Clinical trial NCT02679508
Conditions: Erosive Esophagitis
Keywords: Esophagitis
Sponsor: Takeda
Start date: 2016-03-20; Completion date: 2022-03-05
Enrollment: 208 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is exploratorily evaluate the effect on gastric mucosal tissue and the safety of long-term administration (260 weeks: 5 years) of vonoprazan 10 mg or 20 mg in patients receiving maintenance treatment after healed erosive esophagitis (EE), and the curative effect of vonoprazan 20 mg versus lansoprazole in patients with EE.

Detailed description:
This is a multicenter, open-label, randomized, parallel-group study to exploratorily evaluate the effect on gastric mucosal tissue and the safety of long-term administration of vonoprazan in maintenance treatment after healed EE, and the curative effect of vonoprazan versus lansoprazole in participants with EE.

Participants endoscopically diagnosed with EE of Los Angeles (LA) Classification Grades A to D at the start of treatment (Week 0 of the healing phase) will be randomly assigned to receive either vonoprazan 20 mg or lansoprazole 30 mg to be taken once daily for up to 8 weeks. Subjects with healed EE as confirmed endoscopically at Week 4 or 8 in the healing phase will enter the maintenance phase.

In the maintenance phase, the vonoprazan group and the lansoprazole group will be administered a starting dose of 10 mg and 15 mg, respectively, once daily up to 260 weeks.

If the principal investigator or investigator judged the effect of vonoprazan 10 mg or lansoprazole 15 mg to be insufficient as the maintenance treatment of EE, vonoprazan and lansoprazole may be increased to 20 mg and 30 mg, respectively.

The research period will consist of two subperiods: healing phase in which participants with EE will receive treatment (for 4 or 8 weeks) and maintenance phase in which participants will receive maintenance treatment (for 260 weeks), and thus, a total of up to 268 weeks. The number of visits will be a maximum of 18 visits. Planned number of research subjects, as the number of research subjects for entry to the maintenance phase, will be 130 participants in the vonoprazan group and 65 participants in the lansoprazole group.

Arms: arm 1: Vonoprazan 20 mg administered orally once daily in the healing phase + vonoprazan 10 mg (as the initial dose and adjusted to vonoprazan 10 mg or 20 mg) administered orally once daily in the maintenance phase arm 2: Lansoprazole 30 mg administered orally once daily in the healing phase + lansoprazole 15 mg (as the initial dose and adjusted to lansoprazole 15 mg or 30 mg) administered orally once daily in the maintenance phase
Interventions: intervention 1: Vonoprazan intervention 2: Lansoprazole
Intervention descriptions: intervention 1: Vonoprazan fumarate 10 mg or 20 mg capsules intervention 2: Lansoprazole 15 mg or 30 mg capsules

Protocol documents:
Prot_000.pdf: 
Title: Vonoprazan study in patients with erosive esophagitis to evaluate long-term safety: 
A study to evaluate the safety of long-term administration of vonoprazan in 
maintenance treatment in patients with erosive esophagitis (EE) 
NCT Number: NCT02679508 
Protocol Approve Date: 10-Jun-2021 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 


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PROTOCOL 
Evaluation of Long-term Safety of Maintenance Treatment with Vonoprazan in 
Patients with Erosive Esophagitis 
Vonoprazan study in patients with erosive esophagitis to evaluate long-term safety 
(VISION) 
Protocol number 
Vonoprazan-4003 
Version Number 
Version 5 
Study drug: 
Vonoprazan fumarate 
Creation date 
6/10/2021 
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Revision history 
Date 
Revision number 
Applicable to 
January 20, 2016 
Version 1 
All the study sites 
September 17, 2019 
Version 2 
All the study sites 
August 24, 2020 
Version 3 
All the study sites 
November 10, 2020 
Version 4 
All the study sites 
February 16, 2021 
Version 4.1 
All the study sites 
June 10, 2021 
Version 5 
All the study sites 
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1.0 
STUDY PRINCIPLES AND STUDY ADMINISTRATIVE 
INFORMATION 
1.1 
Clinical research Principals 
•
This study will be conducted as a “specified clinical research” based on the Clinical
Trials Act (Act No. 16 of 2017) with the highest respect for the individual
participants in accordance with the requirements of this protocol and also in
accordance with the following: The ethical principles that have their origin in the
Declaration of Helsinki.
•
Clinical Trials Act (Act No. 16 of 2017)
•
Guideline for Good Clinical Practice (ICH-E6) (hereinafter referred to as
“ICH-GCP”).（just for a reference）
•
All applicable laws and regulations, including, without limitation, data privacy laws
and conflict of interest guidelines.
1.2 
Clinical research System 
This study will be conducted in the following system, in accordance with the protocol of 
the study, which was planned and designed by Takeda: 
Representative investigator 
Certified Review Board 
Secondary Sponsor and the person in charge of supporting the research and 
development plan 
Japan Medical Office, Japan Pharma Business Unit, Takeda 
Takeda is responsible for the planning and design, and the representative investigator 
and Takeda are responsible for the implementation and management, and the results and 
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reporting of this study. A separate procedure describes the way how outsourcing 
providers involved in this study should be supervised. 
Takeda shall pay the expenses* arising from the management of this study. 
*: Takeda shall pay the expenses arising from operations at the research office, 
monitoring activities, operations at the registration and allocation center, statistical 
analyses, and audits to outsourcing providers involved in this study, in accordance 
with the Outsourcing Contract. To study sites, Takeda shall pay the expenses at the 
agreed amount with study sites, which are calculated based on a separate document, 
Research Expenses Calculation Standard. 
Research Steering Committee 
Chairperson (who concurrently serves as “the person who directs the research”): 
 
 
Members: 
 
 
 
 
 
The Research Steering Committee shall be composed of the chairperson and members 
of the committee, and Takeda. The representative investigator and the Research 
Steering Committee shall supervise implementation and reporting of the clinical 
research, secure medical guidance of a high degree of professionalism and a high-level 
scientific quality, and revise the protocol appropriately.  
In addition, the terms used in this protocol are defined as follows: 
Study site: 
Medical institution where this clinical research will be conducted. 
Collaborative study site: 
 
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A study site where this clinical research will be collaboratively conducted in 
accordance with the protocol 
Investigator: 
A physician who is engaged in implementing a specified clinical research and 
directing research-related duties at the study site which he/she belongs to. 
Sub-investigator: 
A physician who is engaged in implementing a part of research-related duties under 
the guidance of investigator at the study site. 
Representative investigator: 
A physician who is representative of investigators of more than one study site in case of 
multicenter study.Person in charge of supporting the research and development plan:  
A person who clarifies the direction of the research as a whole, efficiently plans and 
operates a series of processes from the idea, strategy formulation to publication of 
results (or commercialization), supports the optimization of more than one 
necessitated clinical research, basic research, etc., and supports the creation of a 
framework of the most effective and efficient (optimized) clinical research plan based 
on the clinical development plan. 
Person in charge of practical coordination and management: 
A person who smoothly operates the clinical research based on the knowledge and 
means concerning the planned and efficient operational management of the clinical 
research.  
Person who directs the research: 
A person who procures research funds, etc. for the clinical research, and directs the 
clinical research.  
Research Subject: 
A person (including deceased individual) who corresponds any of the following 
descriptions: 
(1)
An individual on whom research is implemented(including an individual
asked to be enrolled in the research); or
(2)
An individual from whom existing specimen or information had arisen.
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1.3 
Contact Information on the Protocol 
 
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TABLE OF CONTENTS 
1.0 
STUDY PRINCIPLES AND STUDY ADMINISTRATIVE 
INFORMATION ..................................................................................................... 3 
1.1 
Clinical research Principals ............................................................................... 3 
1.2 
Clinical research System ................................................................................... 3 
1.3 
Contact Information on the Protocol ................................................................. 6 
2.0 
STUDY SUMMARY ............................................................................................ 12 
3.0 
ABBREVIATION ................................................................................................. 18 
4.0 
INTRODUCTION ................................................................................................. 19 
4.1 
Background ...................................................................................................... 19 
4.2 
Rationale for the proposed research ................................................................ 20 
5.0 
RESEARCH OBJECTIVES AND ENDPOINTS ................................................. 21 
5.1 
Objectives ........................................................................................................ 21 
5.2 
Definition of endpoints .................................................................................... 21 
5.2.1 Primary endpoint ....................................................................................... 21 
5.2.2 Secondary endpoints .................................................................................. 21 
5.2.3 Additional endpoints ................................................................................. 22 
6.0 
CLINICAL RESEARCH DESIGN ....................................................................... 23 
6.1 
Clinical research design ................................................................................... 23 
6.2 
Rationale for the clinical research design ........................................................ 26 
6.3 
Premature termination of entire clinical research or premature 
termination of clinical research at a study site ................................................ 27 
6.3.1 Criteria for premature termination of entire clinical research ................... 27 
6.3.2 Criteria for premature termination of study sites....................................... 27 
6.3.3 Procedures for clinical research suspension and premature 
termination of entire clinical research or study at a study site .................. 27 
6.4 
Procedures for protocol revision ..................................................................... 28 
7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
SUBJECTS ............................................................................................................ 29 
7.1 
Criteria for inclusion ........................................................................................ 29 
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7.2 
Criteria for exclusion ....................................................................................... 30 
7.3 
Prohibited concomitant drugs .......................................................................... 31 
7.4 
Research subject management ......................................................................... 32 
7.5 
Criteria for discontinuation or withdrawal of a research subject .................... 32 
7.6 
Procedures for discontinuation of individual research subjects ...................... 34 
8.0 
RESEARCH TREATMENT ................................................................................. 35 
8.1 
Study drug or control drug .............................................................................. 35 
8.1.1 Dose and administration method ............................................................... 35 
8.1.2 Overdose of the study drug ........................................................................ 37 
8.2 
Allocation of the study drug and administration procedure ............................ 37 
8.3 
Preparation and storage of allocation list ........................................................ 38 
9.0 
CLINICAL RESEARCH PROTOCOL ................................................................ 39 
9.1 
Research procedures ........................................................................................ 39 
9.1.1 Informed consent procedure ...................................................................... 39 
9.1.2 Demographic data, medical history, and previous therapeutic drugs ........ 39 
9.1.3 Physical examination ................................................................................. 40 
9.1.4 Weight, height, and BMI ........................................................................... 40 
9.1.5 Vital signs .................................................................................................. 40 
9.1.6 Concomitant drug ...................................................................................... 40 
9.1.7 Concurrent disease ..................................................................................... 40 
9.1.8 Laboratory tests ......................................................................................... 41 
9.1.9 Serum gastrin level .................................................................................... 42 
9.1.10 Pepsinogen I/II levels and serum chromogranin A level ........................... 42 
9.1.11 H. pylori urea breath test ........................................................................... 42 
9.1.12 CYP2C19 genotype testing ....................................................................... 42 
9.1.13 Endoscopy (esophagus) ............................................................................. 42 
9.1.14 Endoscopy (stomach) ................................................................................ 44 
9.1.15 Gastric mucosa histopathology .................................................................. 44 
9.1.16 Histological evaluation of gastritis according to the Sydney 
classification .............................................................................................. 46 
9.1.17 Pregnancy .................................................................................................. 46 
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9.1.18 Record of research subjects who are withdrawn before randomization .... 46 
9.1.19 Recording of randomization ...................................................................... 47 
9.2 
Compliance of research subjects ..................................................................... 47 
9.3 
Implementation time point of the test and observation items .......................... 48 
9.3.1 At the start of the healing phase [VISIT H1 (Week 0 in the healing 
phase)] ....................................................................................................... 48 
9.3.2 At the end of the healing phase [VISIT H2 (Week 4 in the healing 
phase)] ....................................................................................................... 49 
9.3.3 At the end or discontinuation of the healing phase [VISIT H3 (Week 
8 in the healing phase)] .............................................................................. 50 
9.3.4 At the start of the maintenance phase [VISIT M1 (Week 0 in the 
maintenance phase)] .................................................................................. 50 
9.3.5 Weeks 12 (VISIT M2) to 228 (VISIT M15) in the maintenance phase .... 51 
9.3.6 At the end [VISIT M16 (Week 260 in the maintenance phase)] or 
discontinuation of the maintenance phase ................................................. 51 
10.0 
ADVERSE EVENTS ............................................................................................ 53 
10.1 
Definitions ....................................................................................................... 53 
10.1.1 Adverse events and disease or the like ...................................................... 53 
10.1.2 Considerations for adverse events ............................................................. 53 
10.1.3 Serious adverse events ............................................................................... 56 
10.1.4 Severity of adverse events ......................................................................... 57 
10.1.5 Causality of adverse events ....................................................................... 57 
10.1.6 Relationship to study procedures ............................................................... 57 
10.1.7 Date of onset .............................................................................................. 58 
10.1.8 Date of resolution ...................................................................................... 58 
10.1.9 Actions taken for the study drug or control drug....................................... 59 
10.1.10Outcome .................................................................................................... 60 
10.2 
Procedures ....................................................................................................... 60 
10.2.1 Collection and reporting of adverse events ............................................... 60 
10.2.2 Collection and reporting of serious adverse events ................................... 61 
10.2.3 Reporting of additional information concerning adverse events ............... 62 
10.3 
Follow-up of serious adverse events ............................................................... 62 
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10.3.1 Reporting of serious disease or the like to the certified review board 
and regulatory authorities .......................................................................... 63 
11.0 
COMMITTEE ESTABLISHED FOR THIS CLINICAL RESEARCH ............... 64 
11.1 
Research Steering Committee ......................................................................... 64 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS ............................... 65 
12.1 
Case report form .............................................................................................. 65 
12.2 
Timing of data entry into the EDC system ...................................................... 66 
12.3 
Storage and disposal of specimens, information, etc....................................... 66 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................. 68 
13.1 
Statistical and analytical plans ......................................................................... 68 
13.1.1 Analysis set ................................................................................................ 68 
13.1.2 Analysis of demographic and other baseline characteristics ..................... 68 
13.1.3 Efficacy analysis ........................................................................................ 68 
13.1.4 Safety analysis ........................................................................................... 69 
13.2 
Criteria for interim analysis and premature discontinuation ........................... 71 
13.3 
Determination of the planned number of research subjects ............................ 71 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 73 
14.1 
Monitoring of the study site ............................................................................ 73 
14.2 
Non-compliance with the Clinical Trials Act and the protocol ....................... 73 
14.3 
Quality assurance audits and regulatory agency inspections........................... 74 
15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH .......................................... 75 
15.1 
Approval of the Certified Review Board ......................................................... 75 
15.2 
Conflict of interests ......................................................................................... 75 
15.3 
Informed consent and information sheet, and the agreement of the 
research subjects .............................................................................................. 76 
15.4 
Personal information of research subjects ....................................................... 78 
15.5 
Consultation windows for research subjects or persons related to the 
research ............................................................................................................ 79 
15.6 
Financial burden or reward to research subjects ............................................. 79 
15.7 
Benefits and inconveniences to research subjects ........................................... 79 
15.7.1 Benefits to research subjects...................................................................... 79 
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15.7.2 Inconveniences to research subjects .......................................................... 80 
15.8 
Attribution of research results and access rights ............................................. 80 
15.8.1 Attribution of research results ................................................................... 80 
15.8.2 Data access rights ...................................................................................... 80 
15.9 
Reporting of results, Publication, disclosure, and clinical research 
registration policy ............................................................................................ 80 
15.9.1 Reporting of results, publication and disclosure ....................................... 80 
15.9.2 Clinical research registration ..................................................................... 81 
15.9.3 Clinical trial results disclosure .................................................................. 81 
15.10 Insurance and compensation for injury ........................................................... 82 
16.0 
REFERENCES ...................................................................................................... 83 
LIST OF IN-TEXT TABLES 
Table 8 (a) Treatment group and administration method .................................................. 36 
Table 9 (a) 
Laboratory tests ......................................................................................... 41 
Table 9 (b) 
Classification of EE severity ..................................................................... 43 
Table 10 (a) Takeda Medically Significant Adverse Event List ....................................... 56 
LIST OF IN-TEXT FIGURES 
Figure 6 (a) Outline of clinical research design ................................................................ 26 
LIST OF APPENDICES 
......... 84 
......... 88 
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2.0 
STUDY SUMMARY 
Representative investigator: Junichi Akiyama, Center Hospital of 
the National Center for Global Health and Medicine 
Secondary Sponsor and the person in charge of supporting the 
research and development plan: Takeda 
Study drug: 
Vonoprazan fumarate 
Study title: 
Vonoprazan study In patients with erosive esophagitis to evaluate long-term safety: 
A study to evaluate the safety of long-term administration of vonoprazan in maintenance treatment in 
patients with erosive esophagitis (EE) 
Protocol number: Vonoprazan-4003 
Clinical research design: 
This is a multicenter, open-label, randomized, parallel-group study to exploratorily evaluate the effect on 
gastric mucosal tissue and the safety of long-term administration of vonoprazan in maintenance treatment 
after healed EE, and the curative effect of vonoprazan versus lansoprazole in patients with EE.  
Patients endoscopically diagnosed with EE of Los Angeles (LA) Classification Grades A to D at the start 
of treatment (Week 0 of the healing phase) will be randomly assigned to receive either vonoprazan 20 mg 
or lansoprazole 30 mg to be taken once daily for up to 8 weeks. Subjects with healed EE as confirmed 
endoscopically at Week 4 or 8 in the healing phase will enter the maintenance phase. 
In the maintenance phase, the vonoprazan group and the lansoprazole group will be administered a 
starting dose of 10 mg and 15 mg, respectively, once daily up to 260 weeks.  
If the investigator or sub-investigator judged the effect of vonoprazan 10 mg or lansoprazole 15 mg to be 
insufficient as the maintenance treatment of EE, vonoprazan and lansoprazole may be increased to 20 mg 
and 30 mg, respectively. 
The research period will consist of two subperiods: healing phase in which patients with EE will receive 
treatment (for 4 or 8 weeks) and maintenance phase in which patients will receive maintenance treatment 
(for 260 weeks), and thus, a total of up to 268 weeks. The number of visits will be a maximum of 18 
visits. Planned number of research subjects, as the number of research subjects for entry to the 
maintenance phase, will be 130 patients in the vonoprazan group and 65 patients in the lansoprazole 
group.  
In addition to the final analysis using data up to the final VISIT, interim analysis using data up to the 
pre-defined VISIT will be performed once a year during the maintenance phase to evaluate the effect of 
long term administration of vonoprazan on gastric mucosal tissue as maintenance treatment in patients 
with recurrent/reactivated erosive esophagitis when data up to the pre-defined VISIT (Week 48 [VISIT 
M5], Week 108 [VISIT M10], Week 156 [VIST M12], and Week 204 [VIST M14] in the maintenance 
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phase) is collected from all the subjects . The interim analysis is not intended to use decision whether to 
continue or terminate this study. 
Objective: 
To exploratorily evaluate the effect on gastric mucosal tissue and the safety of long-term administration 
(260 weeks: 5 years) of vonoprazan 10 mg or 20 mg in patients receiving maintenance treatment after 
healed EE, and the curative effect of vonoprazan 20 mg versus lansoprazole in patients with EE. 
Study population: 
Healing phase: Patients with EE 
Maintenance phase: Patients included for maintenance treatment after healed EE 
Planned number of research subjects: 
As the number of research subjects for entry to the maintenance 
phase, 
Vonoprazan group: 130 patients 
Lansoprazole group: 65 patients 
Number of study sites: 
Approximately 30 sites 
Dose and method of administration: 
< Healing phase > 
Vonoprazan group: Vonoprazan 20 mg orally administered once 
daily 
Lansoprazole group: Lansoprazole 30 mg orally administered once 
daily 
< Maintenance phase > 
Vonoprazan group: Vonoprazan 10 mg or 20 mg orally administered 
once daily 
Lansoprazole group: Lansoprazole 15 mg or30 mg orally 
administered once daily 
Route of administration: 
Oral 
Duration of treatment: 
Healing phase: 4 or 8 weeks 
Maintenance phase: 260 weeks 
Duration of evaluation: 
Healing phase: 4 or 8 weeks 
Maintenance phase: 260 weeks 
Total: 264 or 268 weeks 
Criteria for inclusion: 
Research subjects shall fulfill all of the following criteria to be included in this clinical research. 
< At the start of healing phase > 
1.
Patients endoscopically diagnosed with EE of grades A to D by the LA Classification Grading
System at the start of treatment (Week 0 of the healing phase).
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2.
Patients with H. pylori negative.
3.
Patients who, in the opinion of the investigator or sub-investigator, are capable of understanding the
content of the clinical research and complying with the protocol requirements.
4.
Patients who can sign and date an informed consent form and information sheet prior to the
conduction of the clinical research procedures.
5.
Male or female patients aged 20 years or older at the time of informed consent.
6.
Therapeutic category: Ambulatory.
< At the start of maintenance phase > 
7.
Patients who have endoscopically confirmed EE healing* (mucous membrane disorder is not
observed) at completion of the healing phase (Week 4 or 8 of the healing phase).
* Patients who are classified as grade 0 according to severity classification of EE (See Table 9.b)
8.
Patients who have been determined to be appropriate as subjects for maintenance treatment of EE by
the investigator or sub-investigator.
Criteria for exclusion: 
Research subjects meeting any of the criteria below shall not be included in this research. 
< At the start of healing phase > 
1.
Patients with concurrent peptic ulcer (except scarred stage) or Zollinger-Ellison syndrome.
2.
Patients who received treatment with PPIs (including vonoprazan) within 4 weeks (Week -4 to
Week 0) prior to the start of healing phase (Week 0 of the healing phase).
3.
Patients with a history of H. pylori eradication.
4.
Patients who have received surgery or treatment affecting gastroesophageal reflux (fundoplication or
dilation for esophageal stenosis [excluding Schatzki's ring], etc.) .
5.
Patients with an esophagus-related complication (eosinophilic esophagitis, esophageal varices,
scleroderma, viral or fungal infection, esophageal stenosis, etc.), a history of radiotherapy or
cryotherapy of the esophagus, a caustic or physiochemical trauma (esophageal sclerotherapy, etc.).
However, participants with Schatzki's ring (mucosal tissue ring around inferior esophageal
sphincter) or Barrett's esophagus are allowed to be included.
6.
Patients with clinically apparent hepatic impairment (e.g., AST or ALT levels at the time of
informed consent: >1.5 times the upper limit of normal (ULN).
7.
Patients with renal impairment or renal failure [creatinine clearance (CCr) ˂30 mL/min, etc.]
8.
Patients with a history of hypersensitivity or allergy for PPIs.
9.
Patients with a history of gastrectomy, gastrointestinal resection, or vagotomy.
10.
Patients with a malignant tumor.
11.
Patients who are pregnant, breast-feeding, possibly pregnant, or planning to become pregnant
12.
Patients with one of the diseases listed under administration contraindication in the vonoprazan or
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lansoprazole package insert. 
13.
Patients planning to take prohibited concomitant medications during the research period.
14.
Patients participating in other clinical studies.
15.
Patients who have been determined to be inappropriate as subjects in the study by the investigator or
sub-investigator.
<At the start of maintenance phase > 
16.
Patients who have taken PPIs other than the study drug or the control drug during the healing phase.
17.
Patients who have been determined to be inappropriate as subjects in the study by the investigator or
sub-investigator.
Endpoints: 
Primary endpoint: 

Histopathological examination of gastric mucosa
Presence/absence of

Malignant transformation of epithelial cells

Parietal cell protrusion (PCP)/hyperplasia

Crypt epithelial hyperplasia

Endocrine cell proliferation

G-cell hyperplasia
Secondary endpoints: 
Efficacy endpoints: 

Endoscopic EE recurrence rate

EE healing rate at completion of the healing phase
Safety endpoints: 

Adverse events

Endoscopic findings
    Presence/absence of 

Fundic gland polyp

Hyperplastic polyp
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
Cobblestone mucosa

Multiple white and flat elevated lesions

Black spots

Histological assessment of gastritis using the Sydney classification

Inflammation (mononuclear cell infiltration)

Active (neutrophil infiltration)

Atrophy

Intestinal metaplasia

H. pylori

Incidence of gastric polyp
< Additional endpoints > 

Serum gastrin level

Pepsinogen I and II levels

Pepsinogen I/II ratio

Serum chromogranin A level

Laboratory test (AST, ALT, Fe, Mg, Ca, vitamin B12)

