A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Oral TAK-438 10 mg Once-daily in the Treatment of Non-Erosive Gastroesophageal Reflux Disease
Phase: PHASE3
Conditions: Non-erosive Gastroesophageal Reflux Disease
Sponsor: Takeda

 
 
Title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase 3 Study to 
Evaluate the Efficacy and Safety of Oral TAK-438 10 mg Once-daily in the Treatment of 
Non-Erosive Gastroesophageal Reflux Disease 
 
NCT Number: NCT02954848 
Protocol Approve Date: 31-Aug-2016 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

1.0 TITLE PAGE 
 
TAKEDA PHARMACEUTICALS 
PROTOCOL 
 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase 3 Study to Evaluate the 
Efficacy and Safety of Oral TAK-438 10 mg Once-daily in the Treatment of Non-Erosive 
Gastroesophageal Reflux Disease 
 
 
A Double-Blind, Phase 3 Study of TAK-438 (10 mg) in the Treatment of Non-Erosive 
Gastroesophageal Reflux Disease 
 
 
 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1 Doshomachi 4-chome, Chuo-ku, Osaka 540-8645, Japan 
Study Number: 
Vonoprazan-3001 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
TAK-438 (Vonoprazan Fumarate) 
Date: 
31 August 2016 
Version/Amendment 
Number: 
Initial version 
 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study. 

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1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
See the annex. 
1.2 
Principles of Clinical Studies 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
 
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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES .............................................................................................................................2 
1.1 
Contacts and Responsibilities of Study-Related Activities ...........................................2 
1.2 
Principles of Clinical Studies .........................................................................................2 
2.0 
STUDY SUMMARY...........................................................................................................8 
3.0 
LIST OF ABBREVIATIONS ............................................................................................13 
4.0 
INTRODUCTION .............................................................................................................14 
4.1 
Background ..................................................................................................................14 
4.2 
Rationale for the Proposed Study ................................................................................15 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................16 
5.1 
Objectives ....................................................................................................................16 
5.1.1 
Primary Objective ..................................................................................................16 
5.1.2 
Secondary Objectives.............................................................................................16 
5.2 
Endpoints .....................................................................................................................16 
5.2.1 
Primary Endpoints .................................................................................................16 
5.2.2 
Secondary Endpoints .............................................................................................16 
5.2.3 
Additional Endpoints .............................................................................................16 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................18 
6.1 
Study Design ................................................................................................................18 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................20 
6.3 
Premature Termination or Suspension of Study or Study Site ....................................23 
6.3.1 
Criteria for Premature Termination or Suspension of the Study ...........................23 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites ........................23 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites ....................................................................................23 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............24 
7.1 
Inclusion Criteria .........................................................................................................24 
7.2 
Exclusion Criteria ........................................................................................................25 
7.3 
Excluded Medications, Restricted Medications and Prohibited Treatments ...............27 
7.4 
Diet, Fluid and Activity Control ..................................................................................29 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................................30 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject .......................................31 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT .........................................................33 
8.1 
Study Drug and Materials ............................................................................................33 
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8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ......................................33 
8.1.1.1 Study Drug .......................................................................................................33 
8.1.2 
Storage ...................................................................................................................34 
8.1.3 
Dose and Regimen .................................................................................................34 
8.1.4 
Overdose ................................................................................................................35 
8.2 
Study Drug Assignment and Dispensing Procedures ..................................................35 
8.3 
Randomization Code Creation and Storage .................................................................35 
8.4 
Study Drug Blind Maintenance ...................................................................................35 
8.5 
Unblinding Procedure ..................................................................................................36 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs.......................................36 
9.0 
STUDY PLAN ...................................................................................................................37 
9.1 
Study Procedures .........................................................................................................37 
9.1.1 
Informed Consent Procedure .................................................................................37 
9.1.1.1 Pharmacogenomic Informed Consent Procedure .............................................37 
9.1.2 
Demographics, Medical History, and Medication History Procedure ...................37 
9.1.3 
Acid Suppressants ..................................................................................................38 
9.1.4 
Physical Examination Procedure ...........................................................................38 
9.1.5 
Patient Diary ..........................................................................................................38 
9.1.6 
Weight, Height and BMI........................................................................................39 
9.1.7 
Vital Sign Procedure ..............................................................................................39 
9.1.8 
QOL Survey ...........................................................................................................39 
9.1.9 
Documentation of Concomitant Medications ........................................................40 
9.1.10 Documentation of Concurrent Medical Conditions ...............................................40 
9.1.11 Procedures for Clinical Laboratory Samples .........................................................40 
9.1.12 Contraception and Pregnancy Avoidance Procedure .............................................42 
9.1.13 Pregnancy ...............................................................................................................42 
9.1.14 ECG Procedure ......................................................................................................42 
9.1.15 Pharmacogenomic Sample Collection ...................................................................43 
9.1.16 Serum Gastrin and Pepsinogen I/II Levels ............................................................43 
9.1.17 Anti-H. pylori Antibody Titer ................................................................................43 
9.1.18 Documentation of Subjects Failure ........................................................................43 
9.1.19 Documentation of Randomization .........................................................................44 
9.1.20 Endoscopic Assessment .........................................................................................44 
9.2 
Monitoring Subject Treatment Compliance.................................................................45 
9.3 
Schedule of Observations and Procedures ...................................................................45 
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9.3.1 
Start of Run-in Period (Visit 1) ..............................................................................45 
9.3.2 
Start of Treatment Period (Visit 2) ........................................................................46 
9.3.3 
After 2 Weeks of Treatment (Visits 3) ..................................................................47 
9.3.4 
After 4 Weeks of Treatment (Visit 4) ....................................................................48 
9.3.5 
Early Termination ..................................................................................................48 
9.3.6 
Post Study Care ......................................................................................................49 
9.4 
Biological Sample Retention and Destruction .............................................................49 
10.0 
ADVERSE EVENTS .........................................................................................................50 
10.1 
Definitions....................................................................................................................50 
10.1.1 AEs .........................................................................................................................50 
10.1.2 Additional Points to Consider for AEs ..................................................................50 
10.1.3 SAEs ......................................................................................................................52 
10.1.4 AEs of Special Interest...........................................................................................53 
10.1.5 Severity of AEs ......................................................................................................53 
10.1.6 Causality of AEs to Study Drug(s) ........................................................................54 
10.1.7 Causality of AEs to Study Procedures ...................................................................54 
10.1.8 Start Date ...............................................................................................................54 
10.1.9 End Date.................................................................................................................55 
10.1.10 
Pattern of Adverse Event .................................................................................55 
10.1.11 
Action Taken with Study Treatment ................................................................55 
10.1.12 
Outcome ...........................................................................................................55 
10.2 
Procedures ....................................................................................................................56 
10.2.1 Collection and Reporting of AEs ...........................................................................56 
10.2.1.1 
AE Collection Period .................................................................................56 
10.2.1.2 
AE Reporting .............................................................................................56 
10.2.1.3 
AEs of Special Interest Reporting ..............................................................57 
10.2.2 Collection and Reporting of SAEs .........................................................................58 
10.2.3 Reporting of Abnormal Liver Function Tests ........................................................59 
10.3 
Follow-up of SAEs ......................................................................................................59 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities ...................59 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................60 
11.1 
Central Adjudication Committee .................................................................................60 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................61 
12.1 
CRFs (Electronic) ........................................................................................................61 
12.2 
Record Retention .........................................................................................................62 
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13.0 
STATISTICAL METHODS ..............................................................................................63 
13.1 
Statistical and Analytical Plans ....................................................................................63 
13.1.1 Analysis Sets ..........................................................................................................63 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................63 
13.1.3 Efficacy Analysis ...................................................................................................63 
13.1.3.1 
Primary Endpoint and Analytical Methods ................................................63 
13.1.3.2 
Secondary Endpoints and Analytical Methods ..........................................64 
13.1.3.3 
Additional Efficacy Endpoints and Analytical Methods ...........................65 
13.1.3.4 
Data Conversion Method and Handling of Missing Data ..........................66 
13.1.3.5 
Significance Level and Confidence Coefficient ........................................66 
13.1.4 Safety Analysis ......................................................................................................66 
13.1.4.1 
TEAE .........................................................................................................66 
13.1.4.2 
Clinical Laboratory Test Values, ECGs, Vital Signs, Serum Gastrin and 
Pepsinogen I/II Levels .....................................................................................66 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................67 
13.3 
Determination of Sample Size .....................................................................................67 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................68 
14.1 
Study-Site Monitoring Visits .......................................................................................68 
14.2 
Protocol Deviations ......................................................................................................68 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................68 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................69 
15.1 
IRB Approval ...............................................................................................................69 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................70 
15.3 
Subject Confidentiality ................................................................................................71 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................71 
15.4.1 Publication and Disclosure ....................................................................................71 
15.4.2 Clinical Trial Registration......................................................................................71 
15.4.3 Clinical Trial Results Disclosure ...........................................................................72 
15.5 
Insurance and Compensation for Injury .......................................................................72 
16.0 
REFERENCES ..................................................................................................................73 
 
LIST OF IN-TEXT TABLES 
Table 8.a 
Dose and Regimen .................................................................................................35 
Table 9.a 
Severity of Acid Reflux Symptoms .......................................................................39 
Table 9.b 
Clinical Laboratory Tests .......................................................................................41 
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Table 9.c 
The Modified LA Classification ............................................................................45 
Table 10.a 
Takeda Medically Significant AE List ..................................................................53 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................19 
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2.0 
STUDY SUMMARY 
Clinical Study Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: 
TAK-438 (vonoprazan fumarate) 
Study Title: A Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Phase 3 Study to 
Evaluate the Efficacy and Safety of Oral TAK-438 10 mg 
Once-daily in the Treatment of Non-Erosive 
Gastroesophageal Reflux Disease 
IND No.: Not Applicable 
EudraCT No.: Not 
Applicable 
Study Identifier: Vonoprazan-3001 
Phase: 3 
Study Design: 
A phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study will be conducted to 
verify the superiority of TAK-438 (TAK-438 10 mg, once daily, 4 weeks) to placebo (placebo, once daily, 4 weeks) in 
patients with non-erosive gastroesophageal reflux disease (NERD). 
The study consists of a 1-week, single-blind run-in period and a 4-week, double-blind treatment period. The subjects 
will receive the study drug (TAK-438 placebo tablet) for the 1-week single-blind run-in period. After the run-in 
period, eligible subjects will be randomized into TAK-438 10 mg or placebo treatment groups in a 1:1 ratio. The 
randomized subjects will receive the assigned study drug (TAK-438 10 mg tablet or TAK-438 placebo tablet) for the 
4-week double-blind treatment period. 
Primary Objective: 
The primary objective of this study is to verify the superiority of TAK-438 to placebo in patients with NERD. 
Secondary Objectives: 
The secondary objectives of this study are to assess the safety of TAK-438 in patients with NERD compared with that 
of placebo, to determine if the response after 2-week treatment with TAK-438 would allow prediction of the response 
after 4-week treatment with TAK-438. 
Subject Population: Patients aged 20 years or older, with NERD 
Planned Number of Subjects: 
TAK-438 10 mg group: 237 subjects 
Placebo group: 237 subjects 
Estimated total: 474 subjects 
Planned Number of Sites: 
Estimated total: approximately 45 sites in Japan 
Dose Level(s): 
Run-in period: 
One TAK-438 placebo tablet will be orally administered 
once daily. 
Treatment period: 
One TAK-438 DB tablet will be orally administered once 
daily. 
Study Group 
Study Drug 
TAK-438 10 mg  
1 TAK-438 10 mg tablet 
Placebo 
1 TAK-438 placebo tablet 
  
