis Population: Subjects in China
Subjects in Countries other than China
Analytical Methods: (1) The same analyses as those in section 7.2 to 7.4.4 will be conducted for the subjects in 
China.
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(2) The same analyses as those in section 7.2 to 7.4.4 will be conducted for the subjects in 
countries other than China.
Rationale for Amendment
The analyses for the underlined part have been added.
Page 34, Section 7.4.6 Subgroup Analysis for Taiwan, Section 7.4.7 Subgroup Analysis for Safety Analysis Set 
Excluding Accidentally Unblinded Subjects
Added Text
7.4.6 Subgroup Analysis for Taiwan
Analysis Population: Subjects in Taiwan
Analytical Methods: (1) The same analyses as those in section 7.2 to 7.4.4 will be conducted for the subjects in 
Taiwan.
7.4.7 Subgroup Analysis for Safety Analysis Set Excluding Accidentally Unblinded Subjects
Analysis Population: Safety Analysis Set Excluding the Accidentally Unblinded Subjects
Safety Analysis Set Excluding the Accidentally Unblinded Subjects in China
Safety Analysis Set Excluding the Accidentally Unblinded Subjects in Countries other than 
China
Safety Analysis Set Excluding the Accidentally Unblinded Subjects in Taiwan
Analytical Methods: The same analyses as those in sections 7.4.1.1 and 7.4.1.2 ((1), (4) to (17)) will be conducted 
in the safety analysis set that excludes subjects who were accidentally unblinded due to IWRS 
system error.
The same analyses will be conducted for the subjects in China and countries other than China.
The same analyses will be conducted for the subjects in Taiwan.
Rationale for Amendment
The analyses for the underlined part have been added.
Page 34, Section 7.4.6 Significance Level and Confidence Coefficient
Existing Text
・
Significance level: 5% (two-sided test)
・
Confidence coefficient: 95% (two-sided)
No statistical testing will be performed if there are less than 5 subjects.
Revised Text
・
Significance level: 5% (two-sided test)
・
Confidence coefficient: 95% (two-sided)
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Template Title:
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Rationale for Amendment
The analysis plan has been changed that statistical testing will be performed even if there are less than 5 subjects.
Page 54, Section 8.0 REFERENCES
Added Text
Luo N, et. al. (2017) "Estimating an EQ-5D-5L Value Set for China", Value in Health, Volume 20(4): 662-669.
Rationale for Amendment
The above reference has been added.
Page 56, Section 9.1.1 Hematology, Serum Chemistry, Urinalysis, Vital Signs, and 12-lead ECG (except Upper 
MAV Criteria of QTcF Interval)
Existing Text
Body Temperature (°C)
Revised Text
Body Temperature (C)
Rationale for Amendment
The expression "°C" has been replaced with "C" for using more suitable expression.
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8.0
REFERENCES
・
DeLong ER, et. al. (1988) "Comparing the areas under two or more correlated receiver operating characteristic 
curves: a nonparametric approach", Biometrics, Volume 44(3): 837-45.
・
Divine G, et al. (2013) "A review of analysis and sample size calculation considerations for Wilcoxon tests", 
Anesth Analg, Volume 117(3): 699-710.
・
Lehmann EL, et. al. (1975) "Nonparametrics: statistical methods based on ranks", Springer.
・
Mason SJ, et. al. (2002) "Areas beneath the relative operating characteristics (ROC) and relative operating 
levels (ROL) curves: Statistical significance and interpretation", Quarterly Journal of the Royal Meteorological 
Society (128): 2145-2166.
・
O'Brien RG, et. al. (2006) "Exploiting the link between the Wilcoxon-Mann-Whitney test and a simple odds 
statistic", Proceedings of the Thirty-First Annual SAS Users Group International Conference.
・
Luo N, et. al. (2017) "Estimating an EQ-5D-5L Value Set for China", Value in Health, Volume 20(4): 662-669.
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9.0
APPENDIX
9.1
CRITERIA FOR MARKEDLY ABNORMAL VALUES
9.1.1
Hematology, Serum Chemistry, Urinalysis, Vital Signs, and 12-lead ECG 
(except Upper MAV Criteria of QTcF Interval)
For each parameter, all evaluable data (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.