Barrett’s esophagus

Esophageal hiatal hernia
Statistical method: 
Percentage of “presence” of each of the variables in histopathological examination of gastric mucosa 
(presence/absence of malignant transformation of epithelial cells, parietal cell protrusion 
/hyperplasia, crypt epithelial hyperplasia, endocrine cell proliferation, G-cell hyperplasia) in the 
“safety analysis set in the maintenance phase” will be calculated by assessment time point and 
treatment group. 
Rationale for the number of planned research subjects: 
As the number of research subjects for entry to the maintenance phase, 
Vonoprazan group: 130 subjects 
Lansoprazole group: 65 patients  
[Rationale for the number of planned research subjects] 
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In view of the withdrawal rate over 1 year (52 weeks) in the vonoprazan study conducted in Japan, and 
for integration of data regarding the effect of long-term administration on gastric mucosal tissue and 
further safety data in the vonoprazan group, the number of research subjects for entry to the maintenance 
phase, considering the feasibility, was determined to be a total of 130 as the number of randomized 
subjects in the vonoprazan group. Referring to the vonoprazan studies conducted in the past, at least 
approximately 100 patients, 50 patients, and 30 patients can be expected to be recruited in 1 year, 3 years, 
and 5 years, respectively. In this study, for the exploratory evaluation with lansoprazole as a control, the 
number of patients in the lansoprazole group was determined to be 65 with a 2:1 ratio between 
vonoprazan and lansoprazole groups.  
These numbers were not determined on a statistical basis.   
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3.0 
ABBREVIATION 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
COI 
conflict of interest 
CRO 
contract research organization 
EDC 
electronic data capture 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
H. pylori 
helicobacter pylori
ICH 
International Conference on 
Harmonisation 
LA 
classification 
Los Angeles classification 
MedDRA 
Medical Dictionary for Regulatory 
Activities 
PPI 
proton pump inhibitor  
TEAE 
treatment emergent adverse event 
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4.0 
INTRODUCTION 
4.1 
Background 
The prevalence of erosive esophagitis (erosive GERD) in Japan, which used to be 
considered lower than that in the West, has reportedly been increasing since the late 
1990s. 1) This increase may be primarily due to westernization of diets and decreased 
prevalence of H. pylori in young people, which affect gastric acid secretion.  
Erosive esophagitis (erosive GERD) is caused by reflux of gastric acid due to relaxation 
of the inferior esophageal sphincter, reduced esophageal clearance function, impaired 
esophageal mucosal defense mechanisms, etc. Severity of erosive esophagitis is 
correlated with the duration of esophageal exposure to acid and pH of refluxed gastric 
contents. In the treatment of erosive esophagitis, therefore, drugs that can suppress 
gastric acid secretion more strongly and more continuously may be more effective in 
healing it.  
The first choice for initial treatment of erosive esophagitis is proton pump inhibitors 
(PPIs), which suppress gastric acid secretion effectively. PPIs are highly effective for 
erosive esophagitis, with high healing rates known to range from 80% to 90% at Week 
8 of treatment 2); however, it has been reported that healing rates at Week 8 of PPI 
treatment were lower in patients with endoscopically more severe disease at baseline. 3) 
In addition, erosive esophagitis is known to often recur, and repeated healing and 
recurrence may result in increased risk of complications such as Barrett’s esophagus and 
esophageal stenosis. For prevention of recurrent erosive esophagitis, continuous drug 
therapy (maintenance treatment) is important; in particular, the Guidelines for 
Management of Gastroesophageal Reflux Disease published by the Japanese Society of 
Gastroenterology recommend aggressive maintenance treatment for severe erosive 
esophagitis. Maintenance treatment is intended to prevent recurrence and is therefore 
administered on a long-term basis in some patients. Accordingly, it is very important to 
establish the safety of long-term maintenance treatment.  
It has been concerned that conventional PPIs, especially when used for a long period of 
time, may induce carcinoid tumor due to increased serum gastrin, impair absorption of 
vitamins, and accelerate the progression of atrophic gastritis by suppressing gastric acid 
secretion; however, long-term outcomes in and outside Japan show that long-term use 
was associated with few clinical problems. 4)5)  
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On the other hand, vonoprazan is an acid suppressant in a new category that suppresses 
gastric acid secretion more strongly and more continuously than conventional PPIs by 
reversibly inhibiting H+, K+ -ATPase in the final stage of acid secretion in a K +
-competitive manner. In a 1-year long-term clinical research of vonoprazan, serum 
gastrin levels tended to increase, as did with PPIs; however, serum gastrin had no effect 
on neuroendocrine cells in the fundic glands or no great effect on neuroendocrine cells 
(Grimelius-positive cells, chromogranin A-positive cells, and synaptophysin-positive 
cells) in the fundic gland. These results indicate that vonoprazan is a new acid 
suppressant with a safety profile similar to that of conventional PPIs. However, since 
there have been few reports of long-term treatment with vonoprazan, safety data 
collected during long-term treatment will be useful in maintenance treatment of erosive 
esophagitis.
The present study will be conducted in patients with erosive esophagitis to evaluate the 
effect on gastric mucosa and safety of vonoprazan 10 mg or 20 mg given for 260 weeks 
(5 years) as maintenance treatment on an exploratory basis with lansoprazole as control, 
with an aim to evaluate the long-term safety of vonoprazan in patients under 
maintenance treatment. 
4.2 
Rationale for the proposed research 
This study will be conducted in patients with recurrent/reactivated erosive esophagitis 
(EE) to evaluate the effect on gastric mucosa and safety of vonoprazan 10 mg or 20 mg 
given for 260 weeks as maintenance treatment or for up to 268 weeks including the 
healing phase, with an aim to provide long-term maintenance treatment of EE and 
contribute to prevention of recurrence.  
Meanwhile, this study is not planned as an additional pharmacovigilance activity in the 
risk management plan of vonoprazan. 
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5.0 
RESEARCH OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
To evaluate the effect on gastric mucosa and safety of long-term treatment (260 weeks: 
5 years) with vonoprazan 10 mg or 20 mg in patients under maintenance treatment of 
recurrent/reactivated EE as well as the healing efficacy of vonoprazan 20 mg in patients 
with EE on an exploratory basis with lansoprazole as control  
5.2 
Definition of endpoints 
5.2.1 Primary endpoint 
Gastric mucosa histopathology

Presence or absence of malignant alteration of epithelial cells

Presence or absence of prominence/hyperplasia of wall cells

Presence or absence of hyperplasia of crypt epithelial cells

Presence or absence of proliferation of endocrine cells

Presence or absence of hyperplasia of G cells
5.2.2 Secondary endpoints 
Efficacy endpoints 
Endoscopic EE recurrence rate
EE healing rate at the end of the healing phase
Safety endpoints 
Incidence of adverse events
Endoscopic findings

Presence or absence of fundic gland polyp

Presence or absence of hyperplastic polyp

Presence or absence of cobblestone mucosa

Presence or absence of multiple white flat elevation

Presence or absence of black spots
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Histological evaluation of gastritis according to the Sydney classification

Inflammation (mononuclear infiltration)

Activity (neutrophilic infiltration)

Atrophy

Intestinal metaplasia

H. pylori
Incidence of gastric polyp
5.2.3 Additional endpoints 
Serum gastrin level
Pepsinogen I/II levels
Pepsinogen I/II ratio
Serum chromogranin A level
Laboratory test (AST, ALT, Mg, Fe, Ca, and vitamin B12)
Barrett’s esophagus
Esophageal hiatal hernia
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6.0 
CLINICAL RESEARCH DESIGN 
6.1 
Clinical research design 
<Clinical research design> 
This is a multicenter, open-label, randomized, parallel-group study to exploratorily 
evaluate the effect on gastric mucosal tissue and the safety of long-term 
administration of vonoprazan in maintenance treatment after healed EE, and the 
curative effect of vonoprazan versus lansoprazole in patients with EE.  
Patients endoscopically diagnosed with EE of Los Angeles (LA) Classification 
Grades A to D at the start of treatment (Week 0 of the healing phase) will be 
randomly assigned to receive either vonoprazan 20 mg or lansoprazole 30 mg to be 
taken once daily for up to 8 weeks. Subjects with healed EE as confirmed 
endoscopically at Week 4 or 8 in the healing phase will enter the maintenance 
phase. 
In the maintenance phase, the vonoprazan group and the lansoprazole group will be 
administered a starting dose of 10 mg and 15 mg, respectively, once daily up to 260 
weeks.  
If the investigator or sub-investigator judged the effect of vonoprazan 10 mg or 
lansoprazole 15 mg to be insufficient as the maintenance treatment of EE, 
vonoprazan and lansoprazole may be increased to 20 mg and 30 mg, respectively. 
The research period will consist of two subperiods: healing phase in which patients 
with EE will receive treatment (for 4 or 8 weeks) and maintenance phase in which 
patients will receive maintenance treatment (for 260 weeks), and thus, a total of up 
to 268 weeks. The number of visits will be a maximum of 18 visits. Planned 
number of research subjects, as the number of research subjects for entry to the 
maintenance phase, will be 130 patients in the vonoprazan group and 65 patients in 
the lansoprazole group.  
In addition to the final analysis using data up to the final VISIT, interim analysis 
using data up to the pre-defined VISIT will be performed once a year during the 
maintenance phase to evaluate the effect of long term administration of vonoprazan 
on gastric mucosal tissue as maintenance treatment in patients with 
recurrent/reactivated erosive esophagitis when data up to the pre-defined VISIT 
(Week 48 [VISIT M5], Week 108 [VISIT M10], Week 156 [VIST M12], and Week 
204 [VIST M14] in the maintenance phase) is collected from all the subjects. The 
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interim analysis is not intended to use decision whether to continue or terminate 
this study. 
<Study treatment> 
1.
Drugs to be administered
Vonoprazan or lansoprazole shall be administered.
2.
Start of study drug administration and dose
After acquisition of informed consent, research subjects determined eligible for the
study in accordance with the inclusion and exclusion criteria shall enter the healing
phase to orally receive vonoprazan 20 mg (once daily) or lansoprazole 30 mg (once
daily).
Research subjects with healed EE as confirmed endoscopically at the end of the
healing phase (Week 4 or 8 in the healing phase) shall enter the maintenance phase
to orally receive vonoprazan 10 mg (once daily) or lansoprazole 15 mg (once
daily).
Research subjects with no endoscopic healing of EE at the end of the healing phase
(Week 8 in the healing phase) shall complete the study without entering the
maintenance phase.
If the investigator or sub-investigator determines that maintenance treatment of EE
with vonoprazan 10 mg or lansoprazole 15 mg is not sufficiently effective in the
maintenance phase, the dose may be increased to vonoprazan 20 mg or lansoprazole
30 mg. There will be no criteria for dose reduction.
3.
Duration of treatment
Healing phase: up to 8 weeks
Maintenance phase: 260 weeks
<Planned duration of participation and number of visits for research subjects> 
In this study, the duration of the study will be a maximum of 268 weeks, including the 
8-week healing phase and the 260-week maintenance phase. During the healing phase, 
research subjects shall visit the study site at the start (Week 0) and end [(Week 4)
(Week 8 for subjects with no endoscopic healing of EE at Week 4 in the healing phase)] 
of the healing phase.
 
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Research subjects with healed EE as confirmed endoscopically at the end of the healing 
phase shall enter the maintenance phase and visit the study site every 12 weeks up to 
Week 108 in the maintenance phase. After that, research subjects visit the study site 
every 24 weeks up to Week 228 in the maintenance phase and the final VISIT is the end 
of the maintenance phase (Week 260). The number of visits will be a maximum of 18, 
including a maximum of 3 in the healing phase and 16 in the maintenance phase.  
<Planned number of research subjects> 
As the number of research subjects for entry to the maintenance phase, 
Vonoprazan group 
 130 subjects 
Lansoprazole group 
 65 subjects 
<Number of study sites> 
Approximately 30 sites 
Figure 6 (a) shows a schematic of the clinical research design. Refer to 
 for 
schedule of examinations, observations, and assessments. 
<Outline of clinical research> 
Healing phase: 4 or 8 weeks 
Maintenance phase: 260 weeks 
Number of visits: up to 18 
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<Rationale for the planned number of research subjects> 
Refer to Section 13.3. 
6.3 
Premature termination of entire clinical research or premature termination 
of clinical research at a study site 
6.3.1 Criteria for premature termination of entire clinical research 
The representative investigator, the person who directs the research, and Takeda should 
immediately discontinue the study when at least one of the following criteria is 
applicable: 

When new information or other evaluation on the safety or efficacy of the study
drug or control drug becomes available that shows a change in the known
risk/benefit profile of the concerned compound, and risks/benefits are no longer
tolerable for research subject participation in the study.

When there is serious deviation from the Clinical Trials Act or ICH-GCP that may
threaten safety of the research subjects.
6.3.2 Criteria for premature termination of study sites 
Termination of involvement of a study site in the study may be requested prematurely at 
the discretion of the representative investigator, the person who directs the research, or 
Takeda if the entity (e.g., investigator) is found in significant violation of the Clinical 
Trials Act protocol, or contractual agreement, or is unable to ensure proper conduct of 
the research. 
6.3.3 Procedures for clinical research suspension and premature termination of 
entire clinical research or study at a study site 
In the event that the representative investigator, the person who directs the research, 
Takeda, or the certified review board decides to prematurely suspend or terminate the 
entire clinical research or clinical research at a study site, a study-specific procedure in 
accordance with the Clinical Trials Act shall be discussed among the representative 
investigator, the person who directs the research, and Takeda , and its discussion results 
shall be presented. The procedure shall be followed by the applicable study sites during 
the course of clinical research suspension or premature termination. 
 
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6.4 
Procedures for protocol revision 
If the protocol needs to be revised, the representative investigator, the person who 
directs the research, and Takeda shall consider and decide whether to revise the protocol. 
The investigator of each study site shall be informed of the details of each protocol 
revision after obtaining approval from the certified review board. Investigators shall 
confirm the content of the revision of the protocol and submit a letter of agreement to 
Takeda as evidence of agreement with the protocol revision. 
The protocol shall be revised only when it meets the following criteria, and not be 
revised for minor changes that do not meet the following criteria. 
[Protocol revision is required in the following cases:] 
1. Change or addition of objectives;
2. Change in or addition of efficacy or safety evaluation methods;
3. More frequent or additional laboratory tests for which research subjects incur
additional expenses or changes in laboratory test methods;
4. Change in dose (including adding an additional treatment group);
5. Significant change in or addition of inclusion and/or exclusion criteria;
6. Change in the planned number of research subjects;
7. Change in plans or in description of the protocol due to serious adverse events or
other reasons; and
8. Change which is considered as a significant change, as a result of discussion among
the representative investigator, the person who directs the research, and Takeda.
Upon notification, the investigator at each study site shall obtain approval from the 
supervisor of the study site based on review results of the certified review board. 
according to institutional regulations.  
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7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
SUBJECTS 
Before the start of the healing phase and the start of maintenance phase, the research 
subject’s data, including test results, should be checked against all of the 
inclusion/exclusion criteria. 
7.1 
Criteria for inclusion 
Research subjects shall fulfill all of the following criteria to be included in this clinical 
research. 
<At the start of healing phase> 
1. Patients endoscopically diagnosed with EE of grades A to D by the LA
Classification Grading System at the start of treatment (Week 0 of the healing
phase).
2. Patients with H. pylori negative.
3. Patients who, in the opinion of the investigator or sub-investigator, are capable
of understanding the content of the clinical research and complying with the
protocol requirements.
4. Patients who can sign and date an informed consent form and information sheet
prior to the conduction of the clinical research procedures.
5. Male or female patients aged 20 years or older at the time of informed consent
6. Therapeutic category: Ambulatory.
<At the start of maintenance phase> 
7. Patients who have endoscopically confirmed EE healing* (mucous membrane
disorder is not observed) at completion of the healing phase (Week 4 or 8 of the
healing phase).
* Patients who are classified as grade 0 according to severity classification of
EE (See Table 9.b).
8. Patients who have been determined to be appropriate as subjects for maintenance
treatment of EE by the investigator or sub-investigator.
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[Rationale for the inclusion criteria] 
1.3.4.6. - 8. These were set as essential conditions for the clinical research. 
2.
The Japanese Guidelines for the Management of Helicobacter Pylori
Infection in 2009 6) recommend eradication of H. pylori for people
infected with H. pylori, with no exception for those with erosive
esophagitis. On the grounds that eradication of H. pylori should precede
treatment of EE, therefore, this criterion was set.
5.
This was set to allow for separate assessment of male/female. The
lower age limit was set to 20 years to allow patients to make a
voluntary decision regarding their participation in this clinical research.
7.2 
Criteria for exclusion 
Research subjects meeting any of the criteria below shall not be included in this 
research. 
<At the start of healing phase> 
1. Patients with concurrent peptic ulcer (except scarred stage) or Zollinger-Ellison
syndrome.
2. Patients who received treatment with PPIs (including vonoprazan) within 4
weeks (Week -4 to Week 0) prior to the start of healing phase (Week 0 of the
healing phase).
3. Patients with a history of H. pylori eradication.
4. Patients who have received surgery or treatment affecting gastroesophageal
reflux (fundoplication or dilation for esophageal stenosis [excluding Schatzki's
ring], etc.).
5. Patients with an esophagus-related complication (eosinophilic esophagitis,
esophageal varices, scleroderma, viral or fungal infection, esophageal stenosis,
etc.), a history of radiotherapy or cryotherapy of the esophagus, a caustic or
physiochemical trauma (esophageal sclerotherapy, etc.). However, participants
with Schatzki's ring (mucosal tissue ring around inferior esophageal sphincter)
or Barrett's esophagus are allowed to be included.
6. Patients with clinically apparent hepatic impairment (e.g., AST or ALT levels at
the time of informed consent: >1.5 times the upper limit of normal (ULN).
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7. Patients with renal impairment or renal failure [creatinine clearance (CCr) ˂30
mL/min, etc.]
8. Patients with a history of hypersensitivity or allergy for PPIs.
9. Patients with a history of gastrectomy, gastrointestinal resection, or vagotomy.
10. Patients with a malignant tumor.
11. Patients who are pregnant, breast-feeding, possibly pregnant, or planning to
become pregnant.
12. Patients with one of the diseases listed under administration contraindication in
the vonoprazan or lansoprazole package insert.
13. Patients planning to take prohibited concomitant medications during the research
period.
14. Patients participating in other clinical studies
15. Patients who have been determined to be inappropriate as subjects in the study
by the investigator or sub-investigator.
<At the start of maintenance phase> 
16. Patients who have taken PPIs other than the study drug or the control drug
during the healing phase.
17. Patients who have been determined to be inappropriate as subjects in the study
by the investigator or sub-investigator.
[Rationale for the exclusion criteria] 
1.4. - 10. 
These were set in consideration of safety of the research subjects. 
2.16. 
This was set because it would affect pharmacometrics. 
3.
This was set to eliminate any effect of H. pylori infection or eradication
of H. pylori on gastric mucosa.
11. - 15.17. These were set as fundamental items for the research.
7.3 
Prohibited concomitant drugs 
The following drugs should not be used concomitantly with the study drug or control 
drug during the study: 
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1.
Drugs with which vonoprazan or lansoprazole should not be used concomitantly
according to the package insert.
2.
PPIs other than the study drug or control drug.

Omeprazole

Esomeprazole

Rabeprazole, etc.
[Rationale for the prohibited concomitant drugs] 
1.
These were set in consideration of safety of the research subjects.
2.
These were set because they would affect pharmacometrics.
7.4 
Research subject management 
The investigator and sub-investigator shall instruct research subjects to adhere to the 
following throughout the research period:  
1. Adhere to the instructions or restrictions prescribed in the research period
(compliance with study or control treatment, prohibited concomitant drugs).
2. Inform the investigator or sub-investigator of any planned treatment by another
physician. Promptly report any treatment done by another physician.
3. Visit the study site as scheduled to undergo physical examination or other
specified tests. Cancel an appointment for study visit in a timely manner if
applicable.
4. Visit the study site after at least 10 hours of fasting when endoscopy or
laboratory test (e.g., serum gastrin level, pepsinogen I/II levels, Fe, vitamin B12)
is scheduled. Visit the study site without taking the study drug or control drug.
5. Avoid excessive eating or drinking, excessive diet change (e.g., change to
extremely high-fat diet), and excessive exercise throughout the research period.
7.5 
Criteria for discontinuation or withdrawal of a research subject 
The investigator or sub-investigator shall record the main reason for discontinuation of 
protocol treatment on the case report form (CRF) according to the classification 
described below. Refer to Section 9.1.18 for research subjects who withdraw from the 
research before randomization. 
 
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1. Adverse event
When the research subject had an adverse event that requires withdrawal of the
research subject from the study because continued participation in the study would
impose an unacceptable risk to the research subject’s health, or when the research
subject is unwilling to continue study participation because of the adverse event.
2. Major protocol deviation
When it is discovered after randomization that a research subject does not meet the
eligibility criteria or is not adhering to the protocol, and continued participation in
the research would impose an unacceptable risk to the research subject’s health.
3. Lost to follow-up
When the research subject failed to make visits and could not be contacted. The
attempts that were made to contact the research subject shall be recorded in the
source documents.
4. Voluntary termination
When the research subject wishes to withdraw from the research. The reason for
discontinuation shall be recorded on the CRF when it is clarified.
Note: Every effort shall be made to clarify the reason for voluntary termination
(discontinuation due to an adverse event is not classified into “voluntary 
termination”).  
5. Research termination
When the representative investigator, the person who directs the research, Takeda,
the certified review board, or the regulatory authority has decided to terminate the
study. Refer to Section 6.3.1 for details.
6. Pregnancy
When a female research subject is found to be pregnant.
Note: Research participation shall be immediately discontinued when pregnancy is
known. Refer to Section 9.1.17. 
7. Lack of efficacy
When efficacy of the study drug or control drug is not evident and continuation of
the research may pose an unacceptable risk to the research subjects in the opinion of
the investigator or sub-investigator.
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8. Others
When the investigator or sub-investigator decides to withdraw the research subject
from the study for any other reason.
Note: The specific reasons should be recorded on the CRF.
7.6 
Procedures for discontinuation of individual research subjects 
The investigator or sub-investigator shall terminate a research subject’s research 
participation when the research subject meets the criteria described in Section 7.5. 
Individual research subjects may discontinue their research participation without giving 
a reason at any time during the research. Should a research subject’s participation be 
discontinued, the primary reason for termination shall be recorded on the CRF by the 
investigator or sub-investigator. In addition, efforts shall be made to perform all 
tests/observations/evaluations scheduled at the time of discontinuation. 
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8.0 
RESEARCH TREATMENT 
This section indicates the treatment regimen of this clinical research. Information on all 
treatment regimens prescribed in the protocol will be stated. See the latest package 
insert for details and handling of each drug. 
8.1 
Study drug or control drug 
Study drug: 
Generic name: vonoprazan fumarate [JAN] 
Chemical name: 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]- 
N-methylmethanamine monofumarate
Control drug:  
Generic name: lansoprazole [JAN] 
Chemical name: 
(RS )-2-({[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl) 
benzimidazole 
8.1.1 Dose and administration method 
The investigator or sub-investigator shall orally administer the study drug or control 
drug to research subjects as shown in Table 8.a.  
In the healing phase, vonoprazan 20 mg or lansoprazole 30 mg shall be orally 
administered once daily for 4 or 8 weeks.  
In the maintenance phase, vonoprazan 10 mg or lansoprazole 15 mg shall be orally 
administered as the initial dose once daily for 260 weeks. If vonoprazan 10 mg or 
lansoprazole 15 mg is not sufficiently effective, the dose may be increased to 
vonoprazan 20 mg or lansoprazole 30 mg, which shall also be orally administered once 
daily.  
Research subjects shall be instructed to visit the study site for this study without taking 
the study drug or control drug throughout the healing phase and maintenance phase. 
At the start of the healing phase (VISIT H1), research subjects who enter the healing 
phase shall be administered the study drug or control drug for the day after the 
completion of tests/observations/evaluations and then released from the study site.  
 
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Research subjects with healed EE as confirmed endoscopically at Week 4 in the healing 
phase (VISIT H2) shall complete the study or control treatment for the healing phase. 
Research subjects with no healing shall be administered the study drug or control drug 
for the day and then released from the study site.  
Research subjects with healed EE as confirmed endoscopically at Week 8 in the healing 
phase (VISIT H3) shall complete the study or control treatment for the healing phase. 
Research subjects with no healing shall complete this study and then receive treatment 
in accordance with normal medical practice.  
At the start of the maintenance phase (VISIT M1), research subjects who enter the 
maintenance phase shall be administered the study drug or control drug for the day after 
the completion of tests/observations/evaluations and then released from the study site. 
Likewise at Week 12 in the maintenance phase (VISIT M2) and subsequent study visits, 
research subjects shall be administered the study drug or control drug for the day after 
the completion of tests/observations/evaluations and then released from the study site.  
Table 8 (a) Treatment group and administration method 
Healing phase 
Treatment group 
Dose 
Administration method 
Vonoprazan group 
Vonoprazan 20 mg 
Orally administered once daily 
Lansoprazole group 
Lansoprazole 30 mg 
Orally administered once daily 
Maintenance phase 
Treatment group 
Dose 
Administration method 
Vonoprazan group 
Vonoprazan 10 mg as the initial dose and 
adjusted to vonoprazan 10 mg or 20 mg 
Orally administered once daily 
Lansoprazole group 
Lansoprazole 15 mg as the initial dose 
and adjusted to lansoprazole 15 mg or 
30 mg 
Orally administered once daily 
<Criteria for dose change> 
If the investigator or sub-investigator determines that maintenance treatment of EE with 
vonoprazan 10 mg or lansoprazole 15 mg is not sufficiently effective during the 
 
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maintenance phase, the dose may be increased to vonoprazan 20 mg or lansoprazole 30 
mg. There will be no criteria for dose reduction.  
Any dose change shall be recorded with dates of administration at the altered dose on 
the CRF.  
Research subjects for whom the dose is changed shall be administered the study drug or 
control drug for the day and then released from the study site.  
<Orally disintegrating tablet> 
Lansoprazole may be administered in the form of orally disintegrating tablet instead of 
capsule.  
8.1.2 Overdose of the study drug 
Overdose is defined as intentional or accidental administration of the study drug or 
control drug at a higher dose than that specified in the protocol, either by a health 
professional or by the research subject. 
To consistently collect important safety information about overdose, the investigator or 
sub-investigator shall record all cases of overdose on the “Overdose” page of the CRF, 
irrespective of the presence or absence of accompanying adverse event. Adverse events 
associated with overdose shall be recorded on the “Adverse events” page of the CRF, in 
accordance with the procedures described in Section 10.0, “ADVERSE EVENTS.” 
In addition, serious adverse events associated with overdose shall be recorded in 
accordance with the procedures described in Section 10.2.2, “Collection and reporting 
of SAEs.” 
In the event of overdose, the investigator or sub-investigator shall treat the subject as 
required based on symptoms.  
8.2 
Allocation of the study drug and administration procedure 
The investigator or sub-investigator shall access the web subject registration system for 
assignment of research subjects. On that occasion, the investigator or the designee shall 
notify necessary information for assignment such as research subject ID codes. 
Subsequently, the drug to be administered to each research subject shall be notified via 
the web registration system. The investigator or sub-investigator shall prescribe the 
study drug or control drug according to the notification and record the drug information 
on the CRF of each research subject.  
 