Route of Administration: 
Oral 
Duration of Treatment: 
Run-in period: 1 week 
Treatment period: 4 weeks 
Study Length: 
Run-in period: 1 week 
Treatment period: 4 weeks 
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Main Criteria for Inclusion: 
Subject eligibility is determined according to the following criteria prior to entry into the study: 
Primary Inclusion Criteria: 
Subjects are eligible to enter the run-in period if they meet all of the following criteria: 
1. 
The subject with NERD. 
2. 
The subject is endoscopically confirmed to have the modified LA Classification Grade N or M at the start of the 
run-in period (Visit 1). 
To allow efficacy evaluation in the subjects with Grade N as well as in those with Grade M, the target number of 
subjects in each grade is at least 30% of the total number of subjects. Enrollment of patients with either Grade N 
or M will end when the number of enrolled subjects with each grade exceeds 332, or 70% of the total planned 
number of subjects. 
3. 
The subject experiences recurrent heartburn*,** on at least 2 days a week over the last 3 weeks prior to the start of 
the run-in period (Visit 1). 
*Heartburn is defined as a burning sensation arising from the stomach or behind the breastbone, and the 
symptoms commonly appear or is exacerbated postprandially, or through forward-bending position and 
abdominal compression. 
**Based on the result of hearing from the subjects, their severity is categorized as follows: 
Without symptoms: no symptoms, no hindrance to daily activities. 
With symptoms: mild (not very painful), moderate (rather painful), severe (painful). 
4. 
The subject is either a male or female outpatient with a minimum age of 20 years at the time of informed consent 
signing. However, subjects who are hospitalized only for examination purposes are also allowed to participate. 
Secondary Inclusion Criteria: 
Subjects are eligible to enter the treatment period if they meet all of the following criteria: 
5. 
The subject’s compliance to the study drug has been good (75% or better) in the run-in period. 
6. 
The subject has experienced heartburn on at least 2 days in the last 1 week prior to randomization. 
7. 
The subject has appropriately provided in the patient’s diary all the required information during the run-in period. 
Main Criteria for Exclusion: 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. 
The subject has received any investigational compound within 84 days prior to the first dose of study drug. 
2. 
The subject has received TAK-438 in a previous clinical study or as a therapeutic agent, except one with 
experience of receiving TAK-438 as adjunct therapy for H. pylori eradication, who can be enrolled in this study. 
3. 
The subject is an immediate family member, study site employee, or is in a dependant relationship with a study 
site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under 
duress. 
4. 
The subject has donated at least 400 mL of blood within the 90 days prior to the start of the run-in period 
(Visit 1). 
5. 
Endoscopic examination for entering this study fails to diagnose NERD within 84 days before the start of the 
run-in period (Visit 1). 
6. 
The subject has any complications affecting the esophagus, including Barrett’s esophagus (3 cm or more, long 
segment Barrett’s esophagus [LSBE]), eosinophilic esophagitis, esophageal varices, scleroderma, viral or fungal 
infection, and esophageal stenosis; a history of radiation  therapy or cryotherapy for the esophagus; or caustic or 
physiochemical trauma (eg, esophageal sclerotherapy). However, subjects with Barrett’s mucosa (less than 3 cm, 
short segment Barrett’s esophagus [SSBE]) or Schatzki’s ring (a mucosal tissue ring lining the inferior 
esophageal sphincter) are permitted to participate. 
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7. 
The subject has a history of surgery or treatment affecting gastroesophageal reflux, including fundoplication and 
mechanical dilatation for esophageal stenosis (except Schatzki’s ring), or a history of gastric or duodenal surgery 
(except endoscopic removal of benign polyps). 
8. 
The subject has acute upper gastrointestinal bleeding or gastric or duodenal ulcer, characterized by a defective 
mucosa with white coating, within 30 days prior to the start of the run-in period (Visit 1). However, subjects with 
gastric or duodenal erosion are permitted to participate. 
9. 
The subject has acute gastritis or acute exacerbation of chronic gastritis. 
10. The subject has, or has a history of, Zollinger-Ellison syndrome or gastric acid hypersecretion disorders. 
11. The subject has, or has a history of chest pain due to cardiac disease, or has chest pain suspectedly caused by 
cardiac disease within 1 year prior to the start of the run-in period (Visit 1). 
12. The subject has any other concurrent upper gastrointestinal symptoms more severe than heartburn. 
13. The subject has depression. 
14. The subject has, has a history of, or is suspected of functional upper gastrointestinal disorders, such as functional 
dyspepsia and functional heartburn diagnosed by the Rome IV criteria. 
15. The subject has a history of hypersensitivity or allergies to TAK-438 (including the formulation excipients). 
16. The subject has a history or complication of drug abuse (defined as any illicit drug use) or of alcohol abuse within 
1 years prior to the start of the run-in period (Visit 1). 
17. The subject requires any excluded medications or treatments listed in Section 7.3. 
18. The female subject who is pregnant, is lactating, or is intending to become pregnant or to donate ova any time 
between the informed consent signing and 4 weeks after the last dose of study drug. 
19. The subject has any serious neurological, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, 
urologic, endocrinological, or hematologic diseases. 
20. The subject needs surgery requiring hospitalization during the course of the study, or surgery requiring 
hospitalization is scheduled for the subject during the course of the study. 
21. The subject has a history of malignancy or is treated for malignancy within 5 years prior to the start of the run-in 
period (Visit 1). However, subjects who have recovered completely from cutaneous basal cell carcinoma or from 
cervical carcinoma in situ are permitted to participate. 
22. The subject has acquired immunodeficiency syndrome (AIDS) or hepatitis, is a human immunodeficiency virus 
(HIV) carrier, or tested positive for the hepatitis B virus surface antigen (HBsAg) or the hepatitis C virus (HCV) 
antibody. However, subjects who tested negative for HCV antigen or HCV-RNA are permitted to participate. 
23. The subject has any of the following abnormal clinical laboratory test values at the start of the run-in period 
(Visit 1): 
• 
Creatinine > 2 mg/dL. 
• 
ALT or AST > ULN. 
• 
Bilirubin (Total bilirubin) > ULN. 
Main Criteria for Evaluation and Analyses: 
Efficacy: 
(1) Primary Endpoints 
Heartburn during the treatment period. The following variables of the primary endpoint in the TAK-438 10 mg 
group are compared with those in the placebo group: 
• 
Primary variable: proportion of days without symptoms. 
• 
Secondary variable: cumulative rate of improvement in symptoms. 
• 
Additional variable: severity of symptoms. 
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(2) Secondary Endpoints 
The primary endpoint is stratified as follows: 
• 
The primary endpoint in subject subgroups stratified by the response (improved or not improved) at Week 2. 
• 
The primary endpoint in subject subgroups stratified by endoscopic finding (Grade N or M). 
• 
The primary endpoint in subject subgroups stratified by the combination of endoscopic finding (Grade N or 
M) and response (improved or not improved) at Week 2. 
• 
The primary endpoint in subject subgroups stratified by the response (improved or not improved) to acid 
suppressants (proton pump inhibitors [PPIs], histamine H2-receptor antagonists [H2RAs], or other agents 
[anticholinergics or anti-gastrin drugs]) in subjects who had a medication history of any of these drugs. 
(3) Additional Endpoints 
Quality of life (QOL) 
Regurgitation during the treatment period 
Safety: 
Treatment emergent adverse events (TEAEs), clinical laboratory test values, electrocardiogram findings (ECG), vital 
signs, serum gastrin and pepsinogen I/II levels 
Statistical Considerations: 
[Analyses for primary endpoint] 
(1) Primary analyses 
The primary analyses for primary endpoint will be performed based on the full analysis set (FAS). 
1. 
Primary variable 
Descriptive statistics will be used to summarize the proportion of days without symptoms during the treatment period 
by treatment group. The point estimate of the median difference between the treatment groups will be calculated using 
the Hodges-Lehmann estimation. For comparisons of the treatment groups, the Wilcoxon rank sum test will be used. 
2. 
Secondary variable 
The cumulative improvement rate of symptoms during the treatment period will be calculated for each treatment 
group using the Kaplan-Meier method. The symptom improvement, event date and censoring date are defined below. 
The cumulative improvement rate in TAK-438 10 mg group will be compared to that of the placebo group using a 
log-rank test. 
Symptom improvement: symptoms experienced on less than 2 days of the last 7 days. 
Event date: the first day of confirmed symptom improvement that continued until the last day of study treatment. 
Censoring date: 6 days prior to the last day with documentation of whether the subject experienced symptoms 
(applicable only to subjects without symptom improvement). 
3. 
Additional variable 
The same analysis used for primary efficacy variable will be performed for mean severity of symptoms over the 
treatment period. 
(2) Secondary analyses  
For sensitivity analysis, the same analyses to those conducted in the primary analyses will be performed on the 
per-protocol set (PPS) to evaluate the stability of the results. 
[Analyses for secondary endpoints] 
Analyses for secondary endpoint will be performed similarly to the primary analyses on the FAS  
When subjects are stratified by the response (improved or not improved) at Week 2, analyses will be performed on 
subjects stratified for both treatment groups and for the TAK-438 10 mg group only. 
Response (improved or not improved) at Week 2 will be assessed in accordance with the following criteria. 
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Criteria 1: 
Improved: the subject experiences heartburn on less than 2 days of the 7 days prior to Week 2 (Day 8 through Day 14). 
Not improved: the subject experiences heartburn on 2 days or more of the 7 days prior to Week 2 (Day 8 through Day 
14). 
Criteria 2: 
Improved: the proportion of days the subject experiences heartburn during the treatment period up to Week 2 (Day 14) 
is lower than that during the run-in period. 
Not improved: the proportion of days the subject experiences heartburn during the treatment period up to Week 2 (Day 
14) is equal to or larger than that during the run-in period. 
Subjects are to be stratified by the following response to acid suppressants: 
Improved: those whose heartburn has been resolved, or whose heartburn has not been resolved but relieved. 
Not improved: those whose heartburn has remained unchanged, or whose heartburn has been worsened. 
Sample Size Justification: 
In a phase 3 double-blind study of lansoprazole (AG-1749/CCT-206) evaluating the proportion of days without 
heartburn in those given AG-1749 15 mg and placebo, the mean proportion of days without heartburn and their 
standard deviations (SD) were shown to be 51.03%±28.388% in the placebo group versus 63.21%±32.200% in the 
AG-1749 15 mg group. Additionally, in the postmarketing study for lansoprazole (AG-1749/CCT-971), the mean 
proportion of days without heartburn and their SD were shown to be 46.83%±32.350% in the placebo group and 
55.36%±34.545% in the AG-1749 15 mg group. In a phase 3 double-blind study of TAK-438 (TAK-438/CCT-201), 
the mean proportion of days without heartburn and their SD were shown to be 22.63%±28.202% in the placebo group 
and 28.89%±34.853% in the TAK-438 10mg group. 
Assuming that, based on these results and assessment method of heartburn in this study, the difference between the 
TAK-438 group and the placebo group will be 10% with a common SD of 32%, 230 subjects per treatment group will 
be required to ensure 90% power of the Wilcoxon rank sum test with a significance level of 5%. Thus, it is appropriate 
that 237 subjects will be required for each treatment group, taking into account some dropouts, around 3%, after 
randomization. 
 
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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
AIDS 
acquired immune deficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BMI 
body mass index 
Cmax 
maximum observed plasma concentration 
CRO 
contract research organization 
CYP 
cytochrome P450 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GER 
gastroesophageal reflux 
GERD 
gastroesophageal reflux disease 
GGT 
gamma glutamyl transferase 
HBsAg 
hepatitis B virus surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
H. pylori 
Helicobacter pylori 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
LA Classification 
Los Angeles Classification 
LDH 
lactate dehydrogenase 
LSBE 
long-segment Barrett’s esophagus 
MedDRA 
Medical Dictionary for Regulatory Activities 
NERD 
non-erosive gastroesophageal reflux disease 
PGx 
pharmacogenomics 
PPI 
proton pump inhibitor 
PT 
preferred term 
QOL 
quality of life 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SOC 
system organ class 
SSBE 
short-segment Barrett’s esophagus 
TAK-438 
vonoprazan fumarate 
TEAE 
treatment emergent adverse event 
ULN 
upper limit of normal 
 