Hematology
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Red Blood Cells (×1012/L)
<0.8×LLN
>1.2×ULN
White Blood Cells (×109/L)
<0.5×LLN
>1.5×ULN
Hemoglobin (g/L)
<0.8×LLN
>1.2×ULN
Hematocrit (%)
<0.8×LLN
>1.2×ULN
Platelets (×109/L)
<75
>600
Neutrophils (%）
<0.5×LLN
>1.5×ULN
Eosinophils (%）
-
>2×ULN
Basophils (%）
-
>3×ULN
Monocytes (%）
-
>2×ULN
Lymphocytes (%）
<0.5×LLN
>1.5×ULN
Serum Chemistry
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
ALT (U/L)
-
>3×ULN
ALP (U/L)
-
>3×ULN
AST (U/L)
-
>3×ULN
GGT (U/L)
-
>3×ULN
Total Bilirubin (μmol/L)
-
>34.2
Direct Bilirubin (μmol/L)
-
>2×ULN
CK (CPK) (U/L)
-
>5×ULN
Albumin (g/L)
<25
-
Total Protein (g/L)
<0.8×LLN
>1.2×ULN
Creatinine (μmol/L)
-
>177
BUN (mmol/L)
-
>10.7
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Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Uric Acid (mmol/L)
-
>0.773
Total Cholesterol (mmol/L)
-
>7.72
Triglycerides (mmol/L)
-
>2.5×ULN
Glucose (mmol/L)
<2.8
>19.4
Potassium (mmol/L)
<3.0
>6.0
Sodium (mmol/L)
<130
>150
Magnesium (mmol/L)
<0.5
>1.2
Calcium (mmol/L)
<1.75
>2.88
Inorganic Phosphorus (mmol/L)
<0.52
>2.00
Chloride (mmol/L)
<75
>126
Vitamin B12 (pmol/L)
<92
-
Vital Signs
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Body Temperature (C)
<35.6
>37.7
Systolic Blood Pressure (mmHg)
<85
>180
Diastolic Blood Pressure (mmHg)
<50
>110
Pulse (bpm)
<50
>120
12-lead ECG
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Heart Rate (bpm)
<50
>120
QT Interval (msec)
<=50
>=460
QTcF Interval (msec)
<=50
-
9.1.2
12-lead ECG (Upper MAV Criteria of QTcF Interval)
All evaluable data (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.
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This version replaces:
TMPL-104
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
QTcF Interval (msec)
-
If either of the following conditions is met:
・
observed value >=500
・
change from baseline >= 30 and observed value >=450
9.2
CRITERIA FOR ELEVATED LIVER ENZYME
All evaluable data (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.
i)
A subject who met criteria (a) at least once after baseline will be considered to have met the criteria for 
elevated liver enzyme.
ii)
If condition i) is not met but if criteria (b) is met at least once after baseline, then the subject will be considered 
to have not met the criteria for elevated liver enzyme.
iii)
If neither i) nor ii) is met, then the subject will be excluded from the analysis for the criteria for elevated liver 
enzyme.
Label
Criteria for Elevated Liver Enzyme
(a) Elevated
(b) Not Elevated
ALT > 3xULN
ALT is greater than 3 times the ULN
ALT is non-missing and less than or equal 
to 3 times the ULN
ALT > 5xULN
ALT is greater than 5 times the ULN
ALT is non-missing and less than or equal 
to 5 times the ULN
ALT > 8xULN 
ALT is greater than 8 times the ULN
ALT is non-missing and less than or equal 
to 8 times the ULN
ALT > 3xULN 
with Tbili > 2xULN
ALT is greater than 3 times the ULN and 
the total bilirubin is greater than twice the 
ULN
Either ALT is non-missing and less than 
or equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN
AST > 3xULN 
AST is greater than 3 times the ULN
AST is non-missing and less than or equal 
to 3 times the ULN
AST > 5xULN 
AST is greater than 5 times the ULN
AST is non-missing and less than or equal 
to 5 times the ULN
AST > 8xULN 
AST is greater than 8 times the ULN
AST is non-missing and less than or equal 
to 8 times the ULN
AST > 3xULN 
with Tbili > 2xULN
AST is greater than 3 times the ULN and 
the total bilirubin is greater than twice the 
ULN
Either AST is non-missing and less than 
or equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN
ALT or AST > 3xULN
Either ALT or AST is greater than 3 times 
the ULN
Both ALT and AST are non-missing and 
less than or equal to 3 times the ULN
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-438_305 Statistical Analysis Plan Version 2
CROSS-REGIONAL TEMPLATE
Template Number:
C-TMPL-DO-801
Page:
58 of 58
Version Number:
1.0
Effective Date:
02 Apr 2014
This version replaces:
TMPL-104
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Label
Criteria for Elevated Liver Enzyme
(a) Elevated
(b) Not Elevated
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 
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
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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