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8.3 
Preparation and storage of allocation list 
The allocation responsible person (designated by Takeda) shall create an allocation list 
and manage allocation information. Information on the allocation shall be kept in a safe 
place and shall not be available to anyone other than authorized persons, to secure 
independency from the clinical research. 
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9.0 
CLINICAL RESEARCH PROTOCOL 
9.1 
Research procedures 
The investigator or sub-investigator shall collect data in accordance with the procedure 
below. The same investigator or sub-investigator shall perform 
tests/observations/evaluation of research subjects, in principle. The study schedule is 
provided in 
. 
9.1.1 Informed consent procedure 
The procedures for obtaining informed consent are described in Section 15.3. 
Consent shall be obtained from the research subject before initiation of research 
procedures. 
Research subject ID code shall be given to each research subject from whom informed 
consent has been acquired. The research subject ID code shall be used throughout the 
research period and shall not be changed. 
9.1.2 Demographic data, medical history, and previous therapeutic drugs 
Demographic data shall be collected regarding date of birth, gender, smoking history, 
drinking history, and consumption of caffeine-containing beverage. 
Medical history data shall be collected regarding clinically problematic diseases or 
symptoms that disappeared or were terminated within 1 year from the start of the 
healing phase. When the symptoms or disease persists, it shall be considered as a 
concurrent disease (Refer to Section 9.1.7). 
EE
Other upper gastrointestinal diseases (non-erosive gastroesophageal reflux
disease, gastric ulcer, and duodenal ulcer) and treatments
Previous therapeutic drug data shall be collected regarding the following drugs used 
within 12 weeks before the start of the healing phase and that are related to criteria for 
eligibility and assessment of efficacy/safety in terms of drug name (trade name or 
generic name) and treatment end date.  
PPIs (including vonoprazan)
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9.1.3 Physical examination 
All subsequent physical examinations after the start of the healing phase shall be 
assessed for clinically significant changes from the baseline examination. 
9.1.4 Weight, height, and BMI 
Body weight and height shall be measured. Takeda shall calculate the BMI using the 
following formula: 
Body Mass Index: 
BMI = weight (kg) / (height (m))2 
Height shall be measured to the nearest whole number in centimeters. Body weight shall 
be measured to one decimal place in kilograms. The result of BMI shall be shown to 
one decimal place. 
[Example: 
Height = 176 cm, weight = 79.2 kg, BMI = 79.2/1.762 = 25.6 kg/m2] 
9.1.5 Vital signs 
For vital signs, blood pressure in sitting position (after resting for ≥ 5 minutes) and 
pulse rate (bpm) shall be measured. 
When timing for the vital signs measurement overlaps with blood collection, priority 
shall be given to blood collection, and the vital signs shall be measured within 30 
minutes before or after the blood collection. 
9.1.6 Concomitant drug 
Concomitant drugs are all drugs to be given in addition to the study drug or control drug. 
Drugs prescribed by doctors or the over-the-counter medicines purchased by the 
research subjects shall be included. At every hospital visit of the research subject, the 
status of use (drug name, route of administration, healing phase) of the drugs (including 
vitamin compound, over-the-counter medication, and Chinese medicine) used, other 
than the study drug or control drug, from the start of the healing phase to the completion 
of the clinical research shall be monitored. 
9.1.7 Concurrent disease 
A concurrent disease is defined as a disease or symptom that is present at the start of the 
healing phase. Clinically problematic laboratory test data and abnormal physical 
examination findings observed up to immediately before the start of the healing phase 
 
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shall be considered as a concurrent disease at the discretion of the investigator or 
sub-investigator. The content of concurrent disease (diagnosis) shall be investigated. 
9.1.8 Laboratory tests 
The laboratory tests listed below shall be performed. Blood samples shall be collected 
under fasted conditions (after at least 10 hours of fasting) preferably at the same time of 
the day for each research subject. Analysis shall be performed at the laboratory test 
measurement institution (refer to the attached sheet). 
The investigator or sub-investigator shall evaluate and keep the reported laboratory test 
results. 
Table 9 (a) 
Laboratory tests 
Blood test 
AST 
ALT 
Fe 
Mg 
Ca 
Vitamin B12 
Close observation should be made, and if any hepatic abnormality is observed, such 
appropriate measures as discontinuation of study drug or control drug should be taken. 
When ALT or AST is > 3 times the upper limit of normal (ULN), a reexamination (at 
least ALP, ALT, AST, total bilirubin, and γ-GTP) shall be performed as soon as 
possible.  
(Refer to Sections 7.5 and 10.2.3) 
When ALT or AST is > 3 times the upper limit of the reference value two times 
sequentially, the investigator or sub-investigator shall contact Takeda to discuss 
additional examination, detailed monitoring, discontinuation of treatment with the study 
drug or control drug, advisability of continued study treatment, detailed information of 
the research subjects, and/or factors other than the study drug or control drug. 
The investigator shall keep laboratory test reference values, including the historical 
data. 
 
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9.1.9 Serum gastrin level 
Serum gastrin level shall be measured. Blood samples for serum gastrin (collected 
together with those for laboratory tests) shall be collected according to the clinical 
research schedule (
).  
Blood samples shall be collected under fasted conditions (after at least 10 hours of 
fasting) preferably at the same time of the day for each research subject. Analysis shall be 
performed at the laboratory test measurement institution (refer to the attached sheet).  
9.1.10 Pepsinogen I/II levels and serum chromogranin A level 
Pepsinogen I/II levels (pepsinogen I level, pepsinogen II level, and pepsinogen I/II ratio) 
and serum chromogranin A level shall be measured. Blood samples for pepsinogen I/II 
and serum chromogranin A (collected together with those for laboratory tests ) shall be 
collected according to the clinical research schedule (
).  
Blood samples shall be collected under fasted conditions (after at least 10 hours of 
fasting) preferably at the same time of the day for each research subject. Analysis shall be 
performed at the laboratory test measurement institution (refer to the attached sheet).  
9.1.11 H. pylori urea breath test 
Information on H. pylori infection (positive, negative), which may affect the 
development of EE and the gastric mucosa, shall be collected in H. pylori urea breath 
test to determine the eligibility for this study. H. pylori urea breath test shall be 
performed according to the clinical research schedule (
).  
9.1.12 CYP2C19 genotype testing 
CYP2C19 genotype testing shall be performed to collect information on the CYP2C19 
genotype [EM (*1/*1, *1/*2, *1/*3), PM (*2/*2, *2/*3, *3/*3)], which affects the 
kinetics of lansoprazole in blood. Blood samples (approximately 2 mL of whole blood) 
for CYP2C19 genotype testing shall be collected according to the clinical research 
schedule (
). CYP2C19 genotype testing shall be performed at the laboratory 
test measurement institution (refer to the attached sheet).  
9.1.13 Endoscopy (esophagus) 
The investigator or sub-investigator shall perform endoscopy according to the clinical 
research schedule (
). The investigator or sub-investigator shall take pictures 
in accordance with a procedure manual (refer to the attached sheet) so that the LA 
 
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Classification grade can be determined.  
For each research subject, preferably the same person shall perform endoscopy. Prior to 
endoscopy, the origin of previous pictures shall be located, and preferably the adjacent 
areas shall be photographed.  
Research subjects shall visit the study site for endoscopy under fasted conditions. 
The investigator or sub-investigator shall classify the grade of EE in accordance with 
Table 9.b, “Classification of EE severity”, which defines Grade O as “no mucosal 
break,” in addition to the Los Angeles Classification (LA classification). 7)  
The investigator or sub-investigator shall record Barrett mucosa at endoscopy according 
to the following classification: 
•Yes (≥ 3 cm), yes (< 3 cm), no, unknown
Esophageal hiatal hernia shall be recorded at endoscopy according to the following
classification:
•Yes (≥ 2 cm), yes (< 2 cm), no, unknown
The investigator or sub-investigator (with assistance of the research collaborator if
necessary) shall store endoscopic pictures taken at each time point in the medical record.
In addition, endoscopic results (LA classification, and classification of Barrett mucosa
and esophageal hiatal hernia) shall be recorded on electronic media or described in the
medical record and stored, as well as be recorded on the CRF. An endoscopy report may
be affixed to the medical record, instead of describing the results in the medical record.
Table 9 (b) 
Classification of EE severity 
Grade O 
No mucosal break 
Grade A 
Mucosal break with a diameter of no longer than 5 mm that does not extend 
between the tops of two mucosal folds 
Grade B 
At least one mucosal break with a diameter of longer than 5 mm that does not 
extend between the tops of two mucosal folds 
Grade C 
At least one mucosal break that is continuous between the tops of two or 
more mucosal folds, but which involves less than 75% of the circumference 
Grade D 
Mucosal break which involves at least 75% of the circumference 
Mucosal break: area with white coating or redness clearly demarcated from the adjacent normal mucosa 
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Definition of “healed” 
A research subject who has no endoscopic mucosal break (assessed as Grade O 
according to the classification of EE severity) during the healing phase shall be 
considered healed.  
Definition of “recurred” 
A research subject who has endoscopically confirmed EE of LA Classification Grades 
A to D during the maintenance phase shall be considered recurred.  
9.1.14 Endoscopy (stomach) 
The investigator or sub-investigator shall perform endoscopy according to the clinical 
research schedule (
). The investigator or sub-investigator shall take pictures 
in accordance with a procedure manual (refer to the attached sheet) so that endoscopic 
findings can be determined. At endoscopy at the start of the healing phase, as many 
areas of the stomach as possible shall be photographed to understand the pre-study 
conditions. 
For each research subject, preferably the same person shall perform endoscopy. Prior to 
endoscopy, the origin of previous pictures shall be located, and preferably the adjacent 
areas shall be photographed.  
The investigator or sub-investigator shall classify endoscopic findings into the presence 
or absence of fundic gland polyp, hyperplastic polyp, cobblestone mucosa, multiple 
white flat elevation, and black spots, as well as other findings.  
Research subjects shall visit the study site for endoscopy under fasted conditions. 
Endoscopic results (presence or absence of fundic gland polyp, hyperplastic polyp, 
cobblestone mucosa, multiple white flat elevation, and black spots, as well as other 
findings) obtained at each time point shall be recorded on electronic media or described 
in the medical record and stored, as well as be recorded on the CRF by the investigator 
or sub-investigator (with assistance of the research collaborator if necessary). An 
endoscopy report may be affixed to the medical record, instead of describing the results 
in the medical record. 
9.1.15 Gastric mucosa histopathology 
Gastric mucosa shall be sampled according to the clinical research schedule (
 
) to evaluate the effect of the study drug on gastric mucosa of the middle gastric body 
and around the pyloric region (refer to the attached sheet).
 
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Gastric mucosa histopathology shall be performed by the person responsible for gastric 
mucosa evaluation using gastric mucosa specimens prepared by the pathological 
specimen preparation facility (refer to the attached sheet).  
Observation and evaluation items are as follows: 
[Observation and evaluation items] 
1)
Greater curvature of the middle gastric body
Presence or absence of malignant alteration of epithelial cells [no] [yes] [unevaluable]
Presence or absence of prominence/hyperplasia of wall cells [no] [yes] [unevaluable] 
Presence or absence of hyperplasia of crypt epithelial cells [no] [yes] [unevaluable] 
Presence or absence of proliferation of endocrine cells 
[no] [yes*: 1, 2, 3, 4] [unevaluable] 
2)
Greater curvature of the antrum within 2 cm from the pylorus
Presence or absence of hyperplasia of G cells
   [no] [yes] [unevaluable] 
*Classification of proliferation pattern of endocrine cells:
1=atrophic ECM (endocrine cell micronest), 2=hyperplastic ECM,
3=neoplastic ECM, 4=typical carcinoid
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9.1.16 Histological evaluation of gastritis according to the Sydney classification 
Gastric mucosa shall be sampled according to the clinical research schedule (
 
) to evaluate gastritis histologically according to the Sydney classification. 8)
Histological evaluation of gastritis according to the Sydney classification shall be 
performed by the person responsible for gastric mucosa evaluation using gastric mucosa 
specimens prepared by the pathological specimen preparation facility (refer to the 
attached sheet).  
Observation and evaluation items are as follows: 
[Observation and evaluation items] 
1)
Greater curvature of the middle gastric body and greater curvature of the antrum within 2 cm from the
pylorus
Inflammation (mononuclear infiltration) 
[no] [yes: mild, moderate, severe] [unevaluable]
Activity (neutrophilic infiltration) 
[no] [yes: mild, moderate, severe] [unevaluable] 
Atrophy 
[no] [yes: mild, moderate, severe] [unevaluable] 
Intestinal metaplasia 
[no] [yes: mild, moderate, severe] [unevaluable] 
H. pylori
[no] [yes: mild, moderate, severe] [unevaluable] 
9.1.17 Pregnancy 
If pregnancy of a female research subject is found during her participation in this 
clinical research, with agreement of the female research subject, the principal 
investigator or investigator shall inform the research subject’s obstetrics gynecology 
physician about the fact of her participation in the clinical research and details of the 
study drug or control drug at the onset of the pregnancy. 
All reported pregnancies shall be followed up to final outcome, using the pregnancy 
form by the investigator or sub-investigator. The outcome, including any premature 
termination, shall be reported to Takeda. Evaluation after delivery shall also be 
conducted. 
9.1.18 Record of research subjects who are withdrawn before randomization 
A CRF shall be created for all research subjects who sign the consent form and are then 
withdrawn before randomization (before the start of the healing phase).  
The following items are to be recorded on the CRF: 
•
Date of consent obtainment
•
Date of birth
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•
Sex
•
Eligibility
•
Reason for discontinuation
The primary reason for withdrawal before randomization shall be recorded on the CRF 
according to the following classification:  
•
Not satisfying at least one of the inclusion criteria or meeting any of the
exclusion criteria
•
Serious deviation from the protocol
•
Lost to follow-up
•
Voluntary discontinuation <specify the reason>
•
Discontinuation of the entire study
•
Others <specify the reason>
Research subject ID codes assigned to research subjects withdrawn from the research 
before randomization shall not be reused.  
9.1.19 Recording of randomization 
Research subjects to be randomized shall meet all of the inclusion criteria and shall not 
meet any of the exclusion criteria according to Section 8.2. The investigator or 
sub-investigator shall specify the reason why the research subject cannot be 
randomized.  
9.2 
Compliance of research subjects 
The investigator or sub-investigator shall confirm the compliance with taking study 
drug or control drug of the research subject at every VISIT. 
Furthermore, at each VISIT, the whole drug-administration status shall be classified into 
4 categories, as follows: “took the drug properly (≥ 90%),” “usually took the drug (≥ 
70%),” “took the drug more than half of the time (≥ 50%),” and “took the drug less than 
half of the time (< 50%).” 
Medication instruction shall be given to research subjects throughout the research 
period. If poor compliance with study treatment (e.g., < 50% of the prescribed dose) 
(excluding suspension/interruption) after the previous visit has been found and does not 
 
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improve, the research subject may be withdrawn from the research if appropriate for the 
circumstances. 
9.3 
Implementation time point of the test and observation items 
The schedule for all tests, observations, and evaluations is shown in 
. The 
investigator or sub-investigator shall perform the tests, observations, and evaluations at 
the time points shown below. 
9.3.1 At the start of the healing phase [VISIT H1 (Week 0 in the healing phase)] 
After acquisition of informed consent, a physical examination and tests for enrollment 
to the research shall be performed. Eligibility of patients shall be determined in 
accordance with the inclusion and exclusion criteria as described in Section 7.0. After 
all tests/observations/evaluations at the start of the healing phase (Week 0 in the healing 
phase) are completed, the registration center shall be informed (access to the web 
subject registration system), and research subjects shall be randomized at the start of the 
healing phase (Week 0 in the healing phase) in accordance with Section 8.2.  
Refer to Section 9.1.18 for the recording of research subjects who are withdrawn before 
randomization.  
Tests and observations to be performed and endpoints to be assessed at the start of the 
healing phase (Week 0 in the healing phase) are shown below. 
•
Informed consent procedure
•
Demographic data, medical history, previous treatment drug(s)
•
Physical examination
•
Vital signs
•
Height, weight, and BMI
•
Concomitant drug(s)
•
Concurrent diseases
•
Laboratory tests
•
Serum gastrin
•
Serum pepsinogen I/II, serum chromogranin A
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•
H. pylori urea breath test
(In principle, the urea breath test shall be performed after endoscopy at the start
of the healing phase.)
•
CYP2C19 genotype testing
(In principle, the genotype testing shall be performed at the start of the healing
phase. It may be performed between the start and end (or discontinuation) of the
healing phase.)
•
Endoscopy
•
Gastric mucosa histopathology
•
Histological evaluation of gastritis
•
Compliance status
9.3.2 
At the end of the healing phase [VISIT H2 (Week 4 in the healing phase)] 
Tests and observations to be performed and endpoints to be assessed at the end of the 
healing phase (Week 4 in the healing phase) are shown below. For research subjects 
with no endoscopic healing of EE at Week 4 in the healing phase, the 
tests/observations/evaluations shall be performed at Week 8 in the healing phase 
(VISIT H3), when the healing phase shall conclude.  
•
Physical examination
•
Vital signs
•
Concomitant drug(s)
•
Laboratory tests
•
Serum gastrin
•
Serum pepsinogen I/II, serum chromogranin A
•
Endoscopy
•
Compliance status
•
Adverse events
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9.3.3  At the end or discontinuation of the healing phase [VISIT H3 (Week 8 in 
the healing phase)] 
For research subjects with no endoscopic healing of EE at Week 4 in the healing phase 
who enter Week 8 in the healing phase (VISIT H3), which is the end of the healing 
phase, tests and observations to be performed and endpoints to be assessed are shown 
below.  
Research subjects with no endoscopic healing of EE at the end of the healing phase 
(Week 8 in the healing phase) shall complete the study.  
For research subjects who are withdrawn from the research during the healing phase, 
efforts shall be made to perform all tests/observations/evaluations scheduled at the end 
of the healing phase. Endoscopy is not mandatory.  
•
Physical examination
•
Vital signs
•
Concomitant drug(s)
•
Laboratory tests
•
Serum gastrin
•
Serum pepsinogen I/II, serum chromogranin A
•
Endoscopy
•
Compliance status
•
Adverse events
9.3.4 At the start of the maintenance phase [VISIT M1 (Week 0 in the 
maintenance phase)] 
A physical examination for entry to the maintenance phase shall be performed after the 
end of the healing phase. Eligibility of research subjects shall be determined in 
accordance with the inclusion and exclusion criteria as described in Section 7.0.  
Research subjects shall receive the study drug or control drug for the maintenance phase 
after the completion of all tests/observations/evaluations at the end of the healing phase 
(at the start of the maintenance phase).  
 
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9.3.5 Weeks 12 (VISIT M2) to 228 (VISIT M15) in the maintenance phase 
Tests and observations to be performed and endpoints to be assessed at Weeks 12 to 228 
in the maintenance phase are shown below. Those to be performed or assessed only at 
specified VISITs are indicated as such by specifying the relevant VISITs.  
•
Physical examination
•
Vital signs
•
Concomitant drug(s)
•
Laboratory tests
•
Serum gastrin
•
Serum pepsinogen I/II, serum chromogranin A
[Weeks 24 (VISIT M3), 48 (VISIT M5), 108 (VISIT M10), 156 (VISIT M12),
and 204 (VISIT M14) in the maintenance phase]
•
Endoscopy
[Weeks 48 (VISIT M5), 108 (VISIT M10), 156 (VISIT M12), and 204 (VISIT
M14) in the maintenance phase]
•
Gastric mucosa histopathology
[Weeks 48 (VISIT M5), 108 (VISIT M10), 156 (VISIT M12), and 204 (VISIT
M14) in the maintenance phase]
•
Histological evaluation of gastritis
[Weeks 48 (VISIT M5), 108 (VISIT M10), 156 (VISIT M12), and 204 (VISIT
M14) in the maintenance phase]
•
Compliance status
•
Adverse events
9.3.6 At the end [VISIT M16 (Week 260 in the maintenance phase)] or 
discontinuation of the maintenance phase 
Week 260 in the maintenance phase shall be the final VISIT (VISIT M16), and the tests, 
observations, and evaluations listed below shall be performed. If the study is 
discontinued, the same tests, observations, and evaluations as those at the end of the 
maintenance phase shall be performed.  
•
Physical examination
•
Vital signs
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•
Concomitant drug(s)
•
Laboratory tests
•
Serum gastrin
•
Serum pepsinogen I/II, serum chromogranin A
•
Endoscopy
•
Gastric mucosa histopathology
•
Histological evaluation of gastritis
•
Compliance status
•
Adverse events
At completion of the clinical research, the status of all research subjects administered 
the study drug or control drug shall be recorded on the CRF.  
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10.0 
Adverse events 
10.1 
Definitions 
10.1.1 Adverse events and disease or the like 
An adverse event is defined as any untoward medical occurrence in a patient or a 
research subject receiving a pharmaceutical product (including the study drug or control 
drug). It does not necessarily have an apparent causal relationship with this 
pharmaceutical product (including the study drug or control drug).  
An adverse event can therefore be any unfavorable and unintended sign (e.g., a 
clinically significant laboratory abnormality), symptom, or disease temporally 
associated with the use of a pharmaceutical product (including the study drug or control 
drug), regardless of whether it is considered related to the pharmaceutical product 
(including the study drug or control drug). 
“Disease or the like” is defined as disease, disability, death, or infection that is 
suspected of being due to the conduct of a specified clinical research including any 
unintended sign, clinically significant laboratory change, symptom and aggravation of a 
concurrent disease. 
An adverse event that was considered causally related to the study drug or control drug, 
or research-specific procedures by the investigator or sub-investigator shall be regarded 
as “disease or the like.” 
10.1.2 Considerations for adverse events 
Generally unfavorable findings are described below: 
•
Newly diagnosed disease or unexpected aggravation of existing symptom
(intermittent event of an existing symptom is not considered an adverse event)
•
Requiring action or medical practice
•
Requiring invasive diagnostic treatment
•
Requiring discontinuation or a change in the dose of the study drug, control drug,
or concomitant medications
•
Considered unfavorable by the investigator or sub-investigator
Diagnosis name and signs/symptoms: 
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Adverse events shall be recorded by diagnosis name. Accompanying signs (including 
abnormal laboratory values, abnormal ECG findings) and symptoms shall not be 
recorded as adverse events. If an adverse event could not be expressed by a diagnosis 
name, the signs or symptoms shall be recorded as the adverse event. 
Laboratory test values and ECG findings: 
Abnormal laboratory values and ECG findings shall be recorded as adverse events when 
the investigator or sub-investigator judges the results are clinically problematic (in other 
words, when certain action or medical practice is required, or when the investigator or 
sub-investigator judges the change has exceeded the normal physiological variation 
range of the research subject). Retest and/or continued monitoring of an abnormality are 
not considered medical practice. Also, repeated or additional conduction of 
non-invasive tests for verification, evaluation, and monitoring of an abnormality are not 
considered medical practice. 
However, when abnormal laboratory values and ECG findings are the accompanying 
symptoms of a disease diagnosed as an adverse event (e.g., increased creatinine due to 
renal dysfunction, etc.), the adverse event shall be handled by its diagnosis name. 
Pre-existing conditions at the start of the healing phase: A disease or symptom that had 
been present since before the start of the healing phase shall be regarded as a concurrent 
disease and not an adverse event. When a concurrent medical condition is aggravated, 
the aggravation shall be determined as an adverse event and the investigator or 
sub-investigator shall record on the CRF that the adverse event is an aggravation of the 
concurrent disease (e.g., “aggravation of hypertension,” etc.). 
If a research subject has a pre-existing episodic condition (e.g., asthma, epilepsy), each 
episode shall be recorded as an adverse event if the episodes become more frequent, 
serious, or severe in nature. If a research subject has a chronic concurrent condition (e.g., 
cataracts, rheumatoid arthritis), worsening of the condition shall be recorded as adverse 
event if the degree of the worsening exceeds that which would be expected. The 
investigator or sub-investigator shall ensure that the adverse event term to be recorded 
represents the change in the condition from baseline (e.g. “worsening of…”). 
Worsening of adverse events: 
If a research subject experiences a worsening of the adverse event after a change in the 
dose of the study drug or control drug, or secondary signs and symptoms are caused by 
the adverse event, the worsening or the secondary signs and symptoms shall be recorded 
 
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as a new adverse event on the CRF. The investigator or sub-investigator shall use an 
adverse event term that explicitly means a change of the condition (e.g., “worsening 
of…”). 
Change of severity of adverse events: 
If the research subject experiences changes in the severity of an adverse event, the event 
shall be recorded once, at its peak severity. 
Previously planned surgery or treatment: 
Preplanned surgeries or interventions that were scheduled before the start of the healing 
phase shall not be considered adverse events. However, when the existing symptom is 
aggravated to a degree requiring emergency surgery or treatment, the condition or the 
event shall be considered an adverse event. A concurrent disease that resulted from 
previously planned surgery shall be reported as an adverse event. 
Non-urgent surgery or treatment: 
Non-urgent surgery or treatment that does not induce a change in the condition of a 
research subject (cosmetic surgery, etc.) shall not be considered an adverse event; 
however, it shall be recorded in the source documents. Concurrent diseases due to a 
non-urgent surgery shall be reported as an adverse event. 
Insufficient clinical response (lack of efficacy): 
Insufficient clinical response, efficacy, or pharmacological action shall not be recorded 
as an adverse event. The investigator or sub-investigator shall make the distinction 
between worsening of a pre-existing condition and lack of therapeutic efficacy. 
Overdose of the study drug or control drug 
Overdose of the study drug without manifested symptoms shall not be recorded as an 
adverse event, but the overdose shall be recorded on the “Overdose” page of the CRF. 
Any manifested symptoms shall also be recorded as adverse events on the “Adverse 
events” of the CRF. 
Serum gastrin level, pepsinogen I/II levels: 
An increase in serum gastrin level, pepsinogen I level, or pepsinogen II level, which is 
due to the pharmacological action of the study drug or control drug, shall not be 
recorded as an adverse event. However, an increase in serum gastrin level leading to 
withdrawal of the research subject from the study shall be reported as an adverse event. 
 