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4.0 
INTRODUCTION 
4.1 
Background 
Non-erosive gastroesophageal reflux disease (NERD) is characterized by uncomfortable 
symptoms due to reflux of gastric content, including gastric acid, into the esophagus without the 
mucosal breaks [1]. The most common symptoms of NERD are acid reflux symptoms including 
heartburn and regurgitation [2]. Recurrence of such symptoms can deteriorate the patient’s quality 
of life (QOL) [3]. Therefore, the clinically relevant goal of NERD treatment is to relieve acid 
reflux symptoms. 
The first-line treatment for NERD is proton pump inhibitors (PPIs), such as lansoprazole, which 
are widely used in Japan as well as other parts of the world [4]. 
PPIs exert potent therapeutic effects through strong and continuous supression of gastric acid 
secretion by inhibiting the proton pump (H+, K+-adenosine triphosphatase [ATPase]) in the final 
step of acid secretion by gastric mucosal parietal cells. 
However, conventional PPIs have some characteristics, which mean that their effect is not always 
satisfactory in terms of extent and onset of symptom relief [5]. The following are some of the 
deficiencies of conventional PPIs that need to be improved: (1) conventional PPIs are relatively 
acid-labile and in enteric-coated dosage form [6], meaning the time to onset of their effect may 
vary widely between individuals; (2) conventional PPIs require about 3 to 5 days to exert their 
maximum acid-inhibitory effects [6, 7, 8]; (3) the acid-inhibitory effects of conventional PPIs are 
satisfactory during the day, but their effect on acid regurgitation during the night (nocturnal acid 
breakthrough) is inadequate in some individuals [8]; and (4) since conventional PPIs are 
metabolized by polymorphic cytochrome P450 (CYP) 2C19, plasma drug concentrations and 
acid-inhibitory effects may differ between extensive metabolizers (EMs) and poor metabolizers 
(PMs) [7, 9]. 
Vonoprazan fumarate (TAK-438) is a novel class of acid suppressants, referred to as a 
potassium-competitive acid blocker (P-CAB), which was developed by Takeda Pharmaceutical 
Company Limited. TAK-438 inhibits H+, K+-ATPase in the final step of acid secretion from 
gastric parietal cells. Unlike conventional PPIs, TAK-438 inhibits H+, K+-ATPase competitively 
with potassium ions without activation by acid. Acid-stability and water-solubility of TAK-438 
enable a smaller variability in time-of-onset of action compared to conventional PPIs and 
consequently, a pharmaceutical dosage form such as enteric-coated formulation is not required. 
TAK-438 is predominantly metabolized by CYP3A4, and the contribution of polymorphic 
CYP2C19 is considered to be limited [10,11,12]. Whereas conventional PPIs require 3 to 5 days to 
exert their maximum acid-inhibitory effects [6,7,8], TAK-438 is expected to exhibit its maximum 
acid-inhibitory effects more quickly compared with conventional PPIs, and to exert potent and 
sustained acid-inhibitory effects, which may translate into better treatment outcomes. 
The efficacy and safety of TAK-438 were established in the clinical studies in patients with 
acid-related diseases. TAK-438 was approved in December 2014 in Japan, indicated for erosive 
esophagitis (including a maintenance treatment of erosive esophagitis), gastric ulcer, duodenal 
ulcer, prevention of recurrent gastric or duodenal ulcer during low-dose aspirin therapy, 
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prevention of recurrent gastric or duodenal ulcer during non-steroidal anti-inflammatory drug 
(NSAID) therapy, and adjunct to Helicobacter pylori (H. pylori) eradication. For the treatment of 
NERD, a randomized, double-blind, parallel-group, phase 3 study (TAK-438/CCT-201) failed to 
verify the superiority of TAK-438 to placebo and thus NERD was not included in the TAK-438 
indications. 
4.2 
Rationale for the Proposed Study 
The past, randomized, double-blind, parallel-group, phase 3 study (TAK-438/CCT-201) was 
conducted to verify the superiority of TAK-438 (TAK-438 10 mg or 20 mg once daily) to placebo 
(TAK-438 placebo) in the treatment of NERD. The median proportion of days without heartburn 
during the treatment period in the full analysis set (FAS) was 7.40% in the placebo group, 10.30% 
in the TAK-438 10 mg group, and 12.00% in the TAK-438 20 mg group. Although there were no 
statistically significant differences between the TAK-438 treatment groups and the placebo group 
(p=0.2310 for the TAK-438 10 mg group, p=0.0504 for the TAK-438 20 mg group using the 
Wilcoxon rank-sum test). The reasons why TAK-438 was not superior to placebo in the study 
TAK-438/CCT-201 was considered to be the change in the symptom scale of heartburn from that 
used in the previous studies of PPIs, and possible enrollment of patients with heartburn unrelated 
to acid reflux. In the study TAK-438/CCT-201, the heartburn was categorized into 6 levels [no 
symptom, very mild, mild, moderate, severe, and very severe], while heartburn had been evaluated 
using 4 levels [none, mild, moderate, severe] in previous studies using PPIs in patients with NERD 
in Japan [13,14,15]. The Evidence-based Clinical Practice Guidelines for GERD 2015 (2nd 
Edition) [16] provides an explanation on different responses to PPI treatment between erosive 
esophagitis and NERD by stating that “especially, since patients with heartburn due to non-acid 
GER1 or functional heartburn unrelated to GER are often included in those diagnosed with NERD, 
treatment of NERD patients with PPI may result in lower proportion of symptom-free patients 
compared to patients with erosive GERD2.” In the study TAK-438/CCT-201, some patients whose 
heartburn had not been caused by acid reflux were possibly enrolled. Therefore, based on these 
reasons, this study has been planned to evaluate the efficacy and safety of TAK-438 in patients 
with NERD. 
Pharmacogenomic analysis may be conducted to evaluate the contribution of genetic variance 
and/or gene expression on drug response, for example, its efficacy and safety. Participation of 
study subjects in pharmacogenomic sample collection is optional. 
As pharmacogenomics is an evolving science, currently many genes and their function are not yet 
fully understood. Future data may suggest a role of some of these genes in drug response, which 
may lead to additional hypothesis-generating exploratory research on stored samples. 
1 gastroesophageal reflux 
2 gastroesophageal reflux disease 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objective 
The primary objective of this study is to verify the superiority of TAK-438 to placebo in patients 
with NERD. 
5.1.2 Secondary Objectives 
The secondary objectives of this study are to assess the safety of TAK-438 in patients with NERD 
compared with that of placebo, to determine if the response after 2-week treatment with TAK-438 
would allow prediction of the response after 4-week treatment with TAK-438. 
5.2 
Endpoints 
5.2.1 Primary Endpoints 
Heartburn during the treatment period. The following variables of the primary endpoint in the 
TAK-438 10 mg group are compared with those in the placebo group: 
• Primary variable: proportion of days without symptoms. 
• Secondary variable: cumulative rate of improvement in symptoms. 
• Additional variable: severity of symptoms. 
5.2.2 Secondary Endpoints 
The primary endpoint is stratified as follows: 
• The primary endpoint in subject subgroups stratified by the response (improved or not 
improved) at Week 2. 
• The primary endpoint in subject subgroups stratified by endoscopic finding (Grade N or M). 
• The primary endpoint in subject subgroups stratified by the combination of endoscopic finding 
(Grade N or M) and response (improved or not improved) at Week 2. 
• The primary endpoint in subject subgroups stratified by the response (improved or not 
improved) to acid suppressants (proton pump inhibitors [PPIs], histamine H2-receptor 
antagonists [H2RAs], or other agents [anticholinergics or anti-gastrin drugs]) in subjects who 
had a medication history of any of these drugs. 
5.2.3 Additional Endpoints 
<Efficacy> 
Quality of life (QOL) 
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Regurgitation during the treatment period 
<Safety> 
Treatment emergent adverse events (TEAEs), clinical laboratory test values, electrocardiogram 
(ECG) findings, vital signs, serum gastrin and pepsinogen I/II levels 
 
In this study, samples for pharmacogenomics (PGx) will be collected and stored for exploratory 
investigation of markers enabling the prediction of drug response. 
In this study using TAK-438, or in a set of clinical trials, if variability is seen in responsiveness to 
study drug and it is suspected to attribute its cause to subject’s gene polymorphism, PGx analyses 
should reveal the following as required: 
• Gene polymorphism and safety and/or tolerability of study drug. 
• Gene polymorphism and efficacy of study drug. 
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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
<Study Design> 
This is a phase 3, double-blind, placebo-controlled, parallel-group, multicenter study to verify the 
superiority of TAK-438 to placebo in the efficacy in patients with NERD of the modified LA 
Classification Grade N or M [17]. This study consists of 1-week single-blind run-in period and 
4-week double-blind treatment period. After the informed consent is obtained, placebo will be 
administered for 1 week in single-blind fashion as a run-in period. Upon completion of the run-in 
period, subject eligibility for this study will be confirmed and only subjects who meet all of the the 
entry criteria will be randomized in a ratio of 1:1 to receive TAK-438 10 mg or placebo for the 
4-week, double-blind, treatment period. 
The target number of the subjects stratified by the Central Adjudication Committee (CAC) 
according to endoscopic findings with the modified LA Classification Grade N or M at the start of 
the run-in period (Visit 1) is at least 30% (143 subjects) of the total planned number of subjects for 
each grade. (Enrollment of patients with either Grade N or M is to end when the number of 
enrolled subjects with each Grade exceeds 332 subjects, or 70% of the total planned number of 
subjects.) 
<Treatment/Assessment Duration> 
This study consists of a 1-week, single-blind, run-in period and a 4-week, double-blind treatment 
period. 
Run-in Period 
The subjects will undergo endoscopic examination within 28 days after signing of the informed 
consent to select patients with the modified LA Classification Grade N or M. Then, the subjects 
will enter the run-in period and take 1 tablet of the study drug for the run-in period (TAK-438 
placebo tablet) orally once daily after breakfast for 1 week. 
The study drugs to be taken during the run-in period will be prescribed after all examinations and 
assessments scheduled at the start of the run-in period (Visit 1) are completed. The subjects will 
receive the first dose of the study drug for the run-in period before leaving the sites. 
Treatment Period 
After subject eligibility is confirmed, the eligible subjects will be randomized to receive TAK-438 
10 mg or placebo. The start date of the study drug for the treatment period is defined as Day 1. 
The subjects will enter the treatment period after randomization and take 1 tablet for the treatment 
period (TAK-438 10 mg tablet or TAK-438 placebo tablet) orally once daily after breakfast for 4 
weeks. 
The study drugs to be taken during the treatment period will be prescribed after all examinations 
and assessments scheduled at the start of the treatment period (Visit 2) are completed. The subjects 
will receive the first study drug for the treatment period before leaving the sites. 
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After 2 weeks and 4 weeks of treatment (Visit 3 and Visit 4), the subjects are required to visit the 
sites without taking the study drug. After 2 weeks of treatment (Visit 3), the subjects will receive 
the study drug after completing all examinations and assessments scheduled for the visit, but 
before leaving the sites. 
<Others> 
This study will be conducted at approximately 45 sites in Japan. The planned number of subjects to 
be randomized is 237 per group, or 474 in total. 
The subjects are required to visit the sites 4 times in total: at the start of the run-in period (Visit 1), 
at the start of the treatment period (Visit 2), after 2 weeks of treatment (Visit 3), and after 4 weeks 
of treatment (Visit 4). 
Endoscopic findings will be assessed by the CAC, and the subject eligibility will be confirmed 
based on the decision by the investigator. 
<Schematic of Study Design> 
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A. 
Figure 6.a 
Schematic of Study Design 
 
Run-in Period (1 week) 
Single-blind 
Treatment Period (4 weeks) 
Double-blind 
 
 
VISIT 1 
VISIT 2 
VISIT 3 
VISIT 4 
Day -7 
Day 1 
Day 15 
Day 29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed  
Consent* 
 
 
 
 
Randomization  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initiation of 
run-in period  
 
 
 
Initiation of 
Treatment 
Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of 
Treatment  
period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TAK-438 10 mg 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
*Informed consent must be obtained within 28 days prior to the start of the run-in period (Visit 1). 
 
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6.2 
Justification for Study Design, Dose, and Endpoints 
(1) Justification for Subject Population Studied 
NERD is characterized by uncomfortable symptoms due to reflux of gastric content, including 
gastric acid, into the esophagus without the mucosal breaks [1]. The LA Classification, first 
presented at the World Congress of Gastroenterology in 1994, has been used widely in Japan for 
the diagnosis of erosive esophagitis in recent years. This study will employ the modified LA 
Classification for assessment of NERD patients, in which the absence of mucosal breaks is divided 
to Grades N and M based on mucosal decoloration [17]. This study will enroll patients with NERD 
of Grade N or M. 
The most common acid reflux symptom of NERD is heartburn, followed by regurgitation [2]. 
Patients with recurrent heartburn will be eligible for this study since the clinically relevant goal of 
NERD treatment is relief of such acid reflux symptoms. 
The basic pathology of NERD is acid reflux symptoms such as heartburn, and NERD is included 
in GERD. According to Rome III criteria [18], functional heartburn should be diagnosed when 
patients complain of heartburn likely due to any factor other than reflux. In the more recent Rome 
IV criteria [19], the current diagnosis of functional heartburn remains focused on a lack of 
conclusive evidence for GERD, no evidence of a symptom reflux correlation, and a negative 
response to acid suppressive therapy because this should alert the physician to the potential of a 
functional disorder. The Evidence-based Clinical Practice Guidelines for GERD 2015 (2nd 
Edition) [16] provides an explanation on different responses to PPI treatment between erosive 
esophagitis and NERD by stating that “ since patients with heartburn due to non-acid GER or 
functional heartburn unrelated to gastroesophageal reflux are often included in those diagnosed 
with NERD, treatment of NERD patients with PPI may result in lower proportion of symptom-free 
patients compared to patients with erosive GERD”. Therefore, the patients with functional 
heartburn caused by factors other than acid reflux will be excluded from this study. 
In clinical practice, dyspeptic symptoms such as epigastric pain, stomach upset, and nausea are 
sometime reported as heartburn because patients do not exactly know what heartburn is, and 
patients with dyspeptic symptom but no heartburn respond poorly to PPIs [20,21]. According to 
Rome IV criteria for gastroduodenal disorders [22], functional dyspepsia is defined as a medical 
condition that significantly impacts on the usual activities of a patient and is characterized by one 
or more of the following symptoms: postprandial fullness, early satiation, epigastric pain, and 
epigastric burning that are unexplained after a routine clinical evaluation. Therefore, the patients 
with functional dyspepsia will be excluded from this study. 
The patients with any concurrent conditions or any medical history that may affect gastric acid 
secretion will be excluded from this study to eliminate the potential effects on the efficacy 
evaluation of the study drug. 
(2) Justification for Study Design 
While it seems rational to confirm the efficacy of TAK-438 in an active-controlled study using a 
PPI as a comparator, the standard treatment for NERD, this study will employ a placebo-controlled 
design for the following reasons. Since large variability between subjects is predicted in the 
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primary endpoint of this study, ie, heartburn recorded in the patient’s diary during treatment period, 
the number of subjects required in an active-controlled study is considered to be unrealistic, and 
setting a non-inferiority margin will also be difficult. In fact, ICH E10 Guideline (Choice of 
Control Group and Related Issues in Clinical Trials) lists symptomatic gastroesophageal reflux as 
a condition in which the minimum effect a drug will have in the setting of a specific trial cannot be 
reliably determined. The large variability in evaluation of NERD will make the sensitivity of this 
study unreliable, if conducted with an active-controlled, non-inferiority design. The 
placebo-controlled design is thus selected in view of study feasibility. The randomized, 
double-blind design is used to minimize possible biases in the selection of subjects and the 
evaluation of symptoms. 
(3) Justification for Sample Size 
Refer to Section 13.3. 
(4) Justification for Selection of Dose 
PPIs have been approved and indicated for the treatment of NERD, and the therapeutic dose for 
NERD is half the maximum dose allowed for the treatment of erosive esophagitis. Therefore, since 
TAK-438 is also expected to be effective at half the dose of erosive esophagitis treatment, and 
previous study of TAK-438 (TAK-438/CCT-201) investigated 20 mg once daily, the dose 
proposed for erosive esophagitis, and its half dose of 10 mg were considered. Consequently, the 
p-value for superiority to placebo was smaller in the TAK-438 20 mg group than that in the 
TAK-438 10 mg, meanwhile the proportion of days without heartburn in the treatment period 
(median) was almost the same in the responders with possibly acid-related heartburn between the 
TAK-438 10 mg and 20 mg groups when stratified by the response (improved or not improved) at 
Week 2. Based on the study results, TAK-438 10 mg once daily is selected as the clinical dose for 
NERD treatment and will be investigated in this study. 
(5) Justification for Route and Mode of Administration of Study Drug 
Effect of food on the TAK-438 pharmacokinetics was investigated at 10 mg and 40 mg doses in 
the phase 1, single-dose study in healthy male subjects in Japan (TAK-438/CPH-001). The 
AUC0-48 and Cmax of TAK-438F were slightly higher under fed than under fasted conditions; the 
relative increases in AUC0-48 and Cmax were 1.32 (90% confidence interval [CI], 1.18 to 1.48) and 
1.21 (90% CI, 0.951 to 1.54), respectively, at the 10 mg dose, and 1.15 (90% CI, 1.05 to 1.27) and 
1.08 (90% CI, 0.944 to 1.23), respectively, at the 40 mg dose. Also, in the pharmacodynamic 
results, once-daily administration of TAK-438 inhibited acid secretion for over 24 hours . Effect of 
food was also investigated using a 20 mg dose of the final TAK-438 formulation in the single-dose 
study in healthy male subjects in Japan (TAK-438/CPH-007). The relative increases in AUC0-48 
and Cmax of TAK-438F were 1.088 (90% CI, 0.942 to 1.256) and 1.077 (90% CI, 1.014 to 1.145). 
No clinically meaningful effect was noted between under fed and fasted conditions. 
In light of the study results above and the timing of medication (usually postprandial), TAK-438 
will be administered once daily after breakfast in this study. 
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(6) Justification for Treatment Period 
In this study, the duration of the treatment period is set at 4 weeks because the approved duration 
of NERD treatment with PPIs, the standard treatment for NERD, is maximum of 4 weeks in Japan. 
(7) Justification for Run-in Period 
In the study TAK-438/CCT-201, antacids were used during the run-in period to exclude the 
responders. However, use of antacids is not required for the run-in period of this study in view of 
NERD treatment in clinical practice. In addition, the results of the previous studies has suggested 
that some subjects had a placebo effect [13,14,15], this study will therefore have the run-in period, 
where subjects will receive a placebo in a single-blind manner, to exclude placebo-responders. 
During the run-in period, treatment compliance will be investigated and the patient diaries will be 
checked to ensure proper entries. 
(8) Justification for Primary and Secondary Endpoints 
1) Primary Endpoint 
Heartburn is a characteristic symptom of NERD [2], and its resolution is the most important goal 
in the treatment of NERD. Following the phase 3, double-blind, comparative studies of 
lansoprazole in NERD patients conducted in Japan (AG-1749/CCT-206) and the phase 3, 
double-blind, comparative study (TAK-438/CCT-201), the primary endpoint of this study is 
heartburn during treatment period, and the proportion of days without heartburn is selected as the 
primary variable. As sustained relief from the symptom and the time to relief are also important in 
NERD treatment in terms of therapeutic benefit, cumulative symptom improvement rate (using 
Kaplan-Meier method) is selected as the secondary variable. To evaluate the improvement in the 
severity of symptoms as well as its disappearance, the severity of symptoms is investigated as 
additional variable. 
2) Secondary Endpoints 
The post-hoc analysis for the phase 3, double-blind, comparative study (AG-1749/CCT-206) 
indicated that response after 2-week treatment was useful for guiding appropriate use of 
lansoprazole. The package insert of lansoprazole accordingly recommends that response be 
assessed after a 2-week treatment with lansoprazole, and if symptoms do not improve, consider 
changing to another treatment as acid reflux may not be the cause. The primary endpoint in 
subjects receiving TAK-438, stratified by the response at Week 2, is therefore investigated in this 
study. 
While the subject population in the phase 3, double-blind, comparative study of lansoprazole 
(AG-1749/CCT-206) was limited to NERD patients with the modified LA Classification Grade M 
at the start of the run-in period, lansoprazole proved to be effective for NERD patients with either 
Grade N or M in its postmarketing study (AG-1749/CCT-971). Hence, the primary endpoint will 
be also investigated in subjects stratified by endoscopic finding in this study. In addition, the 
primary endpoint in subject subgroups stratified by the combination of response at Week 2 and 
endoscopic finding will be investigated. 
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The primary endpoint will also be investigated in subjects stratified by positive or negative 
response to acid suppressants in subjects who has a medication history of any of these drugs to 
ensure that efficacy of TAK-438 is evaluated in subjects with heartburn caused by acid reflux, the 
possible target disease of TAK-438. 
3) Additonal Endpoints 
The improvement in QOL associated with the relief of NERD symptoms was investigated as an 
additional endpoint using the acute (1-week recall) version of the SF-8 Health Survey 
questionnaire to further characterize the therapeutic benefit of TAK-438 treatment. 
Since regurgitation is also one of the most common acid reflux symptoms of NERD [2], the same 
variables as those used in heartburn will be applied. 
Increases in serum gastrin and pepsinogen I/II levels will also be measured as safety endpoints 
since TAK-438 administration may elevate the levels of these parameters. 
6.3 
Premature Termination or Suspension of Study or Study Site 
6.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the product, such that the risk/benefit is 
no longer acceptable for subjects participating in the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety. 
6.3.2 Criteria for Premature Termination or Suspension of Study Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable study sites during the course of termination or study suspension. 
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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study: 
Primary inclusion criteria: 
Subjects are eligible to enter the run-in period if they meet all of the following criteria: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject signs and dates a written informed consent form prior to the initiation of any study 
procedures. 
3. The subject with NERD. 
4. The subject is endoscopically confirmed to have the modified LA Classification Grade N or M 
at the start of the run-in period (Visit 1).3 
To allow efficacy evaluation in the subjects with Grade N as well as in those with Grade M, 
the target number of subjects in each grade is at least 30% of the total number of subjects. 
Enrollment of patients with either Grade N or M will end when the number of enrolled 
subjects with each grade exceeds 332, or 70% of the total planned number of subjects. 
5. The subject experiences recurrent heartburn*,** on at least 2 days a week over the last 3 weeks 
prior to the start of the run-in period (Visit 1). 
*Heartburn is defined as a burning sensation arising from the stomach or behind the 
breastbone, and the symptoms commonly appear or is exacerbated postprandially, or through 
forward-bending position and abdominal compression. 
**Based on the result of hearing from the subjects, their severity is categorized as follows: 
Without symptoms: no symptoms, no hindrance to daily activities. 
With symptoms: mild (not very painful), moderate (rather painful), severe (painful). 
6. The subject is either a male or female outpatient with a minimum age of 20 years at the time of 
informed consent signing. However, subjects who are hospitalized only for examination 
purposes are also allowed to participate. 
7. A female subject of childbearing potential* agrees to use routinely adequate contraception 
from signing of informed consent throughout the duration of the study, and for 4 weeks after 
the last dose of study drug. 
3 Any endoscopic confirmation within 7 days prior to the start of the run-in period (before signing of informed 
consent), if available, is acceptable instead of the endoscopic examination at Visit 1, given the invasive nature of the 
procedure. 
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*A female of childbearing potential are defined in Section 9.1.12 and reporting 
responsibilities are defined in Section 9.1.13. 
 
Secondary inclusion criteria: 
Subjects are eligible to enter the treatment period if they meet all of the following criteria: 
8. The subject’s compliance to the study drug has been good (75% or better)4 in the run-in 
period. 
9. The subject has experienced heartburn on at least 2 days in the last 1 week prior to 
randomization. 
10. The subject has appropriately provided in the patient’s diary all the required information 
during the run-in period. 
Justification of Inclusion Criteria 
Criteria 1 and 2 were set as basic matters to conduct clinical studies. 
Criterion 3 was set because the defined patients are the target patients for this study. 
Criteria 4, 5, 8, 9 and 10 were set to select subjects appropriate for efficacy evaluation of the study. 
Criterion 6 was set because it was appropriate to conduct this study and allow the subject’s 
voluntary participation in the study. 
Criterion 7 was set because the safety of TAK-438 in pregnant women and fetuses has not yet been 
established. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received any investigational compound within 84 days prior to the first dose 
of study drug. 
2. The subject has received TAK-438 in a previous clinical study or as a therapeutic agent, 
except one with experience of receiving TAK-438 as an adjunct therapy for H. pylori 
eradication, who can be enrolled in this study. 
3. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress. 
4. The subject has donated at least 400 mL of blood within the 90 days prior to the start of the 
run-in period (Visit 1). 
5. Endoscopic examination for entering this study fails to diagnose NERD within 84 days before 
the start of the run-in period (Visit 1). 
4 Treatment compliance rate=number of drug administrations/[(Visit 2 date–Visit 1 date)]×100 
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6. The subject has any complications affecting the esophagus, including Barrett’s esophagus 
(3 cm or more, long segment Barrett’s esophagus [LSBE]), eosinophilic esophagitis, 
esophageal varices, scleroderma, viral or fungal infection, and esophageal stenosis; a history 
of radiation therapy or cryotherapy for the esophagus; or caustic or physiochemical trauma (eg, 
esophageal sclerotherapy). However, subjects with Barrett’s mucosa (less than 3 cm, short 
segment Barrett’s esophagus [SSBE]) or Schatzki’s ring (a mucosal tissue ring lining the 
inferior esophageal sphincter) are permitted to participate. 
7. The subject has a history of surgery or treatment affecting  gastroesophageal reflux, including 
fundoplication and mechanical dilatation for esophageal stenosis (except Schatzki’s ring), or a 
history of gastric or duodenal surgery (except endoscopic removal of benign polyps). 
8. The subject has acute upper gastrointestinal bleeding or gastric or duodenal ulcer, 
characterized by a defective mucosa with white coating, within 30 days prior to the start of the 
run-in period (Visit 1). However, subjects with gastric or duodenal erosion are permitted to 
participate. 
9. The subject has acute gastritis or acute exacerbation of chronic gastritis. 
10. The subject has, or has a history of, Zollinger-Ellison syndrome or gastric acid hypersecretion 
disorders. 
11. The subject has, or has a history of chest pain due to cardiac disease, or has chest pain 
suspectedly caused by cardiac disease within 1 year prior to the start of the run-in period 
(Visit 1). 
12. The subject has any other concurrent upper gastrointestinal symptoms more severe than 
heartburn. 
13. The subject has depression. 
14. The subject has, has a history of, or is suspected of functional upper gastrointestinal disorders, 
such as functional dyspepsia and functional heartburn diagnosed by the Rome IV criteria. 
15. The subject has a history of hypersensitivity or allergies to TAK-438 (including the 
formulation excipients5). 
16. The subject has a history or complication of drug abuse (defined as any illicit drug use) or of 
alcohol abuse within 1 years prior to the start of the run-in period (Visit 1). 
17. The subject requires any excluded medications or treatments as listed in Section 7.3. 
18. The female subject who is pregnant, is lactating, or is intending to become pregnant or to 
donate ova any time between the informed consent signing and 4 weeks after the last dose of 
study drug. 
19. The subject has any serious neurological, cardiovascular, pulmonary, hepatic, renal, metabolic, 
gastrointestinal, urologic, endocrinological, or hematologic diseases. 
5 mannitol, microcrystalline cellulose, hydroxypropyl cellulose, fumaric acid, croscarmellose sodium, magnesium 
stearate, hypromellose 2910, macrogol 6000, titanium oxide, ferric oxide, yellow and ferric oxide, red 
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20. The subject needs surgery requiring hospitalization during the course of the study, or surgery 
requiring hospitalization is scheduled for the subject during the course of the study. 
21. The subject has a history of malignancy or is treated for malignancy within 5 years prior to the 
start of the run-in period (Visit 1). However, subjects who have recovered completely from 
cutaneous basal cell carcinoma or from cervical carcinoma in situ are permitted to participate. 
22. The subject has acquired immunodeficiency syndrome (AIDS) or hepatitis, is a human 
immunodeficiency virus (HIV) carrier, or tested positive for the hepatitis B virus surface 
antigen (HBsAg) or the hepatitis C virus (HCV) antibody. However, subjects who tested 
negative for HCV antigen or HCV-RNA are permitted to participate. 
23. The subject has any of the following abnormal clinical laboratory test values at the start of the 
run-in period (Visit 1): 
• 
Creatinine > 2 mg/dL. 
• 
ALT or AST > ULN. 
• 
Bilirubin (Total bilirubin) > ULN. 
Justification of Exclusion Criteria 
Criteria 1, 2, 3, and 5 were set as basic matters to conduct clinical studies. 
Criteria 6, 7, 8, 10, 11, 12, 13, 14 and 17 were set because it could influence the evaluation of 
efficacy in this study. 
Criteria 4, 9, 15, 16, 18, 19, 20, 21, 22 and 23 were set with respect to the safety of the subjects. 
7.3 
Excluded Medications, Restricted Medications and Prohibited Treatments 
The subjects must be instructed not to take any medications, including over-the-counter (OTC) 
medications, without consulting the investigator. However, on-demand medications for 
endoscopic examination and topical medications, including liniments, ophthalmic drops, nasal 
drops, ear drops, inhaled drugs, adhesive skin patches, and gargle (mouthwash), are allowed, 
whether or not they are excluded or restricted. 
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(1) Excluded Medications 
A list of excluded concomitant medications is provided below. 
Excluded medications 
 
Excluded period 
(1) Medications for gastrointestinal tract* 
PPIs [including TAK-438 
(vonoprazan fumarate)] 
From 14 days before the start 
of the run-in period to 
completion of the study 
 
H2RAs 
From 7 days before the start of 
the run-in period to completion 
of the study 
 
Prokinetics 
Anticholinergic drugs 
Prostaglandins 
Antacids 
Anti-gastrin drugs 
Mucosal protective agents 
From the start of the run-in 
period to completion of the 
study 
(2) H. pylori eradication 
Triple therapy with PPI+2 
antibiotics 
From 14 days before the start 
of the run-in period to 
completion of the study 
(3) Concomitant use is contraindicated 
for TAK-438 (vonoprazan fumarate) 
Atazanavir sulfate 
Rilpivirine hydrochloride 
From the start of the run-in 
period to completion of the 
study 
(4) Antidepressants 
Medications with the indication of 
antidepressants on the label (eg, 
tricyclic antidepressant, tetracyclic 
antidepressant, SSRI, SNRI, 
NaSSA) 
From 14 days before the start 
of the run-in period to 
completion of the study 
(5) Anxiolytics 
Medications with the indication of 
anti-anxiety on the label (eg, 
benzodiazepine anxiolytic, 
serotonin 1A receptor partial 
agonist) 
From 42 days before the start 
of the run-in period to 
completion of the study 
(6) Other investigational products 
Other investigational products and 
postmarketing study products 
From 84 days before the start 
of the run-in period to 
completion of the study 
* Use of agents for gastrointestinal tract not listed here (eg, herbal medicines) is permitted. Use of drugs with no 
gastrointestinal indications is also permitted. 
 