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10.1.3 Serious adverse events 
Of all the unfavorable medical events that develop with administration of drugs 
(including the study drug or control drug, irrespective of dose), a serious adverse event 
is an event that: 
1. results in death,
2. is life threatening*,
3. requires inpatient hospitalization or prolongation of existing hospitalization,
4. results in persistent or significant disability/incapacity,
5. leads to a congenital anomaly/birth defect,
6. other medically significant condition: a medically important event that causes a
risk to a research subject even if it is not immediately life-threatening and does
not result in death or hospitalization, or requires an action or treatment to
prevent the results described in 1 to 5 above. In addition, points described in the
Takeda Medically Significant Adverse Event List (Table 10 (a)) are included in
this section.
* The term “life threatening” refers to an event in which the research 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.
Table 10 (a) Takeda Medically Significant Adverse Event List 
Acute respiratory failure/acute respiratory 
distress syndrome (ARDS) 
Torsades de pointes/ ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including convulsion 
and epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/ 
Oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute hepatic failure 
Anaphylactic shock 
Acute renal failure  
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Neuroleptic malignant syndrome/ malignant 
hyperpyrexia 
Spontaneous abortion/ stillbirth and fetal death 
Confirmed or suspected transmission of 
infection by a medicinal product 
Confirmed or suspected endotoxin shock 
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10.1.4 Severity of adverse events 
The severity of adverse events shall be classified and defined as shown below. 
Mild 
The event is transient and easily tolerated 
by the subject. 
Moderate 
The event interrupts the subject’s usual 
activities. 
Severe 
The event causes considerable interference 
with the subject’s usual activities. 
10.1.5 Causality of adverse events 
The causal relationship of each adverse event to the study drug or control drug shall be 
classified and defined as shown below. 
Related 
An adverse event that follows an apparent temporal sequence (including clinical course 
after discontinuation). Possibly due to the study drug or control drug, although other 
factors such as underlying disease, concurrent diseases, or concomitant drugs/treatment 
are also suspected. 
Not 
related 
An adverse event that does not follow an apparent temporal sequence from 
administration of the study drug and control drug. Very likely due to other factors such 
as underlying disease, concurrent diseases, or concomitant drugs/treatment. 
10.1.6 Relationship to study procedures 
The relationship shall be recorded as “Yes” if the investigator or sub-investigator 
considers that there is reasonable possibility that an adverse event is due to a study 
procedure. Otherwise, the relationship shall be recorded as “No.” 
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10.1.7 Date of onset 
The date of onset of adverse events shall be determined according to the following 
rules: 
Adverse event 
Date of onset 
Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
research subject and/or the investigator or sub-investigator. 
Asymptomatic diseases 
The date on which a diagnosis was confirmed through a test(s). 
The date on which a diagnosis was confirmed, even when the test 
results indicate an old sign(s) of the disease or an approximate time 
of its onset. 
Exacerbation of concurrent 
diseases 
The date on which the first worsening of diseases/symptoms was 
noted by the research subject and/or the investigator or 
sub-investigator. 
Onset of a test abnormality after 
the start of the healing phase 
The date on which a clinically significant laboratory abnormality 
was detected. 
Worsening of a baseline test 
abnormality after the start of the 
healing phase 
The date on which a clear increase/decrease in a laboratory 
parameter was clinically confirmed based on the time profile of the 
parameter. 
10.1.8 Date of resolution 
The date of resolution of an adverse event is the date on which the research subject 
recovered (including resolution with sequelae). If a research subject died due to the 
adverse event concerned, it shall be the date of death. The adverse event shall be 
recorded as “ongoing” if the research subject has not yet recovered by the end of the 
study. 
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10.1.9 Actions taken for the study drug or control drug 
Actions taken for the study drug or control drug shall be classified or defined as shown 
below. 
Drug withdrawn 
The study drug or control drug is discontinued because of an adverse event 
(including withdrawal by the research subject at his/her discretion). 
If the study drug or control drug is continued after the study termination, the 
action should be “Dose not changed”. 
Dose not changed 
The dose was not changed after the onset of the adverse event. 
The study drug or control drug was discontinued, reduced, or increased because of 
another adverse event. 
The study drug was discontinued or reduced for a reason other than the adverse 
event, e.g., inadvertence of the research subject. 
Unknown 
It has not been possible to determine what action has been taken because the 
research subject is lost to follow-up. 
Not Applicable 
The administration of the study drug or control drug had already been completed 
or discontinued before the onset of the adverse event. 
Dose reduced 
The dose of the study drug or control drug was reduced because of the adverse 
event (including dose reduction by the research subject at his/her discretion). 
Dose increased 
The dose of the study drug or control drug was increased because of the adverse 
event (including dose increase by the research subject at his/her discretion). 
Washout 
The study drug or control drug was suspended (i.e., interrupted) because of the 
adverse event (including suspension/interruption by the research subject at his/her 
discretion), but resumed later. 
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10.1.10 Outcome 
Outcome of adverse events is classified as follows: 
Category 
Criteria 
Recovered 
Disappearance or recovery of symptoms and findings 
Laboratory values returned to normal or baseline 
Improved 
The intensity is lowered by one or more stages 
Symptoms or findings mostly disappeared 
Laboratory values improved, but have not returned to normal or baseline 
The research subject died from a cause other than the concerned adverse event while 
the condition was resolving (recording of the date of death unnecessary) 
Not recovered 
No change in symptoms, findings, or laboratory data 
The symptoms, findings, or laboratory data on the final day of observable period 
were aggravated compared with the date of onset 
Irreversible congenital anomaly 
The research subject died from another cause before resolution of the concerned 
adverse event (recording of the date of death unnecessary) 
Recovered 
with sequelae 
Disability that disturbs daily life 
Death 
Direct relationship between death and the concerned adverse event 
“Direct relationship” means that the concerned adverse event was the cause of 
death, or the concerned adverse event was clearly responsible for death. 
Outcome of an adverse event which was not determined (judged, presumed) a direct 
cause of death observed in the same research subject is not considered as death. 
The date of death shall be recorded. 
Unknown 
Follow-up specified in the protocol after the date of onset was not possible due to 
change of hospitals or relocation, etc. 
10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Adverse event collection period 
Collection of adverse events shall commence at the start of the healing phase (VISIT 
H1) and continue until the end of the maintenance phase (VISIT M23). 
10.2.1.2 Collection, evaluation, and reporting of adverse events 
At each study visit, the investigator or sub-investigator shall check for the presence of 
any onset of subjective symptoms. A neutral question, such as “How have you been 
feeling since your last visit?” may be asked to collect any adverse events that occurred 
between the previous and present visits. 
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At each study visit, the investigator or sub-investigator shall pay attention to presence of 
diarrhea, gastrointestinal infections, bone fracture and pneumonia. The principal 
investigator or investigator shall conduct an examination and follow up on any relevant 
information as possible, if the onset of subjective symptoms will be suspected. 
The investigator or sub-investigator shall follow up all research subjects experiencing 
an adverse event irrespective of the causal relationship with the study drug or control 
drug, until the symptom has resolved, or any clinically significant abnormal laboratory 
values have returned to baseline or there is a satisfactory explanation for the change 
(permanent and irreversible adverse events). All adverse events shall be entered on the 
CRF, with the event term, onset date, resolution date, onset time, severity, causal 
relationship with the study drug or control drug (i.e. “Unrelated” or “Related”), action 
taken for the study drug or control drug, outcome, causal relationship with any study 
procedure (with specific procedure if assessed to be causally related), and seriousness. 
In addition, the investigator shall report an adverse event in accordance with a 
procedure manual prepared separately, depending on assessment results of its 
seriousness and causal relationship with the study drug or control drug (whether it was 
assessed as “serious” and “disease or the like”). 
Follow-up period of adverse events shall be until recovery of the adverse events, or the 
time when the investigator or sub-investigator judges that further follow-up would be 
unnecessary. 
10.2.2 Collection and reporting of serious adverse events 
When a serious adverse event develops during the period of collecting adverse events, it 
shall be reported according to the following procedures. 
At the time of onset of a serious adverse event or notification of the onset by the 
research subject, etc., the investigator shall report the serious adverse event to the 
contract research organization (CRO) to whom Takeda has entrusted responsibility (for 
the contact information, refer to the attachment) immediately (within 1 working day of 
becoming aware of the event onset) regardless of whether it is considered causally 
related to the study drug or control drug. Furthermore, the investigator shall submit the 
detailed report using the pre-defined form through CRO within 8 working days to the 
representative investigator if the event was assessed as “serious” and “disease or the like” 
and within 10 calendar days to Takeda unless the event was assessed as “serious” and 
not “disease or the like.” The details shall be reported in accordance with a procedure 
manual prepared separately. 
 
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Furthermore, it shall be mandatory to include the contents below in the report to be 
submitted to Takeda within 1 working day, and other items shall be reported as far as 
possible. 
•
Brief description of adverse event and the reason for why it was determined as
serious
•
Clinical research title
•
Research subject ID codes
•
Name of study site
•
Name of the investigator or sub-investigator
•
Name of the study drug or control drug
•
Determined causal relationship
The investigator or sub-investigator shall report spontaneously reported serious adverse 
events that are collected even after the adverse event collection period to Takeda. 
10.2.3 Reporting of additional information concerning adverse events 
If Takeda requests provision of additional information concerning adverse events for 
reporting to regulatory authorities, the investigator or sub-investigator shall confirm the 
necessary additional information and enter in the electronic data capture (EDC) system 
or submit a report within the period specified by Takeda. 
10.3 
Follow-up of serious adverse events 
When information that was not included in the detailed report was obtained later, the 
investigator or sub-investigator shall state it in the copy of the report on serious adverse 
events, or create another document and submit it to the contact address shown on the 
attached sheet. Relevant data collected at the study site (e.g., ECG charts, laboratory test 
values, discharge summary, postmortem results) shall be sent to the representative 
investigator, Takeda, or the certified review board upon request. 
The investigator or sub-investigator shall follow-up all serious adverse events, etc., until 
recovery is confirmed, or the final outcome is determined. 
 
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10.3.1 Reporting of serious disease or the like to the certified review board and 
regulatory authorities 
When the representative investigator receives a report of a serious disease or the like 
from the investigator, he/she shall consult the certified review board, and submit this 
information to investigators at study sites that are conducting this clinical research 
through the CRO consigned by Takeda. The investigators shall report the content of 
such information to the supervisors of the study sites. 
Takeda shall report, in accordance with regulations, unexpected serious adverse drug 
reactions and other serious adverse events that are subject to emergency reporting to 
regulatory authorities, the investigators, and the supervisors of the study sites. 
From the time point of first acknowledging the event or receiving additional 
information, Takeda or the CRO consigned by Takeda shall comply with regulatory 
required time frames for reporting, and make emergency reports concerning unexpected 
serious adverse drug reactions and expected serious adverse drug reactions to regulatory 
authorities. Also, Takeda shall, in the same way, make an emergency report of other 
critical safety information that may have a major effect on the risks/benefits of the study 
drug or control drug, continuation of study drug or control drug administration, or 
continuation of clinical research.  
 
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11.0 
COMMITTEE ESTABLISHED FOR THIS CLINICAL RESEARCH 
11.1 
Research Steering Committee 
The Research Steering Committee shall be composed of the chairperson and members 
of the committee, and Takeda. The Research Steering Committee shall supervise 
implementation and reporting of the clinical research, secure medical guidance of a high 
degree of professionalism and a high-level scientific quality, and revise the protocol 
appropriately. The responsibilities of the committee shall be prescribed in the 
procedures of the Research Steering Committee. 
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12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS 
The CRO to whom Takeda has entrusted responsibility shall be in charge of 
implementing data management operation according to the standard operating 
procedures, independently from Japan Medical Office of Takeda. Adverse events, 
medical history, and concurrent conditions shall be coded using MedDRA. Drugs shall 
be translated using the World Health Organization (WHO) Drug Dictionary.  
12.1 
Case report form 
The investigator or sub-investigator shall complete a CRF for each research subject who 
has signed the informed consent form.  
Takeda or its designee shall provide the study sites with access authorization to the 
EDC system. Before use of the EDC system, the CRO to whom Takeda has entrusted 
responsibility shall provide training to the investigator, sub-investigators, and study 
collaborators. The CRF shall be used to report the information collected during the 
research period to Takeda. The CRF shall be prepared in Japanese. Data shall be 
directly entered in preparing the CRF. 
A change or correction of the CRF shall be recorded as an audit trail that records the 
information before and after the change or correction, the person who made the change 
or correction, date of change or correction, and its reason. 
The investigator shall ensure the accuracy and completeness of the CRF, and provide an 
electronic signature on the relevant page of the CRF. The investigator bear full 
responsibility for the accuracy and reliability of all the data entered on the CRF. 
The following data shall be recorded on the CRF directly, except for those recorded in 
the source documents: 
•
H. pylori urea breath test results
•
Severity, degree, the causal relationship with the study drug, control drug, or the
study procedures, outcome
The following data shall not be directly recorded on the CRF: 
•
Laboratory test results
•
Measured serum gastrin level
•
Measured pepsinogen I/II levels and serum chromogranin A level
When the investigator or sub-investigator makes a change or correction in the data 
entered on the CRF after fixation of clinical data base, a record (Data Clarification 
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Form) of change or correction on the CRF provided by the CRO to whom Takeda has 
entrusted responsibility shall be used. The investigator shall confirm that the record of 
change or correction on the CRF is accurate and complete, and sign or write name/ affix 
a seal, and date it. 
Takeda or the designee shall confirm that the CRF has been made appropriately in 
conformity with the procedure defined for each research. Takeda or its designee shall 
have access to the medical records of the research subjects and in-house records to 
ensure the accuracy of the CRF as necessary. The completed CRF shall be the property 
of Takeda, and the investigator or sub-investigator shall not disclose the information to 
a third party without written permission from Takeda. 
12.2 
Timing of data entry into the EDC system 
Takeda or its designee shall request the investigator or sub-investigator to promptly 
enter data into the EDC system following enrollment of the research subject, each visit 
during study treatment, and completion/discontinuation of the study. 
1. Start of the healing phase: within 2 weeks (14 days) from the start date of the
healing phase
2. During the treatment/maintenance phase: within 2 weeks (14 days) from each
VISIT
3. Discontinuation of the treatment/maintenance phase: within 4 weeks (28 days)
from the date of discontinuation in the treatment/maintenance phase
4. Gastric mucosa histopathology results: within 2 weeks (14 days) from data
obtainment
5. Follow-up period: within 2 weeks (14 days) from request for follow-up
6. Queries for entered data: within 2 weeks (14 days) from issue of a query
12.3 
Storage and disposal of specimens, information, etc. 
The investigator or the supervisor of the study site shall store human-derived specimens 
and the following materials (information, etc.), including those specified in Section 12.1 
and study-specific documents to be used by the regulatory authority and the 
representative investigator or its designee for investigation and audit. The documents 
shall include, but shall not be limited to the materials related to the information used in 
the study such as the research subject ID number list, research subjects’ medical records, 
clinical research work sheet, original signed and dated informed consent forms, an 
electronic copy of the EDC system with audit trails, and the drug management records. 
 
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The investigator shall appropriately retain the specimens/information related to this 
study for at least 5 years from the end date of this study . However, when the 
representative investigator and Takeda require a longer storage period,  investigator 
shall discuss the period and methods of storage with the representative investigator and 
Takeda. When disposing the specimens, information, etc., the investigator shall dispose 
them anonymously. 
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13.0 
STATISTICAL ANALYSIS METHODS 
13.1 
Statistical and analytical plans 
The person in charge of analysis shall prepare a statistical analysis plan before the 
acquisition of the informed consent of the earliest research subject, and issue the first 
edition. Detailed definition of endpoints and analysis methods should be specified in the 
SAP to deal with all the purposes of the research. 
13.1.1 Analysis set 
In this clinical research, 4 types of analysis sets, “Full Analysis Set in the maintenance 
phase,” “Full Analysis Set in the healing phase,” “Safety Data Analysis Set in the 
maintenance phase,” and “Safety Data Analysis Set in the healing phase,” shall be 
established. The “Full Analysis Set in the maintenance phase” is defined as research 
subjects who are randomized and given at least one dose of the study drug or control 
drug for the maintenance phase,” and the “Full Analysis Set in the healing phase” is 
defined as research subjects who are randomized and given at least one dose of the 
study drug or control drug for the healing phase.” In addition, the “Safety Data Analysis 
Set in the maintenance phase” is defined as research subjects who are given at least one 
dose of the study drug or control drug for the maintenance phase,” and the “Safety Data 
Analysis Set in the healing phase” is defined as research subjects who are given at least 
one dose of the study drug or control drug for the healing phase.”   
13.1.2 Analysis of demographic and other baseline characteristics 
For the “Safety Data Analysis Set in the maintenance phase,” major demographic and 
other baseline characteristics shall be aggregated for each treatment group and all 
combined groups.  
13.1.3 Efficacy analysis 
(1) Secondary endpoints and the analytical methods
[Secondary endpoints]
Endoscopic EE recurrence rate 
EE healing rate at the end of the healing phase 
[Analytical methods] 
For the “Full Analysis Set in the maintenance phase”, endoscopic EE recurrence rate at 
each timepoint as well as point estimate and 2-sided 95% confidence interval shall be 
 
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calculated for each treatment group. The research subjects with LA Classification 
Grades whose data are available at each timepoint shall be included in the analysis set. 
For the “Full Analysis Set in the healing phase”, EE healing rate at the end of the 
healing phase as well as point estimate and 2-sided 95% confidence interval shall be 
calculated for each treatment group.  
13.1.4 Safety analysis 
The following analyses shall be performed in the “Safety Data Analysis Set in the 
maintenance phase”: 
(1) Primary endpoint and analytical methods
[Primary endpoint]
Gastric mucosa histopathology
Presence or absence of malignant alteration of epithelial cells 
Presence or absence of prominence/hyperplasia of wall cells 
Presence or absence of hyperplasia of crypt epithelial cells 
Presence or absence of proliferation of endocrine cells 
Presence or absence of hyperplasia of G cells 
[Analytical methods] 
For each gastric mucosa histopathological endpoint (presence or absence of malignant 
alteration of epithelial cells, presence or absence of prominence/hyperplasia of wall 
cells, presence or absence of hyperplasia of crypt epithelial cells, presence or absence of 
proliferation of endocrine cells, and presence or absence of hyperplasia of G cells), the 
proportion of research subjects who have the event for assessment in maintenance phase 
shall be calculated for each treatment group.  
(2) Secondary endpoints and analytical methods
[Secondary endpoints]
Incidence of adverse events (TEAEs)
Endoscopic findings
Presence or absence of fundic gland polyp 
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Presence or absence of hyperplastic polyp 
Presence or absence of cobblestone mucosa 
Presence or absence of multiple white flat elevation 
Presence or absence of black spots 
Histological evaluation of gastritis according to the Sydney classification 
Inflammation (mononuclear infiltration) 
Activity (neutrophilic infiltration) 
Atrophy 
Intestinal metaplasia 
H. pylori
Incidence of gastric polyp 
[Analytical methods] 
A treatment-emergent AE (TEAE) is defined as any AE occurring after the start of 
study or control treatment for the healing phase. For TEAEs in the maintenance phase, 
the analyses listed below shall be performed for each treatment group. TEAEs shall be 
reported using MedDRA terminology and summarized using the Preferred Term (PT) 
and System Organ Class (SOC) of the MedDRA.  

Aggregation of frequencies of all TEAEs in the maintenance phase

Aggregation of frequencies of TEAEs related to the study drug or control drug in
the maintenance phase

Aggregation of frequencies of all TEAEs in the maintenance phase by severity

Aggregation of frequencies of TEAEs related to the study drug or control drug in
the maintenance phase by severity

Aggregation of frequencies of TEAEs leading to discontinuation of study treatment
or control treatment in the maintenance phase

Aggregation of frequencies of serious TEAEs in the maintenance phase

Aggregation of frequencies of all TEAEs in the maintenance phase by time of onset
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
Aggregation of frequencies of TEAEs relating to diarrhea, gastrointestinal
infections, bone fracture and pneumonia.
For each endoscopic endpoint (presence or absence of fundic gland polyp, presence or 
absence of hyperplastic polyp, presence or absence of cobblestone mucosa, presence or 
absence of multiple white flat elevation, and presence or absence of black spots) and 
each histological endpoint of gastritis according to the Sydney classification 
[inflammation (mononuclear infiltration), activity (neutrophilic infiltration), atrophy, 
intestinal metaplasia, and H. pylori], the proportion of research subjects who have the 
event at each time point for assessment shall be calculated for each treatment group.  
The incidence of gastric polyp at each point shall be calculated for each treatment 
group. 
13.2 
Criteria for interim analysis and premature discontinuation 
In addition to the final analysis using data up to the final VISIT, interim analysis using 
data up to the pre-defined VISIT will be performed once a year during the maintenance 
phase to evaluate the effect of long term administration of vonoprazan on gastric 
mucosal tissue as maintenance treatment in patients with recurrent/reactivated erosive 
esophagitis when data up to the pre-defined VISIT (Week 48 [VISIT M5], Week 108 
[VISIT M10], Week 156 [VIST M12], and Week 204 [VIST M14] in the maintenance 
phase) is collected from all the subjects. The interim analysis is not intended to use 
decision whether to continue or terminate this study. 
13.3 
Determination of the planned number of research subjects 
As the number of research subjects for entry to the maintenance phase, 
Vonoprazan group 
 130 subjects 
Lansoprazole group 
 65 subjects 
To collect data on the effect of long-term vonoprazan on gastric mucosa as well as 
additional safety data, a sample size of 130 subjects for entry to the maintenance phase 
was set for the vonoprazan group in consideration of feasibility, with the 1-year 
(52-week) dropout rate in a Japanese clinical research of vonoprazan into account. 
Based on the data from previous clinical studies of vonoprazan, data will be collected 
from approximately at least 100, 50, and 30 subjects in the first, third, and fifth years in 
the present study, respectively. Since this study will be conducted on an exploratory 
basis with lansoprazole as control, a sample size of 65 subjects was set for the 
lansoprazole group with a vonoprazan/lansoprazole ratio of 2:1.  
 