Justification of Excluded Medications 
Excluded concomitant medications (1), (2), (4), and (5) were set because they may affect the 
evaluation of efficacy. 
Excluded concomitant medication (3) was set because concomitant use with acid suppressants 
could reduce solubility and then effects of atazanavir sulfate; and also could reduce absorption and 
then effects of rilpivirine hydrochloride. 
Excluded concomitant medication (6) was set in consideration of safety assurance for subjects. 
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(2) Restricted Medications 
Restricted medications 
Conditions for concomitant use 
Bisphosphonates 
After informed consent signing, the dosage was not changed in subjects who met the 
following criteria (however, switching between once-daily weekly and monthly 
regimens was permitted for drugs containing the same active ingredient): 
Subjects who had been treated with a bisphosphonate before informed consent signing, 
who had no bisphosphonate-associated gastrointestinal inflammation or a history of 
gastrointestinal inflammation before the start of the run-in period, and who were 
compliant with the dosage as instructed by the bisphosphonate package insert. 
 
Justification of Restricted Medications 
The restricted medications listed above were set because they could affect the evaluation of 
efficacy, but the expected impact could be low under a restricted condition for dosage. 
(3) Prohibited Treatments 
The following concomitant therapies are prohibited from the start of the run-in period through the 
end of study. 
• Surgical treatment of EE and NERD (eg, fundoplication). 
• Any surgery affecting gastric acid secretion (eg, resection of upper gastrointestinal tract and 
vagotomy). 
Justification of Prohibited Treatments 
The treatments above were set because they could affect the evaluation of efficacy. 
7.4 
Diet, Fluid and Activity Control 
The investigator, or study collaborator gives the following instructions to the subjects prior to and 
during the study and asks the subjects at each visit if they have followed the instructions. 
• The subjects are to visit the sites as scheduled and undergo all examinations and assessments 
scheduled for the visit. In cases where the subjects are unable to visit the sites as scheduled, 
they are to promptly inform the investigator, or study collaborator. 
• The subjects are required to be compliant with the study treatment, which includes adhering to 
the daily dose and timing (in principle, after breakfast). In the event that a subject misses a dose 
of study drug, the subject is to inform the investigator of the duration of noncompliance with 
the study treatment. The subject is also required to bring the study drug packages (including 
the empty blister packs after use) and any unused study drug at every visit. 
• The subjects are instructed to daily record any acid reflux symptoms (heartburn and 
regurgitation) experienced during the day before bedtime throughout the study. The subjects 
are also instructed to record their compliance with the study treatment. The subjects are 
instructed to bring their diaries at every visit. 
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• The subjects are required to fast before any visit to the study site for endoscopic examination, 
for blood sampling to obtain serum gastrin and pepsinogen I/II levels, or for clinical laboratory 
tests (triglycerides and glucose). 
• The subjects are to visit the sites in the morning, in principle, at the start of the treatment period 
(Visit 2). At Weeks 2 and 4 (Visits 3 and 4), the subjects are to visit the sites in the morning, in 
principle, without taking the study drug. On the day of the start of the run-in period (Visit 1), at 
the start of the treatment period (Visit 2), and the day after 2 weeks of treatment (Visit 3), the 
subjects are to take the study drugs given for the day of site visit after completion of all 
scheduled examinations and assessments, but before leaving the site. 
• On the days the subjects do not have breakfast, they are to take the study drugs at the same time 
of the day as they are to usually do; exceptions are to be made on the days of the endoscopic 
examination, blood testing for serum gastrin and pepsinogen I/II levels, or for clinical 
laboratory tests. 
• The subjects are to consult the investigator, or study collaborator before receiving any therapy 
from other physicians or before taking any medications, including OTC products, other than 
the prescribed study drugs. The subjects are required to inform the investigator of any therapy 
they have received from other physicians and any medication they have taken, including OTC 
products. 
• At every visit, the subjects are to report any symptoms or signs they have experienced, with the 
onset date, severity, outcome, and outcome date of the episode. In the event of an emergency, 
including occurrence of a serious adverse event (SAE), either the subject or the subject’s 
family member is to inform the investigator immediately. 
• Female subjects with childbearing potential are to adhere to acceptable contraception methods 
from signing of informed consent to 4 weeks after the last dose. Any pregnancy is to be 
immediately reported to the sponsor. 
• Blood donation is not permitted during the study. If the subjects have donated blood, they are 
to inform the investigator immediately. 
• The subjects are instructed to avoid, throughout the study, excessive eating and drinking, any 
drastic change in diet (eg, change to excessively fat-rich diet), and excessive exercising. 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the case report form (eCRF) using the following categories. For subject 
failure, refer to Section 9.1.18. 
1. Death. The subject died on study. 
Note: If the subject dies on study, the event will be considered as SAE. See Section 10.2.2 for 
the reporting procedures. 
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2. Adverse event (AE). The subject has experienced an AE that requires early termination 
because continued participation imposes an unacceptable risk to the subject’s health or the 
subject is unwilling to continue because of the AE. 
• 
Liver Function Test (LFT) Abnormalities. 
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status), if the following circumstances occur at any time during study 
drug treatment: 
– 
ALT or AST or bilirubin (total bilirubin) > 2×ULN. 
3. Protocol deviation. The discovery post-randomization that the subject failed to meet protocol 
entry criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health. 
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents. 
5. Withdrawal by subject. The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE). 
6. Study terminated by sponsor. The sponsor terminates the study. 
7. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.13. 
8. Lack of efficacy. The investigator  has determined that the subject is not benefiting from study 
treatment; and, continued participation would pose an unacceptable risk to the subject. 
9. Lack of treatment compliance. The subject’s treatment compliance is poor, and improvement 
in compliance is not expected. Treatment compliance is described in Section 9.2. 
10. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
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the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. 
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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
8.1 
Study Drug and Materials 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study drug refers to all or any of the drugs defined below. 
8.1.1.1 Study Drug 
(1) Dosage Form and Manufacturing 
Drugs being studied in the current protocol are as follow: 
1) Study drug for the treatment period (TAK-438 DB tablet) 
Study drug code: TAK-438 
Chemical name: 
1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine 
monofumarate 
Non-proprietary name: Vonoprazan Fumarate (JAN) 
Study drug 
Ingredients 
TAK-438 10 mg tablet 
A tablet, coated by pale-yellow film, contains 10 mg of TAK-438 (as the free base) 
as active ingredient. 
TAK-438 placebo tablet 
A tablet, coated by pale-yellow film, contains no active ingredient, TAK-438. 
 
TAK-438 10 mg tablets and TAK-438 placebo tablets are manufactured by Takeda 
Pharmaceutical Company Limited. Appearance of TAK-438 DB tablets is indistinguishable from 
that of TAK-438 placebo tablets. 
2) Study drug for the run-in period (TAK-438 placebo tablet) 
Study drug 
Ingredients 
TAK-438 placebo tablet 
A tablet, coated by pale-yellow film, contains no active ingredient, TAK-438. 
 
TAK-438 placebo tablets are manufactured by Takeda Pharmaceutical Company Limited. 
Appearance of TAK-438 DB tablets is indistinguishable from that of TAK-438 placebo tablets. 
(2) Packaging and Labeling 
Study drugs are packaged by Takeda Pharmaceutical Company Limited. 
TAK-438 placebo tablets will be used as study drugs for the run-in period and provided in blister 
packs. Each blister pack contains 7 tablets of TAK-438 placebo (each pack last for 7 days), and 12 
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blister packs are placed into one box. 
TAK-438 DB tablets will be used as study drugs for the treatment period and provided in blister 
packs. Each blister pack contains 7 tablets of TAK-438 DB (each pack last for 7 days), and 5 
blister packs (including extra 7-day supply) are placed into one box for one subject. 
A label for study drug is placed on the box. The label includes a clear indication of investigational 
use, name of study drug, quantity of study drugs, name and address of the sponsor, lot number and 
storage. 
8.1.2 Storage 
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. Study drug must be stored under the conditions 
specified on the label, and remain in the original container until dispensed. A daily temperature log 
of the drug storage area must be maintained every working day. 
8.1.3 Dose and Regimen 
Even in the event that a subject misses a dose of study drug during the run-in period or the 
treatment period, the subject is required to comply with the next dosing scheduled and thereafter. 
The subject should not take any study drugs that he/she has failed to use on the scheduled day. Any 
unused study drugs should be collected. 
Run-in Period 
Each subject will remove 1 tablet of TAK-438 placebo as the study drug for the run-in period from 
the blister pack once a day and take it orally after breakfast in principle for 1 week. The run-in 
period (Visit 1) begins after completion of all scheduled examinations and assessments. 
The study drugs for the run-in period will be prescribed after all scheduled examinations and 
assessments (Visit 1) are completed. The subject will receive their first dose of study drug for the 
run-in period before leaving the site. 
Treatment Period 
Each subject will remove either 1 tablet of TAK-438 10 mg or 1 tablet of TAK-438 placebo for the 
treatment period from the TAK-438 DB blister pack once a day and take it orally after breakfast in 
principle for 4 weeks. Treatment period begins from the day of the randomization (at the start of 
the treatment period [Visit 2]) after completion of all scheduled examinations and assessments. 
The study drugs for the treatment period will be prescribed after all scheduled examinations and 
assessments (Visit 2) are completed. The subject will receive their first dose of study drug for the 
treatment period before leaving the site. After 2 weeks and 4 weeks of treatment (Visits 3 and 4), 
the subject is required to visit the site without taking the study drug. After 2 weeks of treatment 
(Visit 3), the subject will receive the study drug given for the day of site visit after completing all 
scheduled examinations and assessments , but before leaving the site. 
Table 8.a describes the dose and regimen for each group. 
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Table 8.a 
Dose and Regimen 
Run-in Period 
Dose 
Treatment Description (TAK-438 placebo tablet) 
TAK-438 placebo once daily 
One TAK-438 placebo tablet 
 
Treatment Period 
Treatment group 
Dose 
Treatment Description (TAK-438 DB tablet) 
TAK-438 10 mg  
10 mg TAK-438 once daily 
One 10 mg TAK-438 tablet  
Placebo 
TAK-438 placebo once daily 
One TAK-438 placebo tablet 
 
8.1.4 Overdose 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRFs according to Section 10.0. 
SAEs associated with overdose should be reported according to the procedure outlined in Section 
10.2.2. 
In the event of drug overdose, the subject should be treated symptomatically. 
8.2 
Study Drug Assignment and Dispensing Procedures 
Subjects will be assigned to receive the study drugs in order of medication ID number allocated to 
each study site. The investigator or the investigator's designated representatives will enter the 
medication ID number on the eCRF. 
8.3 
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
8.4 
Study Drug Blind Maintenance  
The principal investigator will not receive information on the study drug key code. To maintain 
blinding of the study, the Emergency Key Control Center will keep the emergency keys until 
emergency code-breaking or when all the subjects data are fixed. During regularly scheduled, the 
sponsor or the sponsor’s designee will perform an inventory of the number of unused blinded study 
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drugs and used study drug packages. All unused study drug packages are to be returned to the 
sponsor or the sponsor’s designee before study closure. 
As knowledge of serum gastrin and pepsinogen I/II levels may affect the integrity of blinding, the 
final results of these measurements , in principle, will be kept undisclosed until unblinding at each 
laboratory that performs the clinical laboratory tests. The sponsor should be notified when 
unblinding is permitted. Disclosure of the result to the sponsor, if ever necessary, before 
unblinding, is only permitted by the randomization personnel and only after appropriate masking 
that prevents the laboratory staff from identifying the subject. 
8.5 
Unblinding Procedure 
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. In the event of a medical 
emergency, if possible, the medical monitor should be contacted before the study drug blind is 
broken to discuss the need for unblinding. 
For unblinding a subject, the study drug blind can be obtained by contacting the Emergency Key 
Control Center (contact information is described in the procedure). 
The sponsor must be notified as soon as possible if the study drug blind is broken. The date, time, 
and reason the blind is broken must be recorded in the document called Record of Early 
Blind-Breaking and the same information (except the time) must be recorded on the eCRF. 
If subject’s blind is broken, the investigator should stop administering of study drug to the subject 
immediately, and the subject must be withdrawn from the study. 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
The site designee will receive the procedures for handling, storage and management of study drugs 
created by the sponsor, according to which the site designee will appropriately manage the 
sponsor-supplied drug. The investigator will also receive those procedures from the sponsor. The 
procedures include those for ensuring appropriate receipt, handling, storage, management, 
dispensation of the sponsor-supplied drug, and collection of unused medications from the subject 
as well as return of them to the sponsor or destruction of them. 
The site designee will immediately return unused medications to the sponsor after the study is 
closed at the site. 
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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator whenever possible. The Schedule of Study 
Procedures is located in Appendix A. 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is explained; this subject number will be used throughout the study. 
After the subject sign the informed consent form, the informed consent will be reported to the 
subject registration center. 
9.1.1.1 Pharmacogenomic Informed Consent Procedure 
A separate informed consent form pertaining to storage of the sample must be obtained prior to 
collecting a blood sample for Pharmacogenomic Research for this study. The provision of consent 
to collect and analyze the pharmacogenomic sample is independent of consent to the other aspects 
of the study. 
9.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, race as described by the 
subject, smoking classification, use of alcohol or caffeine-containing drinks, treatment history of 
H. pylori eradication (eg, triple therapy with PPI + amoxicillin + clarithromycin) of the subject, 
and if treated, when the treatment was completed (within the last year or more than one year 
before) at the start of the run-in period (Visit 1). 
Medical history to be obtained will include whether the subject has any significant conditions or 
diseases relevant to the disease under study that stopped prior to signing of informed consent. 
Ongoing conditions are considered concurrent medical conditions (see Section 9.1.10). Any 
significant conditions or diseases relevant to the proposed indication include NERD and other 
diseases or procedures related to upper gastrointestinal tract.6 Extent of medical history for NERD 
should be just prior to signing of informed consent, while for other diseases or procedures related 
to upper gastrointestinal tract it should be for 3 years prior to signing of informed consent. 
The investigator will inquire subjects with possible case of heartburn, and identify and document 
causative factors in the eCRF according to the following categories. Subjects will also be asked 
whether they will voluntarily change their lifestyle to manage their heartburn. 
6 Erosive esophagitis, gastric ulcer, duodenal ulcer, gastritis, and other. 
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• Physical factors: kyphosis, evident obesity. 
• Movement: forward flexion, lying in bed, etc. 
• Diet: fatty foods (eg, fried food), carbohydrates (eg, grains, potatoes), sweet foods (eg, 
chocolate), acidic foods (eg, citrus fruits, carbonated beverages), spices (eg, pepper, curry), 
etc. 
• Habits: smoking, caffeine ingestion, drinking alcohol. 
• The above factors are not applicable. 
Medication history information to be obtained will include any medication relevant to eligibility 
criteria and efficacy evaluation stopped at or within 90 days prior to signing of informed consent. 
These records include the medication’s trade or generic names and the routes of administration. 
The investigation of the subject’s medication history will cover the following agents: that are 
stopped within 28 days prior to signing of informed consent, except PPIs and H2RAs. 
• PPIs. 
• H2RAs. 
• Any other medications for gastrointestinal tract. 
• Antidepressants 
• Anxiolytics 
9.1.3 Acid Suppressants 
Subjects are to be asked whether they have taken any acid suppressants (PPIs, H2RAs, or other 
agents [anticholinergics or anti-gastrin drugs]) within 180 days prior to informed consent. For 
subjects who have been treated with these drugs, the investigator will ask them to identify which 
type of acid suppressants they have taken and categorize them according to a response to any of 
these drugs using 4 scales: ‘heartburn has been resolved’, ‘heartburn has not been resolved but 
relieved’, ‘heartburn has remained unchanged’, or ‘heartburn has been worsened’. 
9.1.4 Physical Examination Procedure 
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and 
(11) other. 
All physical examinations after the start of the study drug administration will assess clinically 
significant changes from before the start of the study drug administration. 
9.1.5 Patient Diary 
Subjects are to record any heartburn and regurgitation, most common acid reflux symptoms of 
NERD, in the patient diary for assessment. 
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The subjects will receive their diary at each visit and be instructed on how to record acid reflux 
symptoms (heartburn and regurgitation) in their diary. 
The subjects are to start the diary before bedtime from the start of the run-in period (Visit 1) and 
then continue daily to record the severity of acid reflux symptom (heartburn or regurgitation) 
throughout the study, according to Table 9.a. Compliance with the study treatment will also need 
to be recorded throughout the study. 
The patient diary will be reviewed at each visit and the subjects will be inquired for any missing 
entries, inconsistencies or questions. After the required entries are recorded by the subjects, the 
investigators are to collect the patient diary. The principal investigator will store the patient diary. 
Table 9.a 
Severity of Acid Reflux Symptoms 
Without symptom 
No symptom 
 
No hindrance to daily activities 
With symptom 
Mild (not very painful) 
 
Moderate (rather painful) 
 
Severe (painful) 
 
9.1.6 Weight, Height and BMI 
A subject should have weight and height measured according to the study procedures (Appendix 
A). The BMI is calculated by the sponsor using weight and height recorded on the eCRF with the 
formula provided below: 
Metric: BMI=weight (kg)/height (m)2 
Standard used by the sponsor for collecting height is in centimeters without decimal places and for 
weight it is kilograms (kg) with 1 decimal place. 
Note that although height is reported in centimeters, the formula uses meters for height; meters can 
be determined from centimeters by dividing by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2 
9.1.7 Vital Sign Procedure 
Vital signs will include body temperature (axilla measurement), sitting blood pressure (systolic 
and diastolic, after at least 5 minutes of rest [mm Hg]), and pulse (beats per minute). Vital signs 
are to be measured according to the study procedures (Appendix A). 
9.1.8 QOL Survey 
QOL survey will be conducted using the acute (1-week recall) version of the SF-8 Health Survey 
questionnaire according to the study procedures (Appendix A). Subjects are instructed on how to 
fill out a QOL survey form, which will be handed out at the time of informed consent. The subjects 
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will be required to fill out the questionnaire on how they have felt in the previous week at the start 
of the run-in period (Visit 1) and at every visit during the study period. 
9.1.9 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by the sponsor. At each study visit, subjects will be asked whether they have taken any medication 
other than the study drug (used from signing of informed consent through the end of the study), 
and all medication including vitamin supplements, over-the-counter medications, and oral herbal 
preparations, must be recorded in the eCRF. 
Information on the following concomitant medications is not mandatory: infusions, rehydrants, 
medications used for endoscopy (eg, analgesics, local anesthetics, anticholinergics, sedatives, 
antagonists, antifoaming agents, and pigments), internal/external diagnostic products, and test 
drugs (eg, pregnancy test agents). 
9.1.10 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at the first examination after signing of informed consent. The 
condition (ie, diagnosis) should be described. 
9.1.11 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 10 mL, and the approximate total volume of 
blood for the study is approximately 40 mL. Clinical laboratory tests are listed in Table 9.b. 
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Table 9.b 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Red blood cells (RBC) 
White blood cells (WBC) 
Hemoglobin 
Hematocrit 
Platelets 
White blood cell differentials 
(neutrophils, eosinophils, basophils, 
monocytes, lymphocytes) 
ALT 
ALP 
AST 
GGT 
Bilirubin (Total bilirubin) 
Direct bilirubin 
LDH 
Creatine kinase 
Albumin 
Protein (Total protein) 
Creatinine 
Blood urea nitrogen 
Uric acid 
Total cholesterol 
Triglycerides* 
Glucose* 
Potassium 
Sodium 
Magnesium 
Calcium 
Inorganic phosphorus 
Chloride 
Protein (qualitative) 
Glucose (qualitative) 
Other: Urine human chorionic gonadotropin (hCG) (for pregnancy test in female subjects with childbearing 
potential) 
*blood sampling under fasted condition. 
 