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The sample size was not statistically calculated. 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of the study site 
The entity in charge of monitoring shall perform periodic monitoring of study sites 
during the research to confirm that the research is conducted in accordance with all 
specifications in the protocol under the supervision of the representative investigator. In 
the monitoring, the data recorded on the CRF will be checked by comparing them with 
those in the source documents. Source documents are the original documents, data and 
records. The investigator and the supervisor of the study site shall ensure that the entity 
in charge of monitoring and the certified review board have access to the source 
documents. 
The entity in charge of monitoring shall access the records, including the list of research 
subject ID codes, medical records of the research subjects, and signed and dated original 
consent forms, to confirm that the research is appropriately conducted in compliance 
with the protocol. Also, confirm the consistency between CRF and the related source 
documents. The investigator, sub-investigator, and other personnel involved in the 
research shall spare sufficient time to facilitate monitoring procedures during visits to 
the study site. 
Detailed procedures for monitoring shall be described in a procedure manual prepared 
separately.  
14.2 
Non-compliance with the Clinical Trials Act and the protocol 
The investigator or sub-investigator shall record all deviations and non-adherences 
(hereinafter referred to as “non-compliance”) from the Clinical Trials Act, ICH-GCP or 
the protocol. 
If any non-compliance is found, the investigator shall promptly report the supervisor of 
the study site and the representative investigator. The representative investigator who 
received the reporting shall provide such information to investigators in all the study 
sites. 
If any significant non-compliance is found, the representative investigator shall hear 
opinions of the certified review board, take preventive measures for recurrence, give 
notice thereof to investigators, sub-investigators, and persons who are engaged in this 
clinical research at all the study sites to surely prevent the recurrence. 
A significant non-compliance is defined as a non-compliance that affects human rights 
or the safety of research subjects, the progress of the research, or the reliability of 
 
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research results. In this clinical research, the following cases are applicable, provided 
that any protocol deviations to avoid an urgent risk for research subjects or for any other 
medically unavoidable reasons are excluded. 
1.
Serious deviations in the course of the conduct of the research (deviation from the
inclusion/exclusion criteria, deviation from the termination/discontinuation criteria,
deviation from the prescription of study drug or control drug, and deviation from
prohibited concomitant medications)
2.
Serious non-adherences to applicable laws and regulations (non-adherence to
informed consent, non-adherence to the contract, non-adherence to deliberations at
the certified review board, and others)
Furthermore, the investigator shall ask the representative investigator, the person who 
directs the research, and Takeda to discuss whether to revise the protocol as needed. For 
the revision of protocol, the procedure described in “6.4 Procedures for protocol 
revision” shall be followed. 
14.3 
Quality assurance audits and regulatory agency inspections 
The study site may be subject to audits by the representative investigator, the CRO to 
whom Takeda has entrusted responsibility, and the certified review board under the 
supervision of the representative investigator as needed. In such a case, the auditor of 
the CRO, etc. shall contact the study site in advance to determine the date of audit. The 
auditor may ask to visit the facilities where laboratory specimens are collected and any 
other facilities used during the research. In addition, this research may be inspected by 
regulatory agencies, including those of foreign governments (e.g., the Food and Drug 
Administration [FDA], the United Kingdom Medicines and Healthcare products 
Regulatory Agency [MHRA]). If the study site is contacted for an inspection by a 
regulatory body, the representative investigator and Takeda should be notified promptly. 
The investigator and the supervisor of the study site shall ensure that the auditor has 
access to all the research-related source documents. 
 
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15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH 
This research shall be conducted with the highest respect for the individual participants 
(i.e., research subjects) according to the protocol, the ethical principles that have their 
origin in the Declaration of Helsinki, the Clinical Trials Act, and ICH-GCP. The 
representative investigator and investigators will conduct the study according to 
regulatory requirements and in accordance with “Responsibilities of Representative 
Investigator and Investigators” in 
. 
15.1 
Approval of the Certified Review Board 
The approval of the certified review board and the permission of the supervisor of each 
study site shall be obtained for conducting this clinical research in accordance with the 
protocol and relevant procedure manuals, etc. 
The representative investigator and investigators shall observe all requirements that the 
certified review board prescribes. The requirements may include notifications to the 
certified review board, for example, change notification for revision of the protocol, and 
submission of reports on “disease or the like” in accordance with the Clinical Trials Act, 
periodic reports, reports on serious non-compliance, and the study completion report. 
The representative investigator or its designee shall obtain written approval from the 
certified review board and all relevant documents concerning the above mentioned 
items. 
15.2 
Conflict of interests 
This clinical research shall be conducted with the support of Takeda. 
Prior to the conduction of this clinical research, the representative investigator and 
investigator shall ensure appropriate management of any conflicts in the conduct of the 
research(conflict of interest; hereinafter referred to as “COI”) of investigators and 
sub-investigators involved in this clinical research in accordance with the COI 
management criteria and the COI management plan. 
Among the representative investigator, investigators, and sub-investigators, there are 
some persons who have received personal advantages that meet the COI management 
criteria from the pharmaceutical company marketing the study drug used in this research, 
therefore, the summary of COI will be disclosed when publishing research results. 
 
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15.3 
Informed consent and information sheet, and the agreement of the research 
subjects 
The informed consent and information sheet form shall contain specific requirements of 
the Declaration of Helsinki, Ethical Guidelines on Biomedical Research Involving 
Human Subjects and all applicable laws and regulations. The informed consent form 
and information sheet shall specify the use of personal information and medical 
information of research subjects in this clinical research (both in and outside Japan: 
supply to a third party), and disclosure. The informed consent form and the information 
sheet will explain in detail the nature of the research, its objectives, and potential risks 
and benefits. The informed consent form will detail the following, in principle, 
including the requirements of the participant and the fact that research subject is free to 
withdraw at any time without giving a reason and without any negative effect on the 
further medical care. 
1. The study title and the conduct of this study have been approved by the chief
executive of the research implementing entity.
2. The name of the research implementing entity and the name of the principal
investigator. (If a collaborative study, the name of the collaborative research
implementing entity and the name of the principal investigator from the
collaborative research implementing entity should be included.)
3. The study objectives and the significance
4. The study methods (including the purposes of use of specimens and information
collected from a research subject) and the duration of the study
5. Reasons for being selected as a research subject
6. Costs that a research subject may need to bear and anticipated risks and benefits
7. A research subject can withdraw his/her consent to participating or staying in the
study at any time. (If there is a difficulty in taking actions for the withdrawal as
requested by a research subject, etc., this should be indicated with the reason,)
8. A research subject, etc. will not experience any disadvantage even if he/she
refuses to participate or continue to be in the study or withdraws the consent.
9. Study information disclosure method
10. A research subject can obtain or have free access to the study protocol and other
documents regarding study methods as per request, as far as personal
information of other research subjects, etc. are protected and originality of this
research is ensured. Also, describe the method to obtain or request access to the
information.
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11. Handling of personal information, etc. (including the method of anonymization,
if applicable)
12. Storage and disposal of specimens and information
13. Research-related conflict of interests of the research implementing entity such as
resources for research funding, and that of investigators, etc. such as personal
financial profit, etc.
14. Consultation windows for research subjects or persons related to the research
15. Financial burden or reward to research subjects, if applicable, including the
details.
16. If the study includes procedures that are not undertaken in regular clinical
practice, information on the other treatment options should be provided.
17. If the study includes procedures that are not undertaken in regular clinical
practice, treatment the research subjects will be able to receive after study
completion should be indicated.
18. Handling of the study results (including accidental findings) related to a research
subject, if a significant finding that may affect the research subject’s health or
genetic characteristics of the offspring may be obtained from the study.
19. If the study includes invasive procedures, indicate whether the health injury
caused by participating in this study will be compensated or not, and the
contents of the compensation, if applied.
20. If specimens and information obtained from a research subject may be used for a
future research unspecified at the time of consent submission or be provided to
other research institutions, this should be indicated with the contents of the
research assumed at the time of consent.
21. If the study includes invasive procedures (except for mild invasions) and
interventions, monitoring staff, audit staff, and Ethical Review Board have
access to specimens and information related to a research subject as necessary,
as long as confidentiality of the research subject is retained.
The principal investigator is responsible for the preparation, contents, and approval of 
the informed consent form and research subject information sheet by the committee 
such as the IEC. The informed consent form and information sheet must be approved by 
the committee prior to use. 
The informed consent form and information sheet shall be written in language that can 
be easily understood by the potential research subjects. The principal investigator or 
 
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investigator shall be responsible for providing detailed explanation of the informed 
consent form and information sheet to the potential subjects. Information should be 
given in both oral and written form whenever possible and in manner deemed 
appropriate by the committee such as the IEC. 
The principal investigator or investigator shall ensure that the potential research subjects 
have (1) an opportunity to inquire about the research and (2) sufficient time to decide on 
their participation. If a potential research subject decides to participate in the research, 
then the informed consent form must be signed and dated by the potential research 
subject prior to entering into the research as a subject. The principal investigator or 
investigator shall instruct the potential research subject to sign using their legal names, 
not nicknames, using a blue or black ball point ink pen. Also the principal investigator 
or investigator shall sign and date the informed consent form prior to entering into the 
research. 
Once signed, the original informed consent form shall be retained by the principal 
investigator or investigator. The principal investigator or investigator shall record the 
date that the potential research subject signed the informed consent form in the subject’s 
medical record. A copy of the signed informed consent form shall be given to the 
research subject. 
The principalinvestigator or sub-investigator shall follow the same procedure as for 
obtaining the initial consent when newly obtaining re-consent from the concerned 
research subject when the informed consent form is revised. The date of obtaining new 
consent shall be recorded in the research subject’s medical record, and a copy of the 
revised consent form shall be provided to the research subject. 
When revising the informed consent form and research subject information sheet, the 
revised version shall be used after obtaining approval from the certified review board. 
15.4 
Personal information of research subjects 
The persons who are or were engaged in this clinical research shall affirm the principle 
of the protection of research subjects’ private/personal information. Throughout this 
study, research subject ID codes shall be used to link the subject’s source data to the 
sponsor’s research database and research-related documents. Limited information on 
research subjects such as gender, age, and date of birth may be used within the scope of 
all applicable laws and regulations for identification of research subjects and 
confirmation of accuracy of research subject ID code. 
 
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For verification of the conduct of the research in compliance with this protocol and the 
Clinical Trials Act, the representative investigator or investigator shall give a 
permission that the representative investigator, Takeda’s designee, representatives of 
regulatory authorities, designated auditors, and the certified review board can have 
direct access to research subjects’ original medical records (source data or documents), 
including laboratory test results, ECG results, admission and discharge records during a 
subject’s research participation, and autopsy reports. The investigator or 
sub-investigator shall obtain specific authorization of the research subject as part of the 
informed consent process for access to research subject’s original medical records by 
the representative investigator, Takeda’s designee and representatives of regulatory 
authorities (see Section 15.3). 
When providing a copy of source documents to Takeda, the investigator or 
sub-investigator shall delete information that may lead to identification of an individual 
(name and address of research subject, other personal information not recorded on the 
CRF of the research subject). 
15.5 
Consultation windows for research subjects or persons related to the 
research 
The investigator shall establish a contact service to respond to inquiries concerning this 
clinical research from research subjects or concerned people. Details of the contacts for 
inquiries will be described in the informed consent form. 
15.6 
Financial burden or reward to research subjects 
Of the expenses for this clinical research, Takeda shall pay for medical treatment not 
covered by health insurance and examinations necessary for the research as research 
expenses. The research subjects shall pay expenses for medical treatment covered by 
ordinary health insurance. 
In addition, the investigator shall pay expenses such as transportation expenses for 
participation in this clinical research to the research subjects at each visit from the 
research funds. Details of the financial burden on the research subjects and rewards 
shall be described in the informed consent form and information sheet. 
15.7 
Benefits and inconveniences to research subjects 
15.7.1 Benefits to research subjects 
The research subjects will obtain detailed information on the status of his or her EE 
through participation in this clinical research.  
 
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15.7.2 Inconveniences to research subjects 
Participation in this clinical research may increase burden on the research subjects due 
to increased frequencies of visits and examinations, as compared with routine medical 
practice. 
The examinations, observations, and assessments will be performed in accordance with 
the Schedule of Research Procedures (
). 
15.8 
Attribution of research results and access rights 
15.8.1 Attribution of research results 
All the research specimens, results and data obtained from this research shall belong to 
Takeda. In addition, secondary use (meta-analysis, etc.) of the specimens and data 
obtained in this clinical research may be possible by Takeda, the representative 
investigator, or members of the Research Steering Committee if used in such a way that 
the specimens and data shall not be linked to personal identification information. The 
specimens and data can be available for secondary use only when it was collected from 
research subjects who consented to the participation in this research, using the informed 
consent form and research subject information sheet in which the possibility of 
secondary use is clearly described. In addition, necessary measures shall be taken not to 
identify individuals when publishing research results. When the representative 
investigator or members of the Research Steering Committee use the specimens and 
data secondarily, to whom such specimens and data would belong for secondary use 
onwards will be determined based on discussions with Takeda. 
15.8.2 Data access rights 
Access rights for all data and information generated from this study will be given to 
personnel approved by Takeda. 
15.9 
Reporting of results, Publication, disclosure, and clinical research 
registration policy 
15.9.1 Reporting of results, publication and disclosure 
The investigator shall report a written summary of results of the research to the 
supervisor of the study site and provide Takeda with all the results and data obtained 
from the research. Only Takeda may disclose the research information to other 
investigators, sub-investigators or regulatory authorities during the research period, 
except when required by laws and regulations. Takeda shall be responsible for 
 
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publication of the protocol and research-related results (including the public web site) 
except for other cases permitted in the research contract. The registration of research 
results to the database introduced and maintained by the Ministry of Health, Labour, 
and Welfare in accordance with the Clinical Trials Act (Japan Registry of Clinical 
Trials, hereinafter referred to as “jRCT”) shall be performed by the representative 
investigator or its designee. 
During and after the research, Takeda or its designee should promptly summarize the 
results and present them to medical journals and academic conferences, etc. Takeda may 
publish any data or information obtained from the research (including data and 
information provided by the investigator) without obtaining agreement of the 
investigator. 
The investigator or sub-investigator should obtain the prior written approval from 
Takeda when publishing the information obtained in this research at an academic 
conference, etc. 
Takeda shall report to the supervisor of the study site when final publication of the 
research results has been made. 
15.9.2 Clinical research registration 
To ensure that information on clinical research is made accessible to the public in a 
timely manner and to comply with applicable laws, regulations, and guidelines, Takeda 
shall register all clinical researches being conducted in patients around the world at 
public trial registration sites, including at least the website(s) of ClinicalTrials.gov and 
Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC), before 
initiation of the clinical research. On such websites, the research location (city, country), 
subject recruitment status, and contact information for Takeda are open to the public. 
The representative investigator or its designee shall register this clinical research to 
jRCT in accordance with the Clinical Trials Act after obtaining approval from the 
certified review board. 
15.9.3 Clinical trial results disclosure 
Takeda shall post the research results, irrespective of the nature of the results, at the 
public trial registration site(s) of Clinical Trials.gov and JAPIC in accordance with 
applicable laws and regulations. 
 
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The representative investigator or its designee shall register research results to jRCT in 
accordance with the Clinical Trials Act after reporting it to the certified review board. 
15.10 Insurance and compensation for injury 
The research subjects participating in this research shall be compensated for any health 
injury according to local regulations applicable to the study site. Takeda or its designee 
shall buy an insurance policy to compensate for health injury in research subjects. 
Healthy injury in a research subject will be compensated as specified in the study 
contract. Compensation-related questions by the investigator or sub-investigator should 
be made to Takeda or its designee. 
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16.0 
REFERENCES 
1.
Fujiwara Y, ArakawaT. Epidemiology and clinical characteristics of GERD in
the Japanese population. :J gastroenterol. 2009;44:518-534.
2.
Edited by the Japanese Society of Gastroenterology. Guidelines for Management
of Gastroesophageal Reflux Disease (GERD). Tokyo. Nankodo. 2009.
3.
Mee AS, Rowley JL. Rapid symptom relief in reflux oesophagitis : a comparison
of lansoprazole and omeprazole. Aliment Pharmacol Ther. 1996;10:757-763.
4.
Sekiguchi T. Drug Therapy for Erosive Esophagitis with PPIs, Primarily
Compared with Histamine H2 Receptor Antagonists. Prog Med.
2003;23:2335-2342.
5.
Klinkenberg-Knol EC, Nelis F, Dent J, et al.: Long-term omeprazole treatment in
resistant gastroesophageal reflux disease:efficacy, safety, and influence on gastric
mucosa. Gastroenterology. 2000;118:661-669.
6.
Japanese Guidelines for the Management of Helicobacter Pylori Infection in
2009. Guideline Committee of the Japanese Society for Helicobacter Research.
Journal of Japanese Society for Helicobacter Research (March 15, 2009) Vol.10
Supplement.
7.
Armstrong D, Bennett JR, Blum AL, et al. The endoscopic assessment of
esophagitis: a progress report on observer agreement. Gastroenterology.
1996;111:85-92.
8.
Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of
gastritis. The updated Sydney System. International Workshop on the
Histopathology of Gastritis, Houston 1994. Am J Surg Pathol.
1996;10:1161-1181.
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SAP_001.pdf: 
Title: Vonoprazan study in patients with erosive esophagitis to evaluate long-term 
safety: A study to evaluate the safety of long-term administration of vonoprazan in 
maintenance treatment in patients with erosive esophagitis (EE) 
NCT Number: NCT02679508 
Statistical analysis plan Approve Date: 01-Feb-2023 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black bar) to protect either personally 
identifiable information or company confidential information. 
Note; This document was translated into English as the language on original version 
was Japanese. 


 
 
 
 
 
 
 Evaluation of Long-term Safety of Maintenance Treatment with Vonoprazan in Patients 
with Erosive Esophagitis 
(Vonoprazan -4003) 
 
Statistical Analysis Plan 
(Ver. 7.0 Date of preparation: 2023/2/1) 
 
 
Sponsor: Takeda Pharmaceutical Company Limited. 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
   
 
   
 
   
 
 
  
        
    
 
 
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TABLE OF CONTENTS 
1.
LIST OF TERMS AND ABBREVIATIONS ................................................................................................. 1 
2.
Handling of TIME WINDOW ...................................................................................................................... 1 
3.
Analysis Sets ................................................................................................................................................. 7 
4.
Analysis Considerations ................................................................................................................................ 7 
5.
Other Handling............................................................................................................................................. 7 
6.
Subjects, demographic and other baseline characteristics .............................................................................. 9 
6.1. Disposition of Subjects ................................................................................................................................ 9 
6.2. Demographic and Other Baseline Characteristics ...................................................................................... 12 
6.3. Compliance ............................................................................................................................................... 14 
7.
EFFICACY EVALUATION ........................................................................................................................ 15 
7.1. Secondary Endpoints and Analytical Methods ........................................................................................... 15 
7.2. Other Analyses .......................................................................................................................................... 15 
8.
SAFETY EVALUATION ............................................................................................................................ 16 
8.1. Primary Endpoint and Analytical Methods ................................................................................................ 16 
8.2. Secondary Endpoints and Analytical Methods ........................................................................................... 17 
9.
List ............................................................................................................................................................. 29 
10.
STATISTICAL/ANALYTICAL ISSUES ................................................................................................ 29 
10.1. Adjustments for Covariates ..................................................................................................................... 29 
10.2. Handling of Dropouts or Missing Data .................................................................................................... 29 
10.3. Interim Analysis and Criteria for Early Termination ................................................................................ 29 
10.4. Multicenter Studies ................................................................................................................................. 30 
10.5. Multiple Comparison/Multiplicity ........................................................................................................... 30 
10.6. Examination of Subgroups ....................................................................................................................... 30 
11.
REVISION HISTORY ............................................................................................................................ 31 
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1 
1.
LIST OF TERMS AND ABBREVIATIONS
・
TEAE:Treatment-emergent adverse event
・
Summary statistics: A general term for the number of subjects, mean, standard deviation, maximum, minimum, and 
quartiles.
・
Treatment groups: Two treatment groups, the vonoprazan group and the lansoprazole group
・
Subjects who entered the maintenance phase: Subjects eligible for enrollment in the maintenance phase
2.
Handling of TIME WINDOW
For each test/observation/assessment item, evaluable data should be handled in the following manner.
If there are multiple evaluable data at the same evaluation time point, the date of examination/observation/evaluation
closest to the reference date will be adopted. If the difference from the reference date is the same, the later data will be
adopted.
Endoscopy (evaluation up to the evaluation time point) 
Timepoint 
Reference date 
Acceptable range 
Days after administration 
Days after the end of 
treatment 
At the start of treatment 
period 
Days after administration: 
1 
-8~1
Treatment Period Week 4 
Days after administration: 
29 
2~42 
<15 
Treatment Period Week 8 
Days after administration: 
57 
2~70 
<15 
Maintenance Period Week 
48 
Days after administration: 
337 
2~421 
<15 
Maintenance Period Week 
108 
Days after administration: 
757 
2~841 
<15 
Maintenance Period Week 
156 
Days after administration: 
1093 
2~1177 
<15 
Maintenance Period Week 
204 
Days after administration: 
1429 
2~1513 
<15 
Maintenance Period Week 
260 
Days after administration: 
1821 
2~1905 
<15 
・
For reference date and number of days after administration in the treatment period, the day before administration
of study product or the control drug in the treatment period is Day -1 and the day of administration of study product 
or the control drug in the treatment period is Day 1.
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2 
・ 
For reference date and number of days after administration in the maintenance phase, the day of administration of 
study product or control drug in the maintenance phase is defined as 1 day. 
・ 
For the treatment period, 1 day is defined as the number of days after the last dose of study product or the comparator. 
For the maintenance phase, Day 1 is defined as the day after the end of administration of study product for the 
maintenance phase or the control drug. 
・ 
Data after administration of study product or the comparator in the maintenance phase will be handled as data in 
the maintenance phase, not as data in the treatment phase, even if the allowable range for Week 4 or 8 of the 
treatment phase is met. 
 
 
 
Endoscopy (evaluation at each time point) 
Timepoint 
Reference date 
Acceptable range 
Days after administration 
Days after the end of 
treatment 
At the start of treatment 
period 
Days after administration: 
1 
-8~1 
 
Treatment Period Week 4 
Days after administration: 
29 
15~42 
<15 
Treatment Period Week 8 
Days after administration: 
57 
43~70 
<15 
Maintenance Period Week 
48 
Days after administration: 
337 
253~421 
<15 
Maintenance Period Week 
108 
Days after administration: 
757 
673~841 
<15 
Maintenance Period Week 
156 
Days after administration: 
1093 
1009~1177 
<15 
Maintenance Period Week 
204 
Days after administration: 
1429 
1345~1513 
<15 
Maintenance Period Week 
260 
Days after administration: 
1821 
1737~1905 
<15 
・ 
For reference date and number of days after administration in the treatment period, the day before administration 
of study product or the control drug in the treatment period is Day -1 and the day of administration of study product 
or the control drug in the treatment period is Day 1. 
・ 
For reference date and number of days after administration in the maintenance phase, the day of administration of 
study product or control drug in the maintenance phase is defined as 1 day. 
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3 
・ 
For the treatment period, 1 day is defined as the number of days after the last dose of study product or the comparator. 
For the maintenance phase, Day 1 is defined as the day after the end of administration of study product for the 
maintenance phase or the control drug. 
・ 
Data after administration of study product or the comparator in the maintenance phase will be handled as data in 
the maintenance phase, not as data in the treatment phase, even if the allowable range for Week 4 or 8 of the 
treatment phase is met. 
 
Histopathological Examination of Gastric Mucosa and Histological Evaluation of Gastritis (Up to Evaluation Time 
Points) 
Timepoint 
Reference date 
Acceptable range 
Days after administration 
Days after the end of 
treatment 
At the start of treatment 
period 
Days after administration: 
1 
-8~1 
 
Maintenance Period Week 
48 
Days after administration: 
337 
2~421 
<15 
Maintenance Period Week 
108 
Days after administration: 
757 
2~841 
<15 
Maintenance Period Week 
156 
Days after administration: 
1093 
2~1177 
<15 
Maintenance Period Week 
204 
Days after administration: 
1429 
2~1513 
<15 
Maintenance Period Week 
260 
Days after administration: 
1821 
2~1905 
<15 
・ 
For reference date and number of days after administration in the treatment period, the day before administration 
of study product or the control drug in the treatment period is Day -1 and the day of administration of study product 
or the control drug in the treatment period is Day 1. 
・ 
For reference date and number of days after administration in the maintenance phase, the day of administration of 
investigational product in the maintenance phase is defined as 1 day. 
・ 
In the maintenance phase, 1 day is defined as the number of days after the last dose of study product or the 
comparator. 
 
Histopathological Examination of Gastric Mucosa and Histological Evaluation of Gastritis at Each Assessment Point 
Timepoint 
Reference date 
Acceptable range 
Days after administration 
Days after the end of 
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4 
treatment 
At the start of treatment 
period 
Days after administration: 
1 
-8~1 
 
Maintenance Period Week 
48 
Days after administration: 
337 
253~421 
<15 
Maintenance Period Week 
108 
Days after administration: 
757 
673~841 
<15 
Maintenance Period Week 
156 
Days after administration: 
1093 
1009~1177 
<15 
Maintenance Period Week 
204 
Days after administration: 
1429 
1345~1513 
<15 
Maintenance Period Week 
260 
Days after administration: 
1821 
1737~1905 
<15 
・ 
For reference date and number of days after administration in the treatment period, the day before administration 
of study product or the control drug in the treatment period is Day -1 and the day of administration of study product 
or the control drug in the treatment period is Day 1. 
・ 
For reference date and number of days after administration in the maintenance phase, the day of administration of 
study product or control drug in the maintenance phase is defined as 1 day. 
・ 
For the treatment period, 1 day is defined as the number of days after the last dose of study product or the comparator. 
For the maintenance phase, Day 1 is defined as the day after the end of administration of study product for the 
maintenance phase or the control drug. 
 