The central laboratory will perform laboratory tests for hematology, chemistries, and urinalysis. 
The hCG test will be performed at the study site. The results of laboratory tests will be returned to 
the investigator, who is responsible for reviewing and filing these results. 
If subjects experience ALT or AST > 2×ULN or bilirubin (total bilirubin) level > 2×ULN, 
follow-up laboratory tests (at a minimum, serum ALP, ALT, AST, bilirubin (total bilirubin), GGT, 
and international normalized ratio [INR]) should be performed within a maximum of 7 days and 
preferably within 48 to 72 hours after the abnormality was noted. For more detail refer to Section 
10.2.1.3. 
Refer to Section 7.5 if ALT or AST or bilirubin (total bilirubin) > 2×ULN. 
In addition, refer to Section 10.2.3 in relation to ALT or AST > 3×ULN in conjunction with 
bilirubin (total bilirubin) > 2×ULN when a decision is made that these abnormalities in the liver 
function test cannot reasonably be explained by other factors. 
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9.1.12 Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, and throughout the duration of the study, and for 4 weeks after 
last dose of study drug, female subjects of childbearing potential (ie, nonsterilized, premenopausal 
female subjects) who are sexually active must use acceptable methods of contraception. 
Such subjects will be provided with information on acceptable methods of contraception as part of 
the subject informed consent process, and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy during the course of the study. During the 
course of the study, regular urine hCG pregnancy tests will be performed, and subjects will receive 
continued guidance with respect to avoiding pregnancy as part of the study procedures (Appendix 
A). 
In addition to a negative urine hCG pregnancy at the start of the run-in period (Visit 1) and the start 
of the treatment period (Visit 2), subjects also must have a negative urine hCG pregnancy test at 
each visit throughout the study. 
9.1.13 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug for the run-in period and the treatment period should be immediately 
discontinued. 
If the pregnancy occurs during administration of study drug for the treatment period, eg, after 
Visit 2 or within 4 weeks of the last dose of active study drug, the pregnancy should be reported 
immediately, using a pregnancy notification form, to Emergency Reception Center for Safety 
Information listed in the annex. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed. 
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time 
she became pregnant and provide details of treatment the subject received (blinded or unblinded, 
as applicable). 
All pregnancies in subjects on active study drug including comparator will be followed up to final 
outcome, using the pregnancy form. The outcome, including any premature termination, must be 
reported to the sponsor. Postnatal evaluation will also be conducted. 
9.1.14 ECG Procedure 
A standard 12-lead ECG will be recorded as part of the study procedures (Appendix A). The 
investigator (or a qualified observer at the study site) will interpret the ECG using 1 of the 
following categories: normal or abnormal. The investigator (or a qualified observer at the study 
site) will judge if it is clinically significant. 
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The following parameters will be recorded on the eCRF from the subject’s ECG trace:  
heart rate, RR interval, PR interval, QT interval, and QRS interval. 
9.1.15 Pharmacogenomic Sample Collection 
When sampling of whole blood for pharmacogenomic analysis occurs, every subject must sign 
informed consent in order to participate in the study and to collect, storage and analyze of the 
pharmacogenomic sample. 
One 5-mL whole blood sample for deoxyribonucleic acid (DNA) isolation will be collected after 2 
weeks of treatment (Visit 3) from each subject in the study, into plastic tubes with K2 
ethylenediamine-tetraacetic acid (EDTA). 
Pharmacogenomic sample should not be collected from any subject who has received comparable 
bone marrow transplant or whole blood transfusion within 6 months of any sample collection. 
See the separately created procedure for directions on collecting, handling, and storage of 
pharmacogenomic samples. 
9.1.16 Serum Gastrin and Pepsinogen I/II Levels  
Serum gastrin and pepsinogen I/II levels (pepsinogen I, pepsinogen II and pepsinogen I/II ratio) 
will be measured since serum gastrin, pepsinogen I and pepsinogen II are expected to increase 
after TAK-438 administration. Blood samples for measurement of serum gastrin and pepsinogen 
I/II levels will be collected with clinical laboratory test samples according to the study procedures 
(Appendix A). Blood sample will be collected under fasted condition, and sampling is recommend 
at the same time period each time. Serum gastrin and pepsinogen I/II levels will be measured by 
the central laboratory. 
Disclosure of the measurement results to the sites is not reported in principle. 
9.1.17 Anti-H. pylori Antibody Titer 
Blood samples for measurement of anti-H. pylori antibody titer will be collected with clinical 
laboratory test samples according to the study procedures (Appendix A). 
Anti-H. pylori antibody titer will be measured by the central laboratory. 
9.1.18 Documentation of Subjects Failure 
Investigators must account for all subjects who sign informed consent. 
If the subject is found to be not eligible after signing of informed consent but prior to the 
randomization, the investigator should complete the eCRF. The following information are to be 
recorded in the eCRF: the date of signing of informed consent, date of birth, sex, self-reported race, 
conditions at the end of run-in period (including the date of study drug discontinuation, and 
reasons for premature discontinuation), and occurrence of an AE. Any case of occurrence of AEs 
should be documented on the eCRF in detail. 
The primary reason for subject failure is recorded in the eCRF using the following categories: 
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• Death 
• Adverse Event 
• Screen Failure (failed inclusion criteria or did meet exclusion criteria) <specify reason>. 
• Protocol deviation. 
• Lost to follow-up. 
• Withdrawal by subject <specify reason>. 
• Study terminated by sponsor. 
• Pregnancy 
• Other <specify reason>. 
Subject numbers assigned to subjects who fail before randomization should not be reused. 
As for subjects who have received the study drug for the run-in period but fail before 
randomization, the eCRF should include the start and completion dates of the study drug for the 
run-in period and history of taking acid suppressants/response after taking the acid suppressants* 
(refer to Section 9.1.3) in addition to the above information. Any overdose should be documented 
on the eCRF. 
* The record of the history of taking acid suppressants/response after taking the acid suppressants 
is required only for those who were determined ineligible for failing to meet the inclusion criterion 
9. 
9.1.19 Documentation of Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment period. 
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF. 
9.1.20 Endoscopic Assessment 
The investigator, or study collaborator (physician) should perform esophagus endoscopy in 
accordance with the schedule of the study procedures (Appendix A). For the esophagus endoscopy, 
the subjects should be asked to visit the site under fasted condition. The investigator, or study 
collaborator (physician) should capture clear photographs of the subject’s esophagus for the 
assessment of the modified LA Classification grade. The endoscopic photographs will be 
classified according to the modified LA Classification [17] shown in Table 9.c. 
Barrett’s mucosa is classified according to the following criteria at the start of the run-in period 
(Visit 1): present (less than 3 cm), absent, or unknown. 
Esophageal hiatal hernia at the start of the run-in period (Visit 1) is classified into the following: 
present (2 cm or more), present (less than 2 cm), absent, or unknown. 
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The investigator (with possible assistance by a study collaborator, if necessary) will provide the 
sponsor with the endoscopic findings at the start of the run-in period (Visit 1) using the modified 
LA Classification in the form of electronic media or of attached paper to the endoscopic test report. 
The Central Adjudication Committee (CAC) will be established. Further information is provided 
in Section 11.1. 
Table 9.c 
The Modified LA Classification 
Grade N 
Normal mucosa 
Grade M 
Minimal changes to the mucosa, such as erythema and/or whitish turbidity 
Grade A 
Nonconfluent mucosal breaks < 5 mm in length 
Grade B 
Nonconfluent mucosal breaks ≥ 5mm in length 
Grade C 
Confluent mucosal breaks < 75% circumferential 
Grade D 
Confluent mucosal breaks > 75% circumferential 
[17] 
A ‘mucosal break’ is defined as ‘an area of slough or erythema with a sharp line of demarcation from adjacent normal 
mucosa’ [23]. 
9.2 
Monitoring Subject Treatment Compliance 
Subjects will be required to bring study drug containers/unused medications to the site at every 
visit. The investigator will investigate treatment compliance using the patient diaries and record 
the following information on the eCRF. 
• Dates of the first and last doses of the study drug for the run-in period. 
• Dates of the first and last doses of the study drug for the treatment period. 
If a subject is persistently noncompliant with the study drug (eg, taking less than 50% of the 
allocated medication for 2 successive visits), it may be appropriate to withdraw the subject from 
the study. All subjects should be reinstructed about the dosing requirement during study contacts. 
The authorized study personnel conducting the re-education must document the process in the 
subject source records. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all examinations and assessments is shown in 
Appendix A. All examinations and assessments should be completed at the designated time points. 
9.3.1 Start of Run-in Period (Visit 1) 
The following procedures will be completed at the start of the run-in period (Visit 1). Subject 
eligibility will be confirmed in accordance with predefined primary inclusion and exclusion 
criteria as described in Section 7.0 and the eligibility will be reported to the subject registration 
center. 
• Informed consent. 
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• Primary inclusion criteria and exclusion criteria. 
• Demographics and medical history. 
• Medication history. 
• History of taking acid suppressants. 
• Physical examination. 
• Vital signs. 
• Weight and height. 
• Concomitant medications. 
• Concurrent medical conditions. 
• Clinical laboratory tests (hematology, chemistry, urinalysis). 
• Anti-H. pylori antibody titer. 
• Pregnancy test (only female subjects with childbearing potential). 
• ECG procedure. 
• Provision of a patient diary, instructions on how to record, and initiate entries in the patient 
diary. 
• QOL survey. 
• Endoscopy. 
• Prescription of the study drug for the run-in period (only for subjects confirmed eligible). 
• Assessment of AEs. 
Subjects will be instructed on when to take the first dose of study drug for the run-in period as 
described in Section 6.1. 
The procedure for documenting subject failures (before randomization) is provided in Section 
9.1.18. 
9.3.2 Start of Treatment Period (Visit 2) 
Subject eligibility will be confirmed in accordance with predefined secondary inclusion and 
exclusion criteria as described in Section 7.0 and the final eligibility will be reported to the subject 
registration center. 
If the subject satisfies all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized as described in Section 8.2. 
The following procedures will be completed at the start of the treatment period (Visit 2). 
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The subjects will be instructed on when to take the first dose of study drug as described in Section 
6.1. The procedure for documenting subject failures before start of study drug treatment is 
provided in Section 9.1.18. 
• Secondary inclusion criteria and exclusion criteria. 
• Physical examination. 
• Vital signs. 
• Concomitant medications. 
• Clinical laboratory tests (hematology, chemistry, urinalysis). 
• Serum gastrin and pepsinogen I/II levels. 
• Pregnancy test (only female subjects with childbearing potential). 
• Collection, review, and provision of a patient diary. 
• QOL survey. 
• Randomization. 
• Prescription of the study drug for the treatment period (only for subjects confirmed eligible). 
• Treatment compliance during the run-in period. 
• Assessment of AEs. 
9.3.3 After 2 Weeks of Treatment (Visits 3) 
Procedures to be completed or documented after 2 weeks of treatment (Visit 3) include: 
• Physical examination. 
• Vital signs. 
• Concomitant medications. 
• Clinical laboratory tests (hematology, chemistry, urinalysis). 
• Serum gastrin and pepsinogen I/II levels. 
• Blood sampling for PGx (only from subjects who have given consent to PGx measurement; 
ideally, blood samples for PGx are to be obtained after 2 weeks of treatment; however, blood 
samples obtained anytime between the start of the study drug administration for the treatment 
period and after 4 weeks of treatment/early termination of the study treatment are acceptable). 
• Pregnancy test (only female subjects with childbearing potential). 
• Collection, review, and provision of a patient diary. 
• QOL survey. 
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• Prescription of the study drug for the treatment period (only for subjects confirmed eligible). 
• Treatment compliance during the treatment period. 
• Assessment of AEs. 
9.3.4 After 4 Weeks of Treatment (Visit 4) 
Procedures to be completed or documented after 4 weeks of treatment (Visit 4) include: 
• Physical examination. 
• Vital signs. 
• Concomitant medications.  
• Clinical laboratory tests (hematology, chemistry, urinalysis). 
• Serum gastrin and pepsinogen I/II levels. 
• Pregnancy test (only female subjects with childbearing potential). 
• ECG procedure. 
• Collection and review of a patient diary. 
• QOL survey. 
• Treatment compliance during the treatment period. 
• Assessment of AEs. 
Study completion should be reported to the subject registration center. 
For all subjects receiving study drug, the investigator must complete the Subject Status eCRF 
page. 
9.3.5 Early Termination 
Early termination should be reported to the subject registration center. Procedures to be completed 
or documented at early termination include: 
• Physical examination. 
• Vital signs. 
• Concomitant medications.  
• Clinical laboratory tests (hematology, chemistry, urinalysis). 
• Serum gastrin and pepsinogen I/II levels. 
• Blood sampling for PGx (only from subjects who have given consent to PGx measurements 
but have not yet finished blood sampling). 
• Pregnancy test (only female subjects with childbearing potential). 
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• ECG procedure. 
• Collection and review of a patient diary. 
• QOL survey. 
• Treatment compliance. 
• Assessment of AEs. 
For all subjects receiving study drug, the investigator must complete the Subject Status eCRF 
page. 
9.3.6 Post Study Care 
The study drug will not be available upon completion of the subject’s participation in the study. 
The subject should be returned to the care of a physician and standard therapies as required. 
9.4 
Biological Sample Retention and Destruction 
Whole blood 5-mL samples for PGx analysis will be stored frozen at 
 
(see the procedure). 
The collected samples will be retained for no longer than 15 years after completion of the 
TAK-438 study or until the drug development of TAK-438 is no longer actively pursued by the 
sponsor. 
When subjects request disposal of a stored sample during the retention period, the site will ask
 
 to destroy the sample via the sponsor according to the procedure.
 
 will destroy the sample in accordance with the procedure, and notify the 
site and sponsor. However, any samples should not be destroyed if all the documents (including 
medical records) have been destroyed which could identify the subject and it is impossible to link 
the sample to the subject. 
Even if the sample can be linked to the subject, when pharmacogenomic investigation has been 
conducted, the remaining samples will be destroyed and the results of pharmacogenomic 
investigation of anonymized subject will be retained by the sponsor. 
The sponsor will build an appropriate management system required for protection of the subject’s 
personal information, define standards for collecting store and destruction of samples, and prepare 
appropriate procedures. 
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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with this treatment or study participation. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the study participation 
whether or not it is considered related to the drug or study procedures. 
10.1.2 Additional Points to Consider for AEs 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.) 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in dose of study drug or a concomitant medication. 
• Be considered unfavorable by the investigator for any reason. 
• AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as an AE. 
Diagnoses vs signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s). 
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG parameters are only considered to be AEs if they are 
judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention. 
• If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE. 
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Pre-existing conditions : 
• Pre-existing conditions present at the time of signing of informed consent are considered 
concurrent medical conditions and should NOT be recorded as AEs. Baseline (the first 
examination after signing of informed consent) evaluations (eg, laboratory tests, ECG, X-rays 
etc.) should NOT be recorded as AEs unless related to study procedures. However, if the 
subject experiences a worsening or complication of such a concurrent medical condition after 
informed consent is signed, the worsening or complication should be recorded appropriately as 
an AE. Investigators should ensure that the event term recorded captures the change in the 
condition from baseline (the signing of informed consent) (eg, “worsening of…”). 
• If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from baseline (the signing of informed consent) (eg “worsening 
of…”). 
• If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be captured as an AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition from baseline (the signing of informed consent) 
(eg, “worsening of…”). 
Worsening of AEs: 
• If the subject experiences a worsening or complication of an AE after starting administration of 
the study drug, the worsening or complication should be recorded appropriately as a new AE. 
Investigators should ensure that the AE term recorded captures the change in the condition (eg, 
“worsening of…”). 
• If the subject experiences a worsening or complication of an AE after any change in study drug, 
the worsening or complication should be recorded as a new AE. Investigators should ensure 
that the AE term recorded captures the change in the condition (eg, “worsening of…”). 
Changes in severity of AEs: 
• If the subject experiences changes in severity of an AE that are not related to starting the study 
drug or changing in the dose or regimen, the event should be captured once with the maximum 
severity recorded. 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs. 
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Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy. 
Overdose: 
• Cases of overdose with any medication without manifested side effects are NOT considered 
AEs, but instead will be documented on an Overdose page of the eCRF. Any manifested side 
effects will be considered AEs and will be recorded on the AE page of the eCRF. 
10.1.3 SAEs 
An SAE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
• 
The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• 
May require intervention to prevent items 1 through 5 above. 
• 
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
• 
Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a). 
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Table 10.a 
Takeda Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
syndrome 
Hepatic necrosis 
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia 
Acute liver failure 
Anaphylactic shock 
Malignant hypertension 
Acute renal failure 
Convulsive seizure 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis  
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson syndrome 
Confirmed or suspected transmission of infectious agent 
by a medicinal product 
 
Neuroleptic malignant syndrome/malignant 
hyperthermia 
 
Spontaneous abortion/stillbirth and fetal death 
 
10.1.4 AEs of Special Interest 
An AE of Special Interest (treatment-emergent only, serious or non-serious) is one of scientific 
and medical concern specific to the compound or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor may be appropriate. Such events may 
require further investigation in order to characterize and understand them and would be described 
in Section 10.2.1.3 as to how and when they should be reported to the sponsor. 
In this study, hepatic function abnormality*, clostridium difficile enteric infection, and 
hypersensitivity* are to be collected as AEs of special interest. Refer to Section 10.2.1.3 for criteria 
for AEs of special interest reporting. 
*: Although both hepatic fuction abnormality and hypersensitivity are identified as risks of 
vonoprazan, these are treated as AEs of special interest in order to collect detail informations. 
10.1.5 Severity of AEs 
The different categories of severity are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
 
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10.1.6 Causality of AEs to Study Drug(s) 
The causality of each AE to study drug(s) will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug is at least a 
reasonable possibility, i.e., the relationship cannot be ruled out, although factors other than the drug, 
such as underlying diseases, complications, concomitant medications and concurrent treatments, may 
also be responsible. 
Not 
related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or that 
can reasonably be explained by other factors, such as underlying diseases, complications, concomitant 
medications and concurrent treatments. 
 
10.1.7 Causality of AEs to Study Procedures 
The causality of each AE to study procedures will be assessed. 
The causality should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the causality should be assessed as 
Not Related.  
10.1.8 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
the investigator. 
The start date of AEs will be determined using the following criteria; 
AEs 
Start Date 
Any signs/symptoms/diseases 
(diagnosis) 
The date that the first signs/symptoms were noted by the subject and/or the 
investigator should be recorded. 
Asymptomatic diseases 
The date when examination was performed for diagnosis and diagnosis was 
confirmed should be recorded. 
The date when diagnosis was confirmed should also be recorded even when 
laboratory findings showed previous findings or the onset time can be 
estimated. 
Worsening of concurrent medical 
conditions or any 
signs/symptoms/diseases before 
treatment from signing of informed 
consent 
The date that a worsening of disease and symptom was noted first by the 
subject and/or the investigator should be recorded. 
The first examination after signing 
of informed consent or the 
examination right before the start of 
the study drug showed abnormal 
findings. 
The date of examination when an abnormal value that was judged to be 
clinically significant was noted should be recorded. 
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The first examination after signing 
of informed consent or the 
examination right before the study 
drug showed abnormal findings, and 
the subsequent examinations 
showed worsening of the symptoms. 
The date of examination when apparent elevation, reduction, increase or 
decrease was confirmed in medical judgment according to the trends in 
laboratory values should be recorded. 
 