Laboratory test values, vital signs, and serum gastrin level 
Timepoint 
Reference date 
Acceptable range 
Days after administration 
Days after the end of 
treatment 
At the start of treatment 
period 
Days after administration: 
1 
-8~1 
 
Treatment Period Week 4 
Days after administration: 
29 
16~43 
<15 
Treatment Period Week 8 
Days after administration: 
57 
44~71 
<15 
Maintenance Period Week 
12 
Days after administration: 
85 
44~127 
<15 
Maintenance Period Week 
Days after administration: 
128~211 
<15 
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5 
24 
169 
Maintenance Period Week 
36 
Days after administration: 
253 
212~295 
<15 
Maintenance Period Week 
48 
Days after administration: 
337 
296~379 
<15 
Maintenance Period Week 
60 
Days after administration: 
421 
380~463 
<15 
Maintenance Period Week 
72 
Days after administration: 
505 
464~547 
<15 
Maintenance Period Week 
84 
Days after administration: 
589 
548~631 
<15 
Maintenance Period Week 
96 
Days after administration: 
673 
632~715 
<15 
Maintenance Period Week 
108 
Days after administration: 
757 
716~799 
<15 
Maintenance Period Week 
132 
Days after administration: 
925 
884~967 
<15 
Maintenance Period Week 
156 
Days after administration: 
1093 
1052~1135 
<15 
Maintenance Period Week 
180 
Days after administration: 
1261 
1220~1303 
<15 
Maintenance Period Week 
204 
Days after administration: 
1429 
1388~1471 
<15 
Maintenance Period Week 
228 
Days after administration: 
1597 
1556~1639 
<15 
Maintenance Period Week 
260 
Days after administration: 
1821 
1780~1863 
<15 
・ 
For reference date and number of days after administration in the treatment period, the day before administration 
of study product or the control drug in the treatment period is Day -1 and the day of administration of study product 
or the control drug in the treatment period is Day 1. 
・ 
For reference date and number of days after administration in the maintenance phase, the day of administration of 
study product or control drug in the maintenance phase is defined as 1 day. 
・ 
For the treatment period, 1 day is defined as the number of days after the last dose of study product or the comparator. 
For the maintenance phase, Day 1 is defined as the day after the end of administration of study product for the 
maintenance phase or the control drug. 
・ 
Data after administration of study product or the comparator in the maintenance phase will be handled as data in 
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6 
the maintenance phase, not as data in the treatment phase, even if the allowable range for Week 4 or 8 of the 
treatment phase is met. 
 
Serum pepsinogen I and II levels, chromogranin A levels 
Timepoint 
Reference date 
Acceptable range 
Days after administration 
Days after the end of 
treatment 
At the start of treatment 
period 
Days after administration: 
1 
-8~1 
 
Treatment Period Week 4 
Days after administration: 
29 
16~43 
<15 
Treatment Period Week 8 
Days after administration: 
57 
44~71 
<15 
Maintenance Period Week 
24 
Days after administration: 
169 
128~211 
<15 
Maintenance Period Week 
48 
Days after administration: 
337 
296~379 
<15 
Maintenance Period Week 
108 
Days after administration: 
757 
716~799 
<15 
Maintenance Period Week 
156 
Days after administration: 
1093 
1052~1135 
<15 
Maintenance Period Week 
204 
Days after administration: 
1429 
1388~1471 
<15 
Maintenance Period Week 
260 
Days after administration: 
1821 
1780~1863 
<15 
・ 
For reference date and number of days after administration in the treatment period, the day before administration 
of study product or the control drug in the treatment period is Day -1 and the day of administration of study product 
or the control drug in the treatment period is Day 1. 
・ 
For reference date and number of days after administration in the maintenance phase, the day of administration of 
study product or control drug in the maintenance phase is defined as 1 day. 
・ 
For the treatment period, 1 day is defined as the number of days after the last dose of study product or the comparator. 
For the maintenance phase, Day 1 is defined as the day after the end of administration of study product for the 
maintenance phase or the control drug. 
・ 
Data after administration of study product or the comparator in the maintenance phase will be handled as data in 
the maintenance phase, not as data in the treatment phase, even if the allowable range for Week 4 or 8 of the 
treatment phase is met. 
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7 
 
3. 
Analysis Sets 
・ 
Full Analysis Set of the Treatment Period 
Subjects who were randomized and received study product for the treatment period or the control drug at least once 
・ 
Full Analysis Set of the maintenance phase 
Subjects who were randomized and received at least one dose of study product for the maintenance phase or the 
control drug 
・ 
Safety Analysis Set of the Treatment Period 
Subjects who received at least one dose of study product or control drug for the treatment period 
・ 
Safety Analysis Set of the maintenance phase 
Subjects who received study product for the maintenance phase or the control drug at least once 
 
4. 
Analysis Considerations 
・ 
confidence coefficient 
The confidence coefficient will be two-sided 95%. 
・ 
Number of digits to be displayed 
[Mean, confidence interval, and quartiles] 
The data will be displayed to the next lower digit by rounding off the number of significant digits. 
[Standard deviation] 
The data will be displayed to the second decimal place by rounding off the data to the 3rd decimal place. 
[Min, Max] 
Display up to the significant digit of the data. 
[Percentage] 
Round the second decimal place and display to the first decimal place. 
 
5. 
Other Handling 
[Handling of study product and control drugs] 
・ 
Duration of treatment with study product or control drug in the treatment period 
The day of the last dose in the treatment period − the day of the first dose in the treatment period + 1 
・ 
Duration of treatment with study product or control drug in the maintenance phase 
Date of the last dose in the maintenance phase - date of the first dose in the maintenance phase + 1 
 
[Endoscopy] 
・ 
Recurrence rate of reflux esophagitis based on endoscopic findings (at each evaluation time point and evaluation 
up to the evaluation time point) 
(Number of subjects with Grade A to D of the severity classification endoscopically assessed at the relevant 
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8 
evaluation time point)/(Number of subjects with non-missing data of the severity classification at the relevant 
evaluation time point) 
・ 
Cumulative incidence of endoscopic recurrence of reflux esophagitis 
(1) Reflux oesophagitis recurrent: 
Subjects assessed as Grade A to D in the severity classification by endoscopy in the maintenance phase 
(2) Censored: 
Subjects who discontinued or completed the study without recurrence of reflux esophagitis 
(3) Time to relapse of reflux esophagitis: 
Date of the first endoscopic assessment of reflux esophagitis recurrence − Date of the first dose in the 
treatment period + 1 
(4) Time to censoring: 
The day of the last dose in the maintenance period − the day of the first dose in the treatment period + 1 
・ 
Cure rate of reflux esophagitis at the end of the treatment period 
(Subjects who were endoscopically assessed as Grade O in the severity classification at the relevant evaluation time 
point)/(subjects with non-missing severity grade at the relevant evaluation point) 
・ 
Occurrence of gastric polyps 
If the presence or absence of fundic gland polyps is present or the presence or absence of hyperplastic polyps is 
present, the presence or absence of gastric polyps is present and the others are absent. 
 
[Handling of histopathological examination of gastric mucosa] 
・ 
Incidence of each histopathological finding in the gastric mucosa (evaluation by and up to the evaluation time point) 
(Number of subjects in whom gastric mucosal histopathological examination was judged to be present (1 ~ 4 for 
endocrine cell proliferation) at the relevant evaluation time point)/(Subjects with histopathological examination of 
gastric mucosa without missing data at the relevant evaluation time point) 
・ 
Cumulative incidence of gastric mucosal histopathological findings 
(1) Occurrence for each finding: 
Subjects with gastric mucosal histopathological positive (1 ~ 4 for endocrine cell proliferation) 
(2) Censored: 
Subjects who discontinued or completed the study without any findings 
(3) Time to onset for each histopathological finding in the gastric mucosa: 
Date of first assessment of each finding in histopathological examination of gastric mucosa − Date of first 
dose in the treatment period + 1 
(4) Time to censoring *: 
The day of the last dose in the maintenance period − the day of the first dose in the treatment period + 1 
*In the interim analysis, the time to censoring will be “cut-off date - date of first dose in the treatment period 
+ 1.” 
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[Handling of TEAEs] 
・ 
Treatment-Emergent Adverse Events During the Treatment Period: 
TEAEs that occurred between the first dose of study product for the treatment period and the first dose of study 
product for the maintenance period 
・ 
Treatment-Emergent Adverse Events During Maintenance Period: 
Treatment-Emergent Adverse Events Following study product Infusion in the Maintenance Period 
・ 
Time of onset of TEAEs during the treatment period 
Date of onset of TEAE in the treatment period - start date of treatment in the treatment period + 1 
・ 
Time of onset of TEAEs during the maintenance phase 
Date of onset of TEAE in the maintenance phase - start date of treatment in the maintenance phase + 1 
・ 
Time of onset of TEAEs during the study period 
Date of onset of TEAE - start date of treatment in the treatment period + 1 
 
6. 
Subjects, demographic and other baseline characteristics 
6.1. Disposition of Subjects 
6.1.1. Clinical research information 
Analysis 
population: 
All subjects who gave informed consent 
Analysis item: 
Date of informed consent, whichever is earlier 
The day of the last dose of study product or the control drug in the maintenance phase, 
whichever is later 
MedDRA Version 
SAS Version 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed. 
(1) Display of Analysis Items 
 
6.1.2. Eligibility of Subjects 
Analysis 
population: 
All subjects who gave informed consent 
Analysis item: 
Randomization     [Yes, No (and the reason)] 
Status of transition to the maintenance phase  [Yes, No (and the reason)] 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed. 
(1) Frequency tabulation 
 
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6.1.3. Disposition of Subjects 
6.1.3.1. End of treatment 
Analysis 
population: 
All randomized subjects 
Analysis item: 
Status of completion of treatment with study product or control drug for the treatment period 
[Completed, incomplete (and the reason)] 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for each 
treatment group and the pooled treatment group. 
(1) Frequency tabulation 
 
6.1.3.2. End of maintenance period 
Analysis 
population: 
Subjects who completed the treatment period 
Analysis item: 
Status of completion of administration of study product or control drug for the maintenance 
phase [Completed, incomplete (and the reason)] 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for each 
treatment group and the pooled treatment group. 
(1) Frequency tabulation 
 
6.1.4. PROTOCOL DEVIATIONS AND DATA SETS TO BE ANALYSED 
6.1.4.1. Protocol Deviations 
6.1.4.1.1 Protocol deviations during the treatment period 
Analysis 
population: 
All randomized subjects 
Analysis item: 
Protocol deviations during the treatment period [Significant violation of GCP, violation of 
inclusion criteria, violation of discontinuation criteria, violation of treatment method/dose, 
violation of prohibited concomitant drug/therapy, deviation to avoid urgent risk, etc.] 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for each 
treatment group and the pooled treatment group. 
The number of subjects with protocol deviations during the treatment period will be 
calculated, and the details of deviations will be presented by classifying them into the above 
categories. A subject falling into more than one category will be counted as 1 subject in each 
of the categories (multiple counting). 
(1) Frequency tabulation 
 
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6.1.4.1.2 Protocol deviations in the maintenance phase 
Analysis 
population: 
Subjects Enrolled in Maintenance Phase 
Analysis item: 
Protocol deviations in the maintenance phase [Significant violation of GCP, violation of 
inclusion criteria, violation of discontinuation criteria, violation of treatment method/dose, 
violation of prohibited concomitant drug/therapy, deviation to avoid urgent risk, etc.] 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for each 
treatment group and the pooled treatment group. 
The number of subjects with protocol deviations in the maintenance phase will be calculated, 
and the details of deviations will be presented by classifying the deviations into the above 
categories. A subject falling into more than one category will be counted as 1 subject in each 
of the categories (multiple counting). 
(1) Frequency tabulation 
 
6.1.4.2. Data Sets Analyzed 
6.1.4.2.1 Data sets to be analyzed (treatment period) 
Analysis 
population: 
All randomized subjects 
Analysis item: 
Subjects in Analysis Sets       [Reason for exclusion] 
Adoption or rejection of analysis sets 
  Full Analysis Set of the Treatment Period      [Adopted] 
  Safety Analysis Set of the Treatment Period  [Adopted] 
Analytical 
methods: 
For the above analytical variables, the following analyses should be performed for each 
treatment group in (1) and for each treatment group and the pooled treatment group in (2). 
In (1), a subject falling into more than one category should be counted as 1 subject in each of 
the categories (multiple counting). 
(1) Calculation of frequencies of subjects in each analysis set 
(2) Calculation of frequencies of subjects included in each analysis set 
 
6.1.4.2.2 Data sets to be analyzed (maintenance phase) 
Analysis 
population: 
Subjects Enrolled in Maintenance Phase 
Analysis item: 
Subjects in Analysis Sets       [Reason for exclusion] 
Adoption or rejection of analysis sets 
  Full Analysis Set of the maintenance phase      [Adopted] 
  Safety Analysis Set of the maintenance phase  [Adopted] 
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Analytical 
methods: 
For the above analytical variables, the following analyses should be performed for each 
treatment group in (1) and for each treatment group and the pooled treatment group in (2). 
In (1), a subject falling into more than one category should be counted as 1 subject in each of 
the categories (multiple counting). 
(1) Calculation of frequencies of subjects in each analysis set 
(2) Calculation of frequencies of subjects included in each analysis set 
 
6.2. Demographic and Other Baseline Characteristics 
6.2.1. Distribution of Baseline Characteristics 
Analysis 
population: 
All randomized subjects 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Age (years)     [Min<= - <65, 65<= - <75, 75<= - <=Max] 
Sex        [Male, female] 
Height (at the start of treatment period) (cm) [Min < = - < 150, 150 < = - < 160, 
160<= - <170, 170<= - <=Max] 
Body weight (at the start of the treatment period) (kg)   [Min<= - <50.0, 50.0<= - <60.0, 
                   60.0<= - <70.0, 70.0<= - <80.0, 
          80.0<= - <=Max] 
BMI (at the start of the treatment period) (kg/m 2) [Min < = - < 18.5, 18.5 < = - < 25.0] 
                    25.0<= - <=Max] 
Smoking history         [I have never smoked, I am a current smoker, 
I used to smoke but now I do not smoke] 
Alcohol history           [Taking it every day, taking it about 2 or 3 days a week, taking 
it about 2 or 3 days a month, not taking it at all] 
Consumption of caffeine-containing beverages      [Yes, No] 
Endoscopy (at the start of the treatment period) 
 Endoscopy (esophagus) 
  Severity classification   [Grade O, Grade A, Grade B, 
                     Grade C, Grade D 
CYP2 C 19 genotyping [* 1/* 1, * 1/* 2, * 1/* 3, * 2/* 2, * 2/* 3, * 3/* 3] 
Serum gastrin level (at the start of the treatment period) [Min < = - < 200, 200 < = - < = Max] 
Serum pepsinogen I/II ratio (at the start of the treatment period) 
[Min<= - <=2.0, 2.0< - <=3.0, 3.0< - <=Max] 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for treatment 
groups combined. 
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13 
(1) 
Calculation of frequencies of categorical data and summary statistics of continuous 
data 
 
6.2.2. Medical history and complications 
Analysis 
population: 
Safety Analysis Set of the Treatment Period 
Analysis item: 
Medical history 
Concomitant conditions 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for each 
treatment group. 
The analysis items will be coded using MedDRA and summarized by SOC and PT. SOCs 
should be displayed in alphabetical order and PTs in descending order of frequency. 
(1) Calculation of frequencies of previous diseases (by SOC/PT) 
(2) Calculation of frequencies of complications (by SOC/PT) 
In calculation of frequencies, events should be counted in the following manner. 
[Number of cases] 
If an event in the same SOC occurs more than once in the same subject, the subject will be 
counted as 1 subject in the SOC. If an event with the same PT occurs more than once in the 
same subject, the subject will be counted as 1 subject with the PT. 
 
6.2.3. Prior and concomitant medications 
Analysis 
population: 
Safety Analysis Set of the Treatment Period 
Analysis item: 
Prior medications 
Concomitant Medications 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for each 
treatment group.      Analysis items will be coded using the World Health Organization 
(WHO) Drug Dictionary. They should be listed in order of frequency. If the same subject is 
administered the same drug more than once, the subject will be counted as 1 subject for the 
drug. 
(1) Calculation of frequencies of prior medications 
(2) Calculation of frequencies of concomitant medications used during and after the 
treatment period, starting before administration of study product or the comparator 
during the treatment period 
(3) Calculation of frequencies of concomitant drugs started after administration of study 
product or control drug in the treatment period 
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14 
(4) Calculation of frequencies of study product used in the treatment period or 
the comparator used in the treatment period, or study product used in the 
maintenance period or the comparator used in the treatment period 
 
6.3. Compliance 
6.3.1. Compliance 
Analysis 
population: 
Safety Analysis Set of the Treatment Period 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Compliance     [Regular dosing (≥ 90%), regular dosing (≥ 70%), half dosing (≥ 50%), 
half dosing missed (< 50%)] 
Timepoint: 
[Safety analysis set in the treatment period] 
Treatment Period Weeks 4 and 8 
[Safety Analysis Set of the maintenance phase] 
Maintenance Period Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 132, 156, 180, 204, 228 
and 260 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed at each 
evaluation time point for treatment groups and treatment groups combined. 
(1) Frequency tabulation 
 
6.3.2. Treatment duration 
Analysis 
population: 
All subjects who received study product or control drug for the treatment period 
All subjects who received study product or control drug for the maintenance phase 
Analysis item: 
Duration (days) of treatment with study product or control drug in the treatment period   
[1<= - <=28, 29<= - <=56, 57<= - <=Max] 
Duration (days) of treatment with study product or control drug in the maintenance phase   
[1<= - <=84, 85<= - <=168, 169<= - <=252, 253<= - <=336, 337<= - <=420, 
421<= - <=504, 505<= - <=588, 589<= - <=672, 673<= - <=756, 757<= - 
<=1092, 1093<= - <=1428, 1429<= - <=1820,1821<= - <=Max] 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for treatment 
groups combined. 
(1) Calculation of frequencies of categorical data and summary statistics of continuous 
data 
      
 
 
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15 
7. 
EFFICACY EVALUATION 
7.1. Secondary Endpoints and Analytical Methods 
7.1.1. Recurrence rate of reflux esophagitis based on endoscopic findings 
Analysis 
population: 
Full Analysis Set of the maintenance phase 
Analysis item: 
Recurrence rate of reflux esophagitis based on endoscopic findings 
Timepoint: 
Maintenance Period Weeks 48, 108, 156, 204 and 260 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for evaluation 
at each evaluation time point and evaluation up to the evaluation time point. 
(1) 
Calculation of frequencies, point estimates, and two-sided 95% CIs for the recurrence 
rate by treatment group 
(2) 
Using the Kaplan-Meier method, the cumulative recurrence rate of reflux esophagitis, 
standard error according to Greenwood's formula, and two-sided 95% confidence 
interval will be calculated for each treatment group, and Kaplan-Meier curves will be 
presented graphically. In addition, the number of patients at risk, cumulative incidence 
of relapse, and two-sided 95% confidence interval according to Greenwood's formula 
will be presented for each evaluation time point. 
 
7.1.2. Healing rate of reflux esophagitis during the treatment period 
Analysis 
population: 
Full Analysis Set of the Treatment Period 
Analysis item: 
Cure rate of reflux esophagitis 
Timepoint: 
Treatment Period Weeks 4 and 8 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for evaluation 
at each evaluation time point and evaluation up to the evaluation time point. 
(1) 
Calculation of frequencies, point estimates, and two-sided 95% CIs for cure rates by 
treatment group 
 
7.2. Other Analyses 
7.2.1. Barrett's mucosa assessment 
Analysis 
population: 
Full Analysis Set of the Treatment Period 
Full Analysis Set of the maintenance phase 
Analysis item: 
Barrett's mucosa [Present (≥ 3 cm), Present (< 3 cm), Absent, Unknown] 
Timepoint: 
[Full analysis set in the treatment period] 
At the start of the treatment period, and Treatment Period Weeks 4 and 8 
[Full analysis set in the maintenance phase] 
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Maintenance Period Weeks 48, 108, 156, 204 and 260 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for each 
evaluation time point. 
(1) 
Calculation of frequencies by treatment group 
 
7.2.2. Evaluation of esophageal hiatal hernia 
Analysis 
population: 
Full Analysis Set of the Treatment Period 
Full Analysis Set of the maintenance phase 
Analysis item: 
hiatal hernia     [Yes (≥ 2 cm), Yes (< 2 cm), 
None, unknown] 
Timepoint: 
[Full analysis set in the treatment period] 
At the start of the treatment period, and Treatment Period Weeks 4 and 8 
[Full analysis set in the maintenance phase] 
Maintenance Period Weeks 48, 108, 156, 204 and 260 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for each 
evaluation time point. 
(1) 
Calculation of frequencies by treatment group 
 
 
8. 
SAFETY EVALUATION 
8.1. Primary Endpoint and Analytical Methods 
Analysis 
population: 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Histopathological examination of gastric mucosa * 
Presence or absence of epithelial cell tumorigenesis    [Yes, No, Not Evaluable] 
Presence or absence of parietal cell elevation/hyperplasia   [Yes, No, Not Evaluable] 
Presence or absence of crypt epithelial hyperplasia        [Yes, No, Not Evaluable] 
Endocrine proliferation    [Present (1 (atrophic ECM), 2 (hyperplastic ECM), 3 (neoplastic 
ECM), 4 (typical carcinoid)), absent, not evaluable] 
Presence or absence of G cell hyperplasia          [Yes, No, Not Evaluable] 
*For evaluation up to the evaluation time point, the presence or absence of endocrine cell 
proliferation should be represented in the order of 4 (typical carcinoid), 3 (neoplastic ECM), 
2 (hyperplastic ECM), and 1 (atrophic ECM) as the details of presence. If all tests conducted 
during TIME WINDOW for each item are “not evaluable, ” the evaluations up to the 
evaluation time point will be considered“ not evaluable.” 
Timepoint: 
Start of the treatment period, and Weeks 48, 108, 156, 204 and 260 of the maintenance period 
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17 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for evaluation 
at each evaluation time point and evaluation up to the evaluation time point. 
(1) 
Calculation of frequencies and percentages by treatment group 
(2) 
Using the Kaplan-Meier method, the cumulative incidence of each finding in 
histopathological examination of gastric mucosa, standard error according to 
Greenwood's formula, and two-sided 95% confidence interval will be calculated for 
each treatment group, and Kaplan-Meier curves will be illustrated. In addition, the 
number of patients at risk, the cumulative incidence, and the two-sided 95% 
confidence interval according to Greenwood's formula will be presented for Weeks 52, 
112, 160, 208, and 264 from the start of the treatment period as the starting point. 
(3) 
For endocrine cell proliferation, cross tabulation tables at the start of the treatment 
period and at each evaluation time point will be prepared. Endocrine proliferation 
response is considered as none, 1 (atrophic ECM), 2 (hyperplastic ECM), 3 (neoplastic 
ECM), 4 (typical carcinoid) or not evaluable. 
 
8.2. Secondary Endpoints and Analytical Methods 
8.2.1. Incidence of Adverse Events (TEAE) 
8.2.1.1. Overview of TEAEs During the Maintenance Period 
Analysis population: 
Safety Analysis Set of the maintenance phase 
Analysis item: 
TEAEs Occurring in the Maintenance Period 
Category: 
Relationship to study product or Control Drugs  [Related, not related] 
Severity                              [Mild, moderate, severe] 
Time of onset         [1<= - <=84, 85<= - <=168, 169<= - <=252, 253<= - <=336, 
337<= - <=420, 421<= - <=504, 505<= - <=588, 589<= 
- <=672, 673<= - <=756, 757<= - <=1092, 1093<= - 
<=1428, 1429<= - <=1820,1821<= - <=Max] 
Analytical methods: 
For the above analytical variable, the following analyses should be performed for each 
treatment group. 
1) 
Calculation of frequencies of all TEAEs 
2) 
Calculation of frequencies of TEAEs by causal relationship with study product 
or control drug 
3) 
Calculation of frequencies of all TEAEs by intensity 
4) 
Calculation of frequencies of TEAEs by severity by causal relationship with 
study product or control drug 
5) 
Calculation of frequencies of TEAEs leading to study drug discontinuation for 
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study product or comparator 
6) 
Calculation of frequencies of serious TEAEs 
7) 
Calculation of frequencies of serious TEAEs by causal relationship with study 
product or the study drug 
8) 
Calculation of frequencies of serious TEAEs leading to treatment 
discontinuation for study product or comparator 
9) 
Calculation of frequencies of TEAEs with outcome of death 
10) 
Calculation of frequencies of TEAEs by time of onset 
11) 
Calculation of frequencies of serious TEAEs by time of onset 
12) 
Calculation of frequencies of TEAEs related to diarrhea 
13) 
Calculation of frequencies of TEAEs related to intestinal infection 
14) 
Calculation of frequencies of TEAEs related to fracture 
15) 
Calculation of frequencies of TEAEs related to pneumonia 
In performing each analysis, events should be counted and incidences should be 
calculated in the following manner. 
[Number of cases] 
 
When "Calculation of frequencies by severity" is performed 
If a subject experiences TEAEs more than once, the subject will be counted as 1 
subject in the severest category. In the calculation of incidences of TEAEs, the 
denominator should be the number of subjects in the safety analysis set in the 
maintenance phase. 
 
When "Calculation of frequencies by time of onset" is performed 
If a TEAE occurs more than once in the same subject, each TEAE will be counted 
as 1 subject in the relevant time of onset category. In the calculation of incidences 
of TEAEs in each time period, the denominator should be the number of subjects 
"who received the study product for the maintenance phase or the control drug 
in and after the time period" or "who experienced the TEAE in and after the time 
period" in the safety analysis set of the maintenance phase, and the numerator is 
the number of subjects "who experienced the TEAE in the time period." 
 
When "Calculation of frequencies by causal relationship" is performed 
A subject who experienced both TEAEs “related ” and“ not related ” to study 
product or control drug will be counted as 1 subject in the “related ” category. 
 
When tabulation other than the above is performed 
A subject who experienced a TEAE more than once will be counted as 1 subject. 
In the calculation of incidences of TEAEs, the denominator should be the number 
of subjects in the safety analysis set in the maintenance phase. 
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19 
 
8.2.1.2. Display of TEAEs Occurring in the Maintenance Period 
Analysis population: 
Safety Analysis Set of the maintenance phase 
Analysis item: 
TEAEs Occurring in the Maintenance Period 
Category: 
Relationship to study product or Control Drugs   [Related, not related] 
Severity                             [Mild, moderate, severe] 
Time of onset          [1<= - <=84, 85<= - <=168, 169<= - <=252, 253<= - <=336, 
337<= - <=420, 421<= - <=504, 505<= - <=588, 589<= 
- <=672, 673<= - <=756, 757<= - <=1092, 1093<= - 
<=1428, 1429<= - <=1820,1821<= - <=Max] 
Analytical methods: 
For the above analytical variable, the following analyses should be performed for each 
treatment group. TEAEs will be coded using MedDRA and summarized by SOC and 
PT. When tabulating by SOC/PT, SOCs should be displayed in alphabetical order and 
PTs in descending order of frequency. 
1) 
Calculation of frequencies of all TEAEs (SOC/PT) 
2) 
Calculation of frequencies of TEAEs by causal relationship with study product 
or control drug (SOC/PT) 
3) 
Calculation of frequencies of all TEAEs by severity (SOC/PT) 
4) 
Calculation of frequencies of TEAEs by severity for each causal relationship 
with study product or control drug (SOC/PT) 
5) 
Calculation of frequencies of TEAEs leading to discontinuation of study product 
or control drug (SOC/PT) 
6) 
Calculation of frequencies of serious TEAEs (SOC/PT) 
7) 
Calculation of frequencies of serious TEAEs by causal relationship to study 
product or the study drug (SOC/PT) 
8) 
Calculation of frequencies of serious TEAEs leading to discontinuation of study 
product or control drug (by SOC/PT) 
9) 
Calculation of frequencies of TEAEs with outcome of death (SOC/PT) 
10) 
Calculation of frequencies of TEAEs by time of onset (SOC/PT) 
11) 
Calculation of frequencies of serious TEAEs by time of onset (SOC/PT) 
12) 
Calculation of frequencies of diarrhea-related TEAEs (SOC/PT) 
13) 
Calculation of frequencies of TEAEs related to intestinal infection (SOC/PT) 
14) 
Calculation of frequencies of fracture-related TEAEs (SOC/PT) 
15) 
Calculation of frequencies of pneumonia-related TEAEs (SOC/PT) 
16) 
Calculation of frequencies of non-serious TEAEs with an incidence of > 5% 
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20 
(SOC/PT) 
In performing each analysis, events should be counted and incidences should be 
calculated in the following manner. 
[Number of cases] 
 
When "frequency tabulation (by SOC/PT)" is performed 
If a subject experiences TEAEs in the same SOC more than once, the subject will 
be counted as 1 subject in the SOC. If a subject experiences TEAEs with the 
same PT more than once, the subject will be counted as 1 subject with the PT. In 
the calculation of incidences of TEAEs, the denominator should be the number 
of subjects in the safety analysis set in the maintenance phase. 
 
When "Calculation of frequencies by severity (SOC/PT)" is performed 
If a subject experiences TEAEs in the same SOC or with the same PT more than 
once, the subject will be counted as 1 subject in the severest category of the SOC 
or PT. In calculation of incidences of TEAEs, the denominator should be the 
number of subjects in the safety analysis set in the maintenance phase. 
 
When "Calculation of frequencies by time of onset (SOC/PT)" is performed 
A subject who experienced TEAEs in the same SOC or with the same PT more 
than once will be counted as 1 subject in each of the categories of time of onset. 
The denominator for the calculation of incidences of TEAEs in each time period 
is the subjects "who received the study product for the maintenance phase or the 
control drug in and after the time period" or "who experienced the TEAE in and 
after the time period" in the safety analysis set of the maintenance phase, and the 
numerator is the number of subjects "who experienced the TEAE in the time 
period." 
 
When "Calculation of frequencies by causal relationship (SOC/PT)" is 
performed 
A subject who experienced more than one TEAE in the same SOC or TEAE with 
the same PT and experienced both TEAEs with a causal relationship of 
“Related ” and“ Not related ” will be counted as 1 subject in the “Related ” 
category. In calculation of incidences of TEAEs, the denominator should be the 
number of subjects in the safety analysis set in the maintenance phase. 
 
8.2.1.3. Overview of Treatment-Emergent Adverse Events During the Treatment Period 
Analysis population: 
Safety Analysis Set of the Treatment Period 
Analysis item: 
Treatment-Emergent Adverse Events During the Treatment Period 
Category: 
Relationship to study product or Control Drugs  [Related, not related] 
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21 
Severity                             [Mild, moderate, severe] 
Time of onset                     [1<= - <=28, 
29<= - <=56, 
57<= - <=Max] 
Analytical methods: 
Analyses should be performed in the same manner as in 8.2. 1.1. In performing each 
analysis, events should be counted and incidences should be calculated in the following 
manner. 
[Number of cases] 
 
When "Calculation of frequencies by severity" is performed 
If a subject experiences TEAEs more than once, the subject will be counted as 1 
subject in the severest category. In the calculation of incidences of TEAEs, the 
denominator should be the number of subjects in the safety analysis set during 
the treatment period. 
 
When "Calculation of frequencies by time of onset" is performed 
If a TEAE occurs more than once in the same subject, each TEAE will be counted 
as 1 subject in the relevant time of onset category. In the calculation of incidences 
of TEAEs in each time period, the denominator should be the number of subjects 
"who received the study product or the control drug for the treatment period in 
and after the time period" or "who experienced the TEAE in and after the time 
period" in the safety analysis set for the treatment period, and the numerator is 
the number of subjects "who experienced the TEAE in the time period." 
 
When "Calculation of frequencies by causal relationship" is performed 
A subject who experienced both TEAEs “related ” and“ not related ” to study 
product or control drug will be counted as 1 subject in the “related ” category. 
 
When tabulation other than the above is performed 
A subject who experienced a TEAE more than once will be counted as 1 subject. 
In the calculation of incidences of TEAEs, the denominator should be the number 
of subjects in the safety analysis set during the treatment period. 
 
8.2.1.4. Display of TEAEs Occurring during the Treatment Period 
Analysis population: 
Safety Analysis Set of the Treatment Period 
Analysis item: 
Treatment-Emergent Adverse Events During the Treatment Period 
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22 
Category: 
Relationship to study product or Control Drugs  [Related, not related] 
Severity                             [Mild, moderate, severe] 
Time of onset                     [1<= - <=28, 
29<= - <=56, 
57<= - <=Max] 
Analytical methods: 
Analyses should be performed in the same manner as in 8.2. 1.2. In performing each 
analysis, events should be counted and incidences should be calculated in the following 
manner. 
[Number of cases] 
 
When "frequency tabulation (by SOC/PT)" is performed 
If an event in the same SOC occurs more than once in the same subject, the 
subject will be counted as 1 subject in the SOC. If an event with the same PT 
occurs more than once in the same subject, the subject will be counted as 1 
subject with the PT. In the calculation of incidences of TEAEs, the denominator 
should be the number of subjects in the safety analysis set during the treatment 
period. 
 
When "Calculation of frequencies by severity (SOC/PT)" is performed 
If an event in the same SOC or with the same PT occurs more than once in the 
same subject, the subject will be counted as 1 subject in the severest category of 
the SOC or PT. In the calculation of incidences of TEAEs, the denominator 
should be the number of subjects in the safety analysis set during the treatment 
period. 
 
When "Calculation of frequencies by time of onset (SOC/PT)" is performed 
If an event under the same SOC or with the same PT occurs more than once in 
the same subject, the subject will be counted as 1 subject in each of the categories 
of the time of onset. The denominator for the calculation of incidences of TEAEs 
in each time period is the subjects "who received the study product for the 
treatment period or the control drug in and after the time period" or "who 
experienced the TEAE in and after the time period" in the safety analysis set for 
the treatment period, and the numerator is the number of subjects "who 
experienced the TEAE in the time period." 
 
When "Calculation of frequencies by causal relationship (SOC/PT)" is 
performed 
A subject who experienced more than one TEAE in the same SOC or TEAE with 
the same PT and experienced both TEAEs with a causal relationship of 
“Related ” and“ Not related ” will be counted as 1 subject in the “Related ” 
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23 
category. In the calculation of incidences of TEAEs, the denominator should be 
the number of subjects in the safety analysis set during the treatment period. 
 
8.2.1.5. Overview of Treatment-Emergent Adverse Events During the Study Period 
Analysis population: 
Safety Analysis Set of the Treatment Period 
Analysis item: 
Treatment-Emergent Adverse Events During the Study Period 
Category: 
Relationship to study product or Control Drugs  [Related, not related] 
Severity                             [Mild, moderate, severe] 
Time of onset    [1<= - <=28, 29<= - <=56, 57<= - <=140, 141<= - <=224, 225<= - 
<=308, 309<= - <=392, 393<= - <=476, 477<= - <=560, 561<= - 
<=644, 645<= - <=728, 729<= - <=812, 813<= - <=1148, 1149<= - 
<=1484, 1485<= - <=1876, 1877<= - <=Max] 
Analytical methods: 
Analyses should be performed in the same manner as in 8.2. 1.1. In performing each 
analysis, events should be counted and incidences should be calculated in the following 
manner. 
[Number of cases] 
 
When "Calculation of frequencies by severity" is performed 
If a subject experiences TEAEs more than once, the subject will be counted as 1 
subject in the severest category. In the calculation of incidences of TEAEs, the 
denominator should be the number of subjects in the safety analysis set during 
the treatment period. 
 
When "Calculation of frequencies by time of onset" is performed 
If a TEAE occurs more than once in the same subject, each TEAE will be counted 
as 1 subject in the relevant time of onset category. In the calculation of incidences 
of TEAEs in each time period, the denominator should be the number of subjects 
"who received study product or the control drug in and after the time period" or 
"who experienced the TEAE in and after the time period" in the safety analysis 
set in the treatment period, and the numerator is the number of subjects "who 
experienced the TEAE in the time period." 
 
When "Calculation of frequencies by causal relationship" is performed 
A subject who experienced both TEAEs “related ” and“ not related ” to study 
product or control drug will be counted as 1 subject in the “related ” category. 
 
When tabulation other than the above is performed 
A subject who experienced a TEAE more than once will be counted as 1 subject. 
In the calculation of incidences of TEAEs, the denominator should be the number 
of subjects in the safety analysis set during the treatment period. 
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24 
 
8.2.1.6. 
Display of TEAEs Occurring during the Study Period 
Analysis population: 
Safety Analysis Set of the Treatment Period 
Analysis item: 
Treatment-Emergent Adverse Events During the Study Period 
Category: 
Relationship to study product or Control Drugs  [Related, not related] 
Severity                             [Mild, moderate, severe] 
Time of onset    [1<= - <=28, 29<= - <=56, 57<= - <=140, 141<= - <=224, 225<= - 
<=308, 309<= - <=392, 393<= - <=476, 477<= - <=560, 561<= - 
<=644, 645<= - <=728, 729<= - <=812, 813<= - <=1148, 1149<= - 
<=1484, 1485<= - <=1876, 1877<= - <=Max] 
Analytical methods: 
Analyses should be performed in the same manner as in 8.2. 1.2. In performing each 
analysis, events should be counted and incidences should be calculated in the following 
manner. 
[Number of cases] 
 
When "frequency tabulation (by SOC/PT)" is performed 
If a subject experiences TEAEs in the same SOC more than once, the subject will 
be counted as 1 subject in the SOC. If a subject experiences TEAEs with the 
same PT more than once, the subject will be counted as 1 subject with the PT. In 
the calculation of incidences of TEAEs, the denominator should be the number 
of subjects in the safety analysis set during the treatment period. 
 
When "Calculation of frequencies by severity (SOC/PT)" is performed 
If a subject experiences TEAEs in the same SOC or with the same PT more than 
once, the subject will be counted as 1 subject in the severest category of the SOC 
or PT. In the calculation of incidences of TEAEs, the denominator should be the 
number of subjects in the safety analysis set during the treatment period. 
 
When "Calculation of frequencies by time of onset (SOC/PT)" is performed 
A subject who experienced TEAEs in the same SOC or with the same PT more 
than once will be counted as 1 subject in each of the categories of time of onset. 
In the calculation of incidences of TEAEs in each time period, the denominator 
should be the number of subjects "who received study product or the control drug 
in and after the time period" or "who experienced the TEAE in and after the time 
period" in the safety analysis set in the treatment period, and the numerator is the 
number of subjects "who experienced the TEAE in the time period." 
 
When "Calculation of frequencies by causal relationship (SOC/PT)" is 
performed 
A subject who experienced more than one TEAE in the same SOC or TEAE with 
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25 
the same PT and experienced both TEAEs with a causal relationship of 
“Related ” and“ Not related ” will be counted as 1 subject in the “Related ” 
category. In the calculation of incidences of TEAEs, the denominator should be 
the number of subjects in the safety analysis set during the treatment period. 
 
8.2.2. Endoscopic findings, histological evaluation of gastritis according to the Sydney classification 
Analysis 
population: 
Safety Analysis Set of the maintenance phase 
Safety Analysis Set of the treatment period (endoscopic findings only) 
Analysis item: 
Endoscopic findings 
 fundic gland polyp     [Yes, No] 
  Hyperplastic polyp      [Yes, No] 
  cobblestone mucosa            [Yes, No] 
  Multiple white flat bumps  [Yes, No] 
  black spot lesion            [Yes, No] 
Histological evaluation of gastritis * (greater curvature of the middle corpus of the stomach, 
greater curvature of the antrum) 
Inflammation (mononuclear cell infiltration)    [Present (Mild, moderate, severe), 
absent, not evaluable] 
Active (neutrophil infiltration)  [Present (Mild, moderate, severe), absent, not evaluable] 
Atrophy         [Present (Mild, moderate, severe), absent, not evaluable] 
Metaplasia, intestinal        [Present (Mild, moderate, severe), absent, not evaluable] 
H.pylori               [Present (Mild, moderate, severe), absent, not evaluable] 
*For assessments made up to the evaluation time point, the details of yes should be 
represented in order of decreasing severity. If all tests conducted during TIME WINDOW 
for each item are “not evaluable, ” the evaluations up to the evaluation time point will be 
considered“ not evaluable.” 
Occurrence of gastric polyp    [Yes, No] 
Timepoint: 
[Endoscopic findings/Safety analysis set in the treatment period] 
At the start of the treatment period, and Treatment Period Weeks 4 and 8 
[Endoscopic findings/Safety analysis set in the maintenance phase] 
Start of the treatment period, and Weeks 48, 108, 156, 204 and 260 of the maintenance 
period 
[Histological evaluation of gastritis] 
Start of the treatment period, and Weeks 48, 108, 156, 204 and 260 of the maintenance 
period 
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26 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for evaluation 
at each evaluation time point and evaluation up to the evaluation time point by treatment 
group. 
(1) 
Calculation of frequencies and percentages 
(2) 
For histological evaluation of gastritis, cross tabulation at the start of the treatment 
period and each evaluation time point will be prepared. The response for histologic 
assessment of gastritis will be none, mild, moderate, severe, or not evaluable. 
 
8.2.3. Other endpoints and analysis methods 
8.2.3.1. Clinical Laboratory Evaluation 
Analysis 
population: 
Safety Analysis Set of the Treatment Period 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Blood tests 
 AST, ALT, Fe, Mg, Ca, and vitamin B 12 
Timepoint: 
[Safety analysis set in the treatment period] 
At the start of the treatment period, and Treatment Period Weeks 4 and 8 
[Safety Analysis Set of the maintenance phase] 
At the start of the treatment period, and Treatment Period Weeks 4, 8, and 12 in the 
maintenance period, 
Maintenance Period Weeks 24, 36, 48, and 60 
Maintenance Period Weeks 72, 84, 96, and 108 
Maintenance Period Weeks 132, 156, 180, and 204 
Maintenance Period Week 228, Maintenance Period Week 260 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for each 
treatment group in the safety analysis set during the treatment period. 
(1) 
Summary statistics of observed values at each evaluation time and summary statistics 
of pre- and post-treatment differences (each evaluation time after treatment - at the 
start of the treatment period) at each evaluation time 
(2) 
Individual Time Profiles 
For the above analytical variable, the following analyses will be performed using the safety 
analysis set in the maintenance phase. 
(3) 
Summary statistics of observed values at each evaluation time and summary statistics 
of pre- and post-treatment differences (each evaluation time after treatment - at the 
start of the treatment period) at each evaluation time 
(4) 
Individual Time Profiles 
(5) 
Time-course plots of mean ± SD and box-and-whisker plots will be prepared for each 
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27 
treatment group at each assessment point during the treatment and maintenance 
periods. Time-course plots of mean ± SD and box-and-whisker plots will be provided 
for each treatment group at each assessment point during the study period in the safety 
analysis set during the treatment period. 
   
8.2.3.2. Serum gastrin, pepsinogen I and II levels, and chromogranin A levels 
Analysis 
population: 
Safety Analysis Set of the Treatment Period 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Serum gastrin level 
Serum pepsinogen I level 
Serum pepsinogen II level 
Serum pepsinogen I/II ratio 
Serum chromogranin A level 
Timepoint: 
[Serum gastrin level/safety analysis set during the treatment period] 
At the start of the treatment period, and Treatment Period Weeks 4 and 8 
[Serum gastrin level/safety analysis set in the maintenance phase] 
At the start of the treatment period, and Treatment Period Weeks 4, 8, and 12 in the 
maintenance period, 
Maintenance Period Weeks 24, 36, 48, and 60 
Maintenance Period Weeks 72, 84, 96, and 108 
Maintenance Period Weeks 132, 156, 180, and 204 
Maintenance Period Week 228, Maintenance Period Week 260 
[Analysis sets for serum pepsinogen I, pepsinogen II, pepsinogen I/II ratio, and chromogranin 
A levels/safety data during the treatment period] 
At the start of the treatment period, and Treatment Period Weeks 4 and 8 
[Serum pepsinogen I, pepsinogen II, pepsinogen I/II ratio, and chromogranin A/safety 
analysis set in the maintenance phase] 
At the start of the treatment period, and Treatment Period Weeks 4, 8, and 24 in the 
maintenance period, 
Maintenance Period Weeks 48, 108, 156, and 204 
Maintenance Period Week 260 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for each 
treatment group in the safety analysis set during the treatment period. 
(1) 
Summary statistics of observed values at each evaluation time and summary statistics 
of pre- and post-treatment differences (each evaluation time after treatment - at the 
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28 
start of the treatment period) at each evaluation time 
(2) 
Individual Time Profiles 
For the above analytical variable, the following analyses will be performed using the safety 
analysis set in the maintenance phase. 
(3) 
Summary statistics of observed values at each evaluation time and summary statistics 
of pre- and post-treatment differences (each evaluation time after treatment - at the 
start of the treatment period) at each evaluation time 
(4) 
Individual Time Profiles 
(5) 
Time-course plots of mean ± SD and box-and-whisker plots will be prepared for each 
treatment group at each assessment point during the treatment and maintenance 
periods. Time-course plots of mean ± SD and box-and-whisker plots will be provided 
for each treatment group at each assessment point during the study period in the safety 
analysis set during the treatment period. 
 
8.2.3.3. Vital signs 
Analysis 
population: 
Safety Analysis Set of the Treatment Period 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Pulse rate, systolic blood pressure, diastolic blood pressure 
Timepoint: 
[Safety analysis set in the treatment period] 
At the start of the treatment period, and Treatment Period Weeks 4 and 8 
[Safety Analysis Set of the maintenance phase] 
At the start of the treatment period, and Treatment Period Weeks 4, 8, and 12 in the 
maintenance period, 
Maintenance Period Weeks 24, 36, 48, and 60 
Maintenance Period Weeks 72, 84, 96, and 108 
Maintenance Period Weeks 132, 156, 180, and 204 
Maintenance Period Week 228, Maintenance Period Week 260 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for each 
treatment group in the safety analysis set during the treatment period. 
(1) 
Summary statistics of observed values at each evaluation time and summary 
statistics of pre- and post-treatment differences (each evaluation time after treatment 
- at the start of the treatment period) at each evaluation time 
(2) 
Individual Time Profiles 
For the above analytical variable, the following analyses will be performed using the safety 
analysis set in the maintenance phase. 
(3) 
Summary statistics of observed values at each evaluation time and summary 
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statistics of pre- and post-treatment differences (each evaluation time after treatment 
- at the start of the treatment period) at each evaluation time 
(4) 
Individual Time Profiles 
 
9. 
List 
The following list will be prepared for "all randomized subjects." 
・Background Information 
・Discontinued patients 
・Deviation 
・Patients excluded from the analysis 
・Compliance 
・Concomitant conditions 
・Prior medications 
・Concomitant Medications 
・Endoscopic findings 
・Histopathological examination of gastric mucosa 
・Histological evaluation of gastritis based on the Sydney classification. 
・Laboratory Values 
・Vital signs 
・Adverse events 
 
10. STATISTICAL/ANALYTICAL ISSUES 
10.1. Adjustments for Covariates 
No adjustment for covariates will be made. 
 
10.2. Handling of Dropouts or Missing Data 
Missing values will not be imputed. 
 
10.3. Interim Analysis and Criteria for Early Termination 
  To evaluate the effects of long-term vonoprazan treatment in the maintenance therapy for recurrent/relapsed reflux 
esophagitis, the analysis will be performed not only until the last visit but also every year in the maintenance phase. When 
data from all patients up to the relevant visit [Maintenance Period Weeks 48 (VISIT M 5), 108 (VISIT M 10), 156 (VISIT 
M 12), and 204 (VISIT M 14)] are obtained, the analysis will be performed using data up to the relevant visit in the 
relevant patients. This tabulation is not intended to determine whether to continue or discontinue this clinical research. 
 
The following items will be analyzed at the time of interim analysis. The details of the analysis will be determined at the 
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30 
time of the interim analysis. 
  ・6. Subjects, demographic and other baseline characteristics 
  ・8. SAFETY EVALUATION 
 
10.4. Multicenter Studies 
  No analysis taking into account study sites will be performed. 
 
10.5. Multiple Comparison/Multiplicity 
  No multiplicity adjustment will be performed. 
 
10.6. Examination of Subgroups 
  No subgroup analysis will be performed. 
 
 
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31 
11. REVISION HISTORY 
Ver. 
Date of 
preparation 
Author 
Revised Item 
Description of Revision 
1.0 
2016/2/22 
 
Newly created 
 
2.0 
2018/10/1 
 
Cover page (approver) 
 
 
8.2.1.2. 
Display 
of 
TEAEs 
Occurring in the Maintenance 
Period 
 
 
9.3. Interim Analysis and Criteria 
for Early Termination 
 
・The principal investigator was added as an approver 
based on the enforcement of the Clinical Research Act. 
 
・Added frequency tabulation of non-serious TEAEs with 
an incidence of more than 5% (by SOC/PT) in the 
tabulation of adverse events by SOC/PT. 
 
・Modified the timing of interim analysis based on the 
results of discussion at the study steering committee held 
on 2017/12/2. 
3.0 
2018/11/13 
 
・Handling of TIME WINDOW 
 
 
 
 
 
 
 
 
 
・8.2.1.1. Overview of TEAEs 
During the Maintenance Period 
~ 8.2.1.6. Display of Treatment-
Emergent Adverse Events During 
the Study Period 
 
 
 
 
 
 
Since the main objective of the present study was to 
evaluate the long-term safety of vonoprazan and the results 
of data review, it was considered desirable to contribute 
data as much as possible to the analysis. Therefore, the 
acceptable range of days after administration was modified 
for endoscopy, histopathological examination of gastric 
mucosa, histological evaluation of gastritis, laboratory test 
values, vital signs, serum gastrin levels, pepsinogen I/II 
levels, and chromogranin A levels. 
 
Corrected the description to perform tabulation of "not 
related" causality, instead of only "related." 
 
Added the frequency tabulation of serious TEAEs by time 
of onset and the frequency tabulation of serious TEAEs by 
time of onset by SOC/PT to the necessity of tabulation. 
 