10.1.9 End Date  
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
10.1.10Pattern of Adverse Event 
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous. 
10.1.11Action Taken with Study Treatment 
• Drug withdrawn – a study drug is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study drug. 
• Unknown – only to be used if it has not been possible to determine what action has been taken. 
• Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE, the AE that occurred before the study drug administration. 
• Dose Reduced – the dose was reduced due to the particular AE. 
• Dose Increased – the dose was increased due to the particular AE. 
• Drug Interrupted – the dose was interrupted due to the particular AE. 
10.1.12Outcome 
• Recovered/Resolved – Subject returned to first assessment status with respect to the AE. 
• Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE with the condition remaining “recovering/resolving”. 
• Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved”. 
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• Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis). 
• Fatal – the AEs which are considered as the cause of death.  
• Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study. 
10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 AE Collection Period 
Collection of AEs will commence from the time the subject signs the informed consent. Routine 
collection of AEs will continue until Visit 4. AEs occurring after the first dose of study drug for the 
run-in period and before start of study drug administration for the treatment period are defined as 
AEs during the run-in period, and AEs occurring after start of study drug administration for the 
treatment period until end of the treatment period are defined as AEs during the treatment period. 
10.2.1.2 AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious AE that occurs prior to the first exposure to study drug must be monitored until the 
symptoms subside and any clinically relevant changes in laboratory values have returned to 
baseline or there is a satisfactory explanation for the change. Non-serious AEs that occur prior to 
the first exposure to study drug, related or unrelated to the study procedure, need not to be 
followed-up for the purposes of the protocol. 
All subjects experiencing AEs after the first exposure to study drug, whether considered associated 
with the use of the study drug or not, must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or until there is a 
satisfactory explanation for the changes observed. All AEs will be documented in the AE page of 
the eCRF, whether or not the investigator concludes that the event is related to the drug treatment. 
The following information will be documented for each event: 
1. Event term. 
2. Start and end date. 
3. Pattern. 
4. Severity. 
5. Investigator’s opinion of the causality between the event and administration of study drug(s). 
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6. Investigator’s opinion of the causality to study procedure(s), including the details of the 
suspected procedure. 
7. Action taken with study treatment. 
8. Outcome of event. 
9. Seriousness. 
10. After administration of study drug. 
11. Treatment emergent. 
Patient diary/QOL survey form will not be used as a primary means to collect AEs. However, 
should the investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the subject for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied. 
10.2.1.3 AEs of Special Interest Reporting 
If this AE of special interest, which occurs during the treatment period or the follow-up period, is 
considered to be clinically significant based on the criteria below, it should be reported to the 
safety information center (contact information is described in the annex) immediately or within 1 
business day of first onset or subject’s notification of the event. Hepatic Function Abnormality 
Form, Clostridium Difficile enteric infection Form, Hypersensitivity Form or an SAE Form should 
be completed, signed and/or sealed by the principal investigator, and reported to appropriate 
personnel in the annex within 10 business days. In case if AE may be drug-induced liver function 
test abnormalities possibly leading to an SAE or a serious hepatic disorder, refer to Section 10.2.2. 
(1) Hepatic Function Abnormality 
In the clinical studies and postmarketing safety data of TAK-438, hepatic function abnormalities 
have been identified as a risk associated with TAK-438. Thus, hepatic function abnormalities are 
treated as AEs of special interest in this study in order to collect detail information. 
Any hepatic function abnormality is to be reported based on the following criteria: 
• ALT or AST > 2×ULN. 
• bilirubin (total bilirubin) > 2×ULN. 
A Hepatic Function Abnormality Form should include relevant subject details, possible alternative 
etiologies (eg, acute viral hepatitis A or B, other acute liver disease, medical history, concurrent 
medical conditions), clinical course and procedures taken for the event. For re-examination, refer 
to Section 9.1.11. 
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(2) Clostridium Difficile Enteric Infection 
As the precautionary statement regarding clostridium difficile enteric infection is provided in the 
package inserts of PPIs which include TAK-438, AEs related to clostridium difficile enteric 
infection are to be collected as AEs of special interest. 
The following AEs are defined as clostridium difficile enteric infection: 
• Clostridial infection, clostridium bacteraemia, clostridium colitis, clostridium difficile colitis, 
clostridium difficile infection, clostridium difficile sepsis, clostridium test positive, 
gastroenteritis clostridial, or pseudomembranous colitis, according to AEs coded by Preferred 
Term (PT) in Medical Dictionary for Regulatory Activities (MedDRA)/Version 19.0. 
Clostridium Difficile Enteric Infection Form should include details of the subject, possible factors 
other than the study drug (eg, concomitant use of antibacterials or immunosuppressive agents, 
medical history, concurrent medical conditions), clinical course and procedures taken for the 
event. 
(3) Hypersensitivity 
Since hypersensitivity events have been reported, and which the causality to TAK-438 can not be 
ruled out. Any hypersensitivity event is to be reported based on the following criterion: 
• Hypersensitivity-related events leading to study discontinuation (eg, anaphylaxis, angioedema, 
erythema multiforme, urticarial, rash). 
Hypersensitivity Form should include the details of the subject, possible factors other than the 
study drug, clinical course and procedures taken for the event. 
The AE of special interest have to be recorded as AEs in the eCRF. An evaluation form along with 
all other required documentation must be submitted to the sponsor. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure. 
An SAE should be reported to the Emergency Reception Center for Safety Information (contact 
information is described in the annex) within 1 business day of first onset or subject’s notification 
of the event. The principal investigator should complete the SAE form within 10 calendar days. 
The information should be completed as fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the study drug(s) 
• Causality assessment. 
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Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation. 
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST > 3×ULN and bilirubin (total bilirubin) > 2×ULN for 
which an alternative etiology has not been identified, the event should be recorded as an SAE and 
reported as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion 
of the relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or 
B or other acute liver disease or medical history/concurrent medical conditions. Follow-up 
laboratory tests as described in Section 9.1.11 must also be performed. 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator should prepare an SAE form and fax it immediately. Copies of any relevant data from 
the hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be 
sent to the addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs/the 
head of the study site, as applicable. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory 
authorities as expedited report within 7 days for fatal and life-threatening events and 15 days for 
other serious events, unless otherwise required by national regulations. The sponsor will also 
prepare an expedited report for other safety issues where these might materially alter the current 
benefit-risk assessment of a study drug/sponsor supplied drug or that would be sufficient to 
consider changes in the study drug/sponsor supplied drug administration or in the overall conduct 
of the trial. The study site also will forward a copy of all expedited reports to his or her IRB. 
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11.0 
STUDY-SPECIFIC COMMITTEES 
The Central Adjudication Committee (CAC) will be established in this study. 
11.1 
Central Adjudication Committee 
The CAC will comprise independent experts with experience and training appropriate for reviews 
of the clinical endpoints. In response to the sponsor’s request, the CAC will review all endoscopic 
assessments reported by the sites in a consistent manner. 
The CAC will review endoscopic assessments at the start of the run-in period (Visit 1) reported by 
investigators, and the CAC review report will be documented. The CAC will submit the 
documented review report to the sponsor. 
The sponsor will provide the site with the results of CAC review. Even if there are inconsistencies 
between the assessment of the investigator and the CAC review, the investigator should take into 
account the CAC report as a reference, but is not required to change the original assessment, in 
principle. 
The sponsor should prepare the CAC Charter and the manual for the CAC secretariat prior to the 
start of the CAC review. The CAC Charter will define the purposes and the responsibilities of the 
committee. 
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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs and medical history including concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary. 
12.1 
CRFs (Electronic) 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by the sponsor (or 
designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
The following data will not be recorded into the eCRFs: 
• Clinical laboratory test results measured at the central laboratory. 
• Measurements of anti-H. pylori antibody titer. 
• Measurements of serum gastrin and pepsinogen I/II levels. 
• Endoscopic assessments provided by the CAC. 
After the lock of the clinical study database, any change of, modification of or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs (Data Clarification Form) provided by the sponsor. The principal investigator must 
review the data change for completeness and accuracy, and must sign, or sign and seal, and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor. 
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12.2 
Record Retention 
The investigator and the head of the study site agree to keep the records stipulated in Section 12.1 
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as thermal 
sensitive paper, source worksheets, all original signed and dated informed consent forms, subject 
authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. Any source documentation printed on degradable thermal sensitive paper should be 
photocopied by the site and filed with the original in the subject’s chart to ensure long term 
legibility. Furthermore, the investigator and the head of the institution are required to retain 
essential relevant documents until the day specified as 1) or 2) below, whichever comes later. 
However, if the sponsor requests a longer time period for retention, the head of the institution 
should discuss how long and how to retain those documents with the sponsor. 
1. The day on which marketing approval of the study drug is obtained (or the day 3 years after the 
date of notification in the case that the investigation is discontinued.) 
2. The day 3 years after the date of early termination or completion of the clinical study. 
In addition, the investigator and the head of the institution should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. 
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject evaluability, 
and appropriateness of the planned statistical methods. 
13.1.1 Analysis Sets 
In this study, three kinds of analysis sets are defined: full analysis set (FAS), per-protocol set (PPS) 
and safety analysis set. The FAS, the main analysis set used for primary efficacy analysis, will be 
defined as “all subjects who were randomized and received at least one dose of the study drug.” 
The definition of each analysis set will be described in the SAP. 
Prior to the database lock, the sponsor will verify the validity of the definitions of the analysis sets 
as well as the rules for handling data, consulting a medical expert as needed, and then finalize the 
SAP. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by treatment group based on 
all the randomized subjects. 
13.1.3 Efficacy Analysis 
13.1.3.1 Primary Endpoint and Analytical Methods 
Primary Endpoint 
Heartburn during the treatment period 
• Primary variable: proportion of days without symptoms. 
• Secondary variable: cumulative rate of improvement in symptoms. 
• Additional variable: severity of symptoms. 
Analytical Methods 
(1) Primary Analyses 
The primary analyses for primary endpoint will be performed based on the FAS. 
1. Primary variable 
Descriptive statistics will be used to summarize the proportion of days without symptoms during 
the treatment period by treatment group. The point estimate of the median difference between the 
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treatment groups will be calculated using the Hodges-Lehmann estimation. For comparisons of the 
treatment groups, the Wilcoxon rank sum test will be used. 
2. Secondary variable 
The cumulative improvement rate of symptoms during the treatment period will be calculated for 
each treatment group using the Kaplan-Meier method. The symptom improvement, event date and 
censoring date are defined below. The cumulative improvement rate in TAK-438 10 mg group will 
be compared to that of the placebo group using a log-rank test. 
Symptom improvement: symptoms experienced on less than 2 days of the last 7 days. 
Event date: the first day of confirmed symptom improvement that continued until the last day of 
study treatment. 
Censoring date: 6 days prior to the last day with documentation of whether the subject experienced 
symptoms (applicable only to subjects without symptom improvement). 
3. Additional variable 
The same analysis in Section 13.1.3.1(1)1 will be performed for mean severity of symptoms over 
the treatment period. 
(2) Secondary Analyses 
For sensitivity analysis, the same analyses to those conducted in Section 13.1.3.1(1) will be 
performed on the per-protocol set (PPS) to evaluate the stability of the results. 
13.1.3.2 Secondary Endpoints and Analytical Methods 
Secondary Endpoints 
• The primary endpoint in subject subgroups stratified by the response (improved or not 
improved) at Week 2. 
• The primary endpoint in subject subgroups stratified by endoscopic finding (Grade N or M). 
• The primary endpoint in subject subgroups stratified by the combination of endoscopic finding 
(Grade N or M) and response (improved or not improved) at Week 2. 
• The primary endpoint in subject subgroups stratified by the response (improved or not 
improved) to acid suppressants (PPIs, H2RAs, or other agents [anticholinergics or anti-gastrin 
drugs]) in subjects who had a medication history of any of these drugs. 
Analytical Methods 
Analyses for secondary endpoint will be performed similarly Section 13.1.3.1(1) on the FAS. 
When subjects are stratified by the response (improved or not improved) at Week 2, analyses will 
be performed on subjects stratified for both treatment groups and for the TAK-438 10 mg group 
only. 
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Response (improved or not improved) at Week 2 will be assessed in accordance with the following 
criteria. 
Criteria 1: 
Improved: the subject experiences heartburn on less than 2 days of the 7 days prior to Week 2 (Day 
8 through Day 14). 
Not improved: the subject experiences heartburn on 2 days or more of the 7 days prior to Week 2 
(Day 8 through Day 14). 
Criteria 2: 
Improved: the proportion of days the subject experiences heartburn during the treatment period up 
to Week 2 (Day 14) is lower than that during the run-in period. 
Not improved: the proportion of days the subject experiences heartburn during the treatment 
period up to Week 2 (Day 14) is equal to or larger than that during the run-in period. 
Subjects are to be stratified by the following response to acid suppressants (exclude naïve subjects 
from this analysis): 
Improved: those whose heartburn has been resolved, or whose heartburn has not been resolved but 
relieved. 
Not improved: those whose heartburn has remained unchanged, or whose heartburn has been 
worsened. 
13.1.3.3 Additional Efficacy Endpoints and Analytical Methods 
Additional Efficacy Endpoints 
• QOL. 
• Regurgitation during the treatment period. 
Analytical Methods 
1. QOL 
The following analyses will be performed by treatment group: 
1) Summary statistics at each visit 
2) Point estimate and its 2-sided 95% CI of the difference between each TAK-438 10 mg group 
and the placebo group at each visit 
2. Regurgitation during the treatment period 
The same analysis as the primary analysis described in Sections 13.1.3.1(1) will be performed 
using the FAS. 
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13.1.3.4 Data Conversion Method and Handling of Missing Data 
Details will be described in the SAP. 
13.1.3.5 Significance Level and Confidence Coefficient 
• The significance level: 5% (2-sided test) 
• Confidence coefficient: 95% (2-sided estimation) 
13.1.4 Safety Analysis 
The following analyses will be performed on the safety analysis set. 
13.1.4.1 TEAE 
A TEAE is defined as an AE occurring after receiving the study drug for the treatment period or an 
aggravation of an existing complication. 
TEAEs will be coded by System Organ Class (SOC) and Preferred Term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). The incidences of TEAEs will be summarized by 
treatment group. 
• All TEAEs 
• TEAEs by intensity 
• TEAEs by period 
• Drug-related TEAEs 
• Drug-related TEAEs by intensity 
• TEAEs leading to study drug discontinuation 
• Serious