8.2.1.5. In the overview of TEAEs that occurred during the 
study period and 8.2.1.6. Display of TEAEs that occurred 
during the study period, the category of "309 < = - < = 362" 
by time of onset was corrected to "309 < = - < = 392" 
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32 
Ver. 
Date of 
preparation 
Author 
Revised Item 
Description of Revision 
 
 
 
・9. LIST 
 
 
・10.3. Interim Analysis and 
Criteria for Early Termination 
 
 
because it was an error. 
 
Added since a list needs to be prepared. 
 
The analysis item at the time of interim analysis was 
modified 
from 
"6.2.1. 
Distribution 
of 
Baseline 
Characteristics" 
to 
"6. 
Subjects, 
demographic 
characteristics and other baseline characteristics." 
4.0 
2019/3/25 
 
・8.2.3.1. Clinical Laboratory 
Evaluations 
8.2.3.2.Serum gastrin, pepsinogen 
I and II levels, and chromogranin 
A levels 
Preparation of time-course plots of mean ± SD at each 
evaluation time point in the treatment and maintenance 
phases was added for each treatment group. In addition, 
preparation of time-course plots of mean ± SD at each 
evaluation time point during the study period was added for 
each treatment group. 
5.0 
2020/9/28 
 
 
・8.1. Primary Endpoint and 
Analytical Methods 
・8.2.2. Endoscopic findings, 
histological evaluation of gastritis 
according 
to 
the 
Sydney 
classification 
Not Evaluable was added to the evaluation category of each 
endpoint (Except for endoscopic findings in 8.2.2.). 
Added that if all tests performed within TIME WINDOW 
for each item are “not evaluable, ” the assessments up to 
that evaluation time point will be“ not evaluable.” 
 
 
 
 
・8 2 3. Other endpoints and 
analysis methods 
Treatment Period Weeks 4 and 8 were added to the 
evaluation time points in the [maintenance phase safety 
analysis set]. 
8.2.3.1.Preparation of box-and-whisker plots was added to 
Section and 8.2.3.2. 
6.0 
2022/8/19 
 
 
3.2 Subgroups 
6.3.3. 
Relation 
between 
recurrence of reflux esophagitis 
and dose increase 
6.3.4. Severity classification at the 
start of the treatment period by 
presence/absence of dose increase 
New addition 
 
 
 
 
 
 
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33 
Ver. 
Date of 
preparation 
Author 
Revised Item 
Description of Revision 
6.3.5. Severity classification and 
endoscopic findings before dose 
increase 
7.2.3. Risk factors for recurrence 
of reflux esophagitis 
8.2.3.3. 
Serum 
gastrin 
and 
chromogranin A levels by the 
presence or absence of endoscopic 
findings 
8.2.3.4. 
Correlation 
between 
serum gastrin and chromogranin A 
levels 
8.2.3.5. Changes in serum gastrin 
level during the maintenance 
phase 
 
6.2.1. Distribution of Baseline 
Characteristics 
8.1. 
Primary 
Endpoint 
and 
Analytical Methods 
 
8.1. 
Primary 
Endpoint 
and 
Analytical Methods 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Addition of subgroup analysis 
 
 
 
The time points at which the number of patients at risk, 
cumulative incidence, and two-sided 95% confidence 
interval according to Greenwood's formula will be 
presented were modified to Weeks 52, 112, 160, 208, and 
264 from the start of the treatment period. 
7.0* 
2023/2/1 
 
 
3.1 (deletion of section numbers) 
3.2 Subgroups 
6.3.3. 
Relation 
between 
recurrence of reflux esophagitis 
and dose increase 
6.3.4. Severity classification at the 
start of the treatment period by 
presence/absence of dose increase 
6.3.5. Severity classification and 
endoscopic findings before dose 
increase 
Deletion of the item on the left newly added in Ver. 6.0 
 
 
 
 
 
 
 
 
 
 
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34 
Ver. 
Date of 
preparation 
Author 
Revised Item 
Description of Revision 
7.2.3. Risk factors for recurrence 
of reflux esophagitis 
8.2.3.3. 
Serum 
gastrin 
and 
chromogranin A levels by the 
presence or absence of endoscopic 
findings 
8.2.3.4. 
Correlation 
between 
serum gastrin and chromogranin A 
levels 
8.2.3.5. Changes in serum gastrin 
level during the maintenance 
phase 
 
6.2.1. Distribution of Baseline 
Characteristics 
8.1. 
Primary 
Endpoint 
and 
Analytical Methods 
 
 
 
 
 
 
 
 
 
 
Deletion of subgroup analysis 
* Preparation of Ver. 7.0: 
It was decided to prepare an additional analysis plan including the items newly added in Ver. 6.0, and Ver. 7.0, which 
retained only the existing analysis items, was separately prepared for the purpose of document organization. 
 
 
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Evaluation of Long-term Safety of Maintenance Treatment with Vonoprazan in Patients 
with Erosive Esophagitis 
(Vonoprazan -4003) 
 
Statistical Analysis Plan 
(additional analysis) 
(Ver. 1.0 Date of preparation: 2023/2/1) 
 
 
Sponsor: Takeda Pharmaceutical Company Limited. 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
   
 
   
 
   
 
 
  
        
    
 
 
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TABLE OF CONTENTS 
1. 
Data handling, etc. ........................................................................................................................................ 1 
2. 
Analysis Sets ................................................................................................................................................. 1 
2.1. Analysis Sets ................................................................................................................................................ 1 
2.2. Subgroup ..................................................................................................................................................... 1 
3. 
Demographic and Other Baseline Characteristics ......................................................................................... 1 
3.1. Distribution of Baseline Characteristics....................................................................................................... 1 
3.2. Compliance ................................................................................................................................................. 2 
4. 
EFFICACY EVALUATION .......................................................................................................................... 3 
4.1. Secondary Endpoints and Analytical Methods ............................................................................................. 3 
4.2. Other Analyses ............................................................................................................................................ 4 
5. 
SAFETY EVALUATION .............................................................................................................................. 5 
5.1. Primary Endpoint and Analytical Methods .................................................................................................. 5 
5.2. Secondary Endpoints and Analytical Methods ............................................................................................. 6 
6. 
STATISTICAL/ANALYTICAL ISSUES ..................................................................................................... 10 
6.1. Multiple Comparison/Multiplicity ............................................................................................................. 10 
7. 
REVISION HISTORY ................................................................................................................................ 11 
 
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1 
1. 
Data handling, etc. 
Handling of evaluation time points, matters to be considered in the analysis, and other handling will be in accordance with the 
analysis plan (Ver. 7.0) for this analysis. 
 
2. 
Analysis Sets 
2.1. Analysis Sets 
・ 
Full Analysis Set of the Treatment Period 
Subjects who were randomized and received study product for the treatment period or the control drug at least once 
・ 
Full Analysis Set of the maintenance phase 
Subjects who were randomized and received at least one dose of study product for the maintenance phase or the 
control drug 
・ 
Safety Analysis Set of the Treatment Period 
Subjects who received at least one dose of study product or control drug for the treatment period 
・ 
Safety Analysis Set of the maintenance phase 
    Subjects who received study product for the maintenance phase or the control drug at least once 
 
2.2. Subgroup 
Based on the mean serum gastrin and chromogranin A levels at Week 12 or later in the maintenance phase, 3 subgroups 
will be established. 
・ 
Serum gastrin level: < 1000 pg/mL, ≥ 1000 pg/mL and < 2000 pg/mL, ≥ 2000 pg/mL 
・ 
Serum chromogranin A level: < 500 ng/mL, ≥ 500 to < 1000 ng/mL, ≥ 1000 ng/mL 
 
3. 
Demographic and Other Baseline Characteristics 
3.1. Distribution of Baseline Characteristics 
Analysis 
population: 
All randomized subjects 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Age (years)     [Min<= - <65, 65<= - <75, 75<= - <=Max] 
Sex        [Male, female] 
Height (at the start of treatment period) (cm) [Min < = - < 150, 150 < = - < 160, 
160<= - <170, 170<= - <=Max] 
Body weight (at the start of the treatment period) (kg)   [Min<= - <50.0, 50.0<= - <60.0, 
                   60.0<= - <70.0, 70.0<= - <80.0, 
          80.0<= - <=Max] 
BMI (at the start of the treatment period) (kg/m 2) [Min < = - < 18.5, 18.5 < = - < 25.0] 
                    25.0<= - <=Max] 
Smoking history         [I have never smoked, I am a current smoker, 
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2 
I used to smoke but now I do not smoke] 
Alcohol history               [Taking it every day, taking it about 2 or 3 days a week, 
taking it about 2 or 3 days a month, not taking it at all] 
Consumption of caffeine-containing beverages      [Yes, No] 
Endoscopy (at the start of the treatment period) 
 Endoscopy (esophagus) 
  Severity classification   [Grade O, Grade A, Grade B, 
                     Grade C, Grade D 
CYP2 C 19 genotyping [* 1/* 1, * 1/* 2, * 1/* 3, * 2/* 2, * 2/* 3, * 3/* 3] 
Serum gastrin level (at the start of the treatment period) [Min < = - < 200, 200 < = - < = Max] 
Serum pepsinogen I/II ratio (at the start of the treatment period)   
[Min<= - <=2.0, 2.0< - <=3.0, 3.0< - <=Max] 
Analytical 
methods: 
For the subgroups described in 2.2 (Serum gastrin level, serum chromogranin A level), 
frequency tabulation of discrete data and summary statistics of continuous data will be 
calculated. 
 
3.2. Compliance 
3.2.1. Relation between recurrence of reflux esophagitis and dose increase 
Analysis 
population: 
Patients with experience of dose increase among all patients who received study product for 
the maintenance phase or control drug 
Analysis item: 
Presence or absence of recurrence at the last endoscopy before dose increase 
Number of days from endoscopic recurrence to dose increase 
Analytical 
methods: 
A list of analysis items will be prepared. 
 
3.2.2. Severity classification at the start of the treatment period by presence/absence of dose increase 
Analysis 
population: 
All subjects who received study product or control drug for the maintenance phase 
Analysis item: 
Severity classification at the start of the treatment period by presence/absence of dose increase 
Analytical 
methods: 
The subjects will be divided into the dose-increasing experienced group and the non-dose-
increasing experienced group, and the frequency will be tabulated for each treatment group. 
 
3.2.3. Severity classification and endoscopic findings before dose increase 
Analysis 
population: 
Patients with experience of dose increase among all patients who received study product for 
the maintenance phase or control drug 
Analysis item: 
Number of dose escalations 
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Severity based on the most recent endoscopic finding before dose increase 
Presence/absence of recent endoscopic findings before dose increase (Fundus gland polyp, 
hyperplastic polyp, cobblestone mucosa, multiple white flat protrusions, black spot lesion) 
Analytical 
methods: 
The following analyses will be performed for subjects with dose escalation experience. 
(1) Calculation of the frequency of findings at the latest endoscopy after dose increase 
Number of dose escalations will be calculated. The number of events and the rate of 
dose increase as denominators will be calculated for severity and presence of each 
finding at the last endoscopy after dose increase. 
 
4. 
EFFICACY EVALUATION 
4.1. Secondary Endpoints and Analytical Methods 
4.1.1. Recurrence rate of reflux esophagitis based on endoscopic findings 
Analysis 
population: 
Full Analysis Set of the maintenance phase 
Analysis item: 
Recurrence rate of reflux esophagitis based on endoscopic findings 
Timepoint: 
Maintenance Period Weeks 48, 108, 156, 204 and 260 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for evaluation 
at each evaluation time point and evaluation up to the evaluation time point. 
(1) 
Frequency tabulation by treatment group, point estimate of recurrence rate, and two-
sided 95% confidence interval will be calculated, and Fisher's exact test will be 
performed for the difference in recurrence rate between the treatment groups. Mann-
Whitney U test will be performed for severity classification. 
(2) 
Using the Kaplan-Meier method, the cumulative recurrence rate of reflux esophagitis, 
standard error according to Greenwood's formula, and two-sided 95% confidence 
interval will be calculated for each treatment group, and Kaplan-Meier curves will be 
presented graphically. In addition, the number of patients at risk, cumulative incidence 
of relapse, and two-sided 95% confidence interval according to Greenwood's formula 
will be presented for each evaluation time point. In addition, comparison between 
groups will be performed by log-rank test. 
 
4.1.2. Healing rate of reflux esophagitis during the treatment period 
Analysis 
population: 
Full Analysis Set of the Treatment Period 
Analysis item: 
Cure rate of reflux esophagitis 
Timepoint: 
Treatment Period Weeks 4 and 8 
Analytical 
For evaluation at and by evaluation time points, frequency tabulation by treatment group, 
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4 
methods: 
point estimate of cure rate, and two-sided 95% confidence interval will be calculated. In 
addition, the difference in the recurrence rate will be compared between the groups by Fisher's 
exact test. 
 
4.2. Other Analyses 
4.2.1. Barrett's mucosa assessment 
Analysis 
population: 
Full Analysis Set of the maintenance phase 
Analysis item: 
Barrett's mucosa [Present (≥ 3 cm), Present (< 3 cm), Absent, Unknown] 
Timepoint: 
Maintenance Period Weeks 48, 108, 156, 204 and 260 
Analytical 
methods: 
For evaluation at each evaluation time point, frequency will be tabulated by treatment group. 
In addition, the Mann-Whitney U test will be used to compare the treatment groups for the 
categories other than non-evaluable. 
 
4.2.2. Evaluation of esophageal hiatal hernia 
Analysis 
population: 
Full Analysis Set of the maintenance phase 
Analysis item: 
hiatal hernia     [Yes (≥ 2 cm), Yes (< 2 cm), 
None, unknown] 
Timepoint: 
Maintenance Period Weeks 48, 108, 156, 204 and 260 
Analytical 
methods: 
For evaluation at each evaluation time point, frequency will be tabulated by treatment group. 
In addition, the Mann-Whitney U test will be used to compare the treatment groups for the 
categories other than non-evaluable. 
 
4.2.3. Risk factors for recurrence of reflux esophagitis 
Analysis 
population: 
Full Analysis Set of the maintenance phase 
Analysis item: 
Recurrence of reflux esophagitis on endoscopic findings 
Analytical 
methods: 
For each treatment group, the following logistic regression analysis will be performed using 
the presence or absence of recurrence of reflux esophagitis based on endoscopic findings as 
the dependent variable. 
(1) 
Univariate analysis with patient background factors (Age, sex, BMI, smoking history, 
drinking history, intake of caffeine-containing beverages, LA classification at the start 
of the treatment period, and CYP2C 19 genotyping), endoscopic findings at the start 
of the treatment period (Fundus gland polyp, hyperplastic polyp, cobblestone mucosa, 
multiple white flat protrusions, black spot lesion), and histological evaluation of 
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5 
gastritis (Inflammation (mononuclear cell infiltration), activity (neutrophil 
infiltration), atrophy, intestinal metaplasia, H. pylori) (greater curvature of the middle 
corpus of the stomach, greater curvature of the antrum) as independent variables 
(2) 
Multivariate analysis using factors suggested in the univariate analysis and medically 
important factors as independent variables 
 
5. 
SAFETY EVALUATION 
5.1. Primary Endpoint and Analytical Methods 
Analysis 
population: 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Histopathological examination of gastric mucosa * 
Presence or absence of epithelial cell tumorigenesis    [Yes, No, Not Evaluable] 
Presence or absence of parietal cell elevation/hyperplasia   [Yes, No, Not Evaluable] 
Presence or absence of crypt epithelial hyperplasia        [Yes, No, Not Evaluable] 
Endocrine proliferation    [Present (1 (atrophic ECM), 2 (hyperplastic ECM), 3 (neoplastic 
ECM), 4 (typical carcinoid)), absent, not evaluable] 
Presence or absence of G cell hyperplasia          [Yes, No, Not Evaluable] 
*For evaluation up to the evaluation time point, the presence or absence of endocrine cell 
proliferation should be represented in the order of 4 (typical carcinoid), 3 (neoplastic ECM), 
2 (hyperplastic ECM), and 1 (atrophic ECM) as the details of presence. If all tests conducted 
during TIME WINDOW for each item are “not evaluable, ” the evaluations up to the 
evaluation time point will be considered“ not evaluable.” 
Timepoint: 
Start of the treatment period, and Weeks 48, 108, 156, 204 and 260 of the maintenance period 
Analytical 
methods: 
For the above analytical variable, the following analyses should be performed for evaluation 
at each evaluation time point and evaluation up to the evaluation time point. 
(1) 
For the safety analysis set in the maintenance phase, between-group comparison by 
Fisher's exact test will be performed for the proportion of "Present" for each finding. 
(2) 
The frequencies in the safety analysis set in the maintenance phase and the subgroups 
described in 2.2 (Serum gastrin level, serum chromogranin A level) will be presented 
by treatment group. 
(3) 
Using the Kaplan-Meier method, the cumulative incidence of each finding in 
histopathological examination of gastric mucosa, standard error according to 
Greenwood's formula, and two-sided 95% confidence interval will be calculated for 
each treatment group, and Kaplan-Meier curves will be illustrated. In addition, the 
number of patients at risk, the cumulative incidence, and the two-sided 95% 
confidence interval according to Greenwood's formula will be presented for Weeks 52, 
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6 
112, 160, 208, and 264 from the start of the treatment period as the starting point. In 
addition, comparison between groups will be performed by log-rank test. 
 
5.2. Secondary Endpoints and Analytical Methods 
5.2.1. Endoscopic findings, histological evaluation of gastritis according to the Sydney classification 
Analysis 
population: 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Endoscopic findings 
 fundic gland polyp     [Yes, No] 
  Hyperplastic polyp      [Yes, No] 
  cobblestone mucosa            [Yes, No] 
  Multiple white flat bumps  [Yes, No] 
  black spot lesion            [Yes, No] 
Histological evaluation of gastritis * (greater curvature of the middle corpus of the stomach, 
greater curvature of the antrum) 
Inflammation (mononuclear cell infiltration)    [Present (Mild, moderate, severe), 
absent, not evaluable] 
Active (neutrophil infiltration)  [Present (Mild, moderate, severe), absent, not evaluable] 
Atrophy         [Present (Mild, moderate, severe), absent, not evaluable] 
Metaplasia, intestinal        [Present (Mild, moderate, severe), absent, not evaluable] 
H.pylori               [Present (Mild, moderate, severe), absent, not evaluable] 
*For assessments made up to the evaluation time point, the details of yes should be 
represented in order of decreasing severity. If all tests conducted during TIME WINDOW 
for each item are “not evaluable, ” the evaluations up to the evaluation time point will be 
considered“ not evaluable.” 
Occurrence of gastric polyp    [Yes, No] 
Timepoint: 
Start of the treatment period, and Weeks 48, 108, 156, 204 and 260 of the maintenance 
period 
[Histological evaluation of gastritis] 
Start of the treatment period, and Weeks 48, 108, 156, 204 and 260 of the maintenance 
period 
Analytical 
methods: 
For the analysis items, frequency of evaluation at each evaluation time point and evaluation 
up to the evaluation time point will be tabulated by treatment group, and the proportion of 
“present ” for each finding will be compared between groups by Fisher's exact test. 
 
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5.2.2. Other endpoints and analysis methods 
5.2.2.1. Clinical Laboratory Evaluation 
Analysis 
population: 
Safety Analysis Set of the Treatment Period 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Blood tests 
 AST, ALT, Fe, Mg, Ca, and vitamin B 12 
Timepoint: 
[Safety analysis set in the treatment period] 
At the start of the treatment period, and Treatment Period Weeks 4 and 8 
[Safety Analysis Set of the maintenance phase] 
At the start of the treatment period, and Treatment Period Weeks 4, 8, and 12 in the 
maintenance period, 
Maintenance Period Weeks 24, 36, 48, and 60 
Maintenance Period Weeks 72, 84, 96, and 108 
Maintenance Period Weeks 132, 156, 180, and 204 
Maintenance Period Week 228, Maintenance Period Week 260 
Analytical 
methods: 
For the analysis items, summary statistics of values at each evaluation time point and 
summary statistics of pre- and post-treatment differences (value at each evaluation time point 
after treatment - value at the start of the treatment period) at each evaluation time point will 
be calculated, and group comparisons of mean pre- and post-treatment differences will be 
performed using the Mann-Whitney U test. 
 
5.2.2.2. Serum gastrin, pepsinogen I and II levels, and chromogranin A levels 
Analysis 
population: 
Safety Analysis Set of the Treatment Period 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Serum gastrin level 
Serum pepsinogen I level 
Serum pepsinogen II level 
Serum pepsinogen I/II ratio 
Serum chromogranin A level 
Timepoint: 
[Serum gastrin level/safety analysis set during the treatment period] 
At the start of the treatment period, and Treatment Period Weeks 4 and 8 
[Serum gastrin level/safety analysis set in the maintenance phase] 
At the start of the treatment period, and Treatment Period Weeks 4, 8, and 12 in the 
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maintenance period, 
Maintenance Period Weeks 24, 36, 48, and 60 
Maintenance Period Weeks 72, 84, 96, and 108 
Maintenance Period Weeks 132, 156, 180, and 204 
Maintenance Period Week 228, Maintenance Period Week 260 
[Analysis sets for serum pepsinogen I, pepsinogen II, pepsinogen I/II ratio, and chromogranin 
A levels/safety data during the treatment period] 
At the start of the treatment period, and Treatment Period Weeks 4 and 8 
[Serum pepsinogen I, pepsinogen II, pepsinogen I/II ratio, and chromogranin A/safety 
analysis set in the maintenance phase] 
At the start of the treatment period, and Treatment Period Weeks 4, 8, and 24 in the 
maintenance period, 
Maintenance Period Weeks 48, 108, 156, and 204 
Maintenance Period Week 260 
Analytical 
methods: 
For the analysis items during the treatment period, summary statistics of values at each 
evaluation time point and summary statistics of pre- and post-treatment differences (value at 
each evaluation time point after treatment - value at the start of the treatment period) at each 
evaluation time point will be calculated, and the mean pre- and post-treatment differences 
will be compared between the groups using the Mann-Whitney U test. 
5.2.2.3. Serum gastrin and chromogranin A levels by the presence or absence of endoscopic findings
Analysis 
population: 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Serum gastrin level, chromogranin A level 
Timepoint: 
[Serum gastrin level/safety analysis set in the maintenance phase] 
At the start of the treatment period, and Treatment Period Weeks 4, 8, and 12 in the 
maintenance period, 
Maintenance Period Weeks 24, 36, 48, and 60 
Maintenance Period Weeks 72, 84, 96, and 108 
Maintenance Period Weeks 132, 156, 180, and 204 
Maintenance Period Week 228, Maintenance Period Week 260 
[Serum chromogranin A level/safety analysis set in the maintenance phase] 
At the start of the treatment period, and Treatment Period Weeks 4, 8, and 24 in the 
maintenance period, 
Maintenance Period Weeks 48, 108, 156, and 204 
Maintenance Period Week 260 
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Analytical 
methods: 
Endoscopic findings (Fundus gland polyp, hyperplastic polyp, cobblestone mucosa, multiple 
white flat protrusions, black spot lesion) will be analyzed by presence/absence at the start of 
the treatment period and further divided into 4 groups: subjects without findings at the start 
of the treatment period who developed them during the study period and subjects without 
findings throughout the study period. The following analyses will be performed. 
(1)
Summary statistics
5.2.2.4. Correlation between serum gastrin and chromogranin A levels
Analysis 
population: 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Correlation between serum gastrin and chromogranin A levels 
Timepoint: 
[Safety Analysis Set of the maintenance phase] 
At the start of the treatment period, and Treatment Period Weeks 4, 8, and 24 in the 
maintenance period, 
Maintenance Period Weeks 48, 108, 156, and 204 
Maintenance Period Week 260 
Analytical 
methods: 
For the safety analysis set in the maintenance phase, a scatter plot of serum gastrin level on 
the abscissa and chromogranin A level on the ordinate will be prepared for each time point. 
Scatter plots will be prepared by treatment group and overlaid with both groups. 
5.2.2.5. Changes in serum gastrin level during the maintenance phase
Analysis 
population: 
Safety Analysis Set of the maintenance phase 
Analysis item: 
Serum gastrin level 
Timepoint: 
[Serum gastrin level/safety analysis set in the maintenance phase] 
At the start of the treatment period, Week 12 of the maintenance period, 
Maintenance Period Weeks 24, 36, 48, and 60 
Maintenance Period Weeks 72, 84, 96, and 108 
Maintenance Period Weeks 132, 156, 180, and 204 
Maintenance Period Week 228, Maintenance Period Week 260 
Analytical 
methods: 
Line charts depicting the proportions of patients with serum gastrin levels < 500 pg/mL, ≥ 
500 pg/mL and < 1000 pg/mL, and ≥ 1000 pg/mL are shown. The denominator will be the 
safety analysis set in the maintenance phase. 
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10 
6.
STATISTICAL/ANALYTICAL ISSUES
6.1. Multiple Comparison/Multiplicity
  No multiplicity adjustment will be performed. 
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11 
7.
REVISION HISTORY
Ver. 
Date of 
preparation 
Author 
Revised Item 
Description of Revision 
1.0 
2023/2/1 
Newly created 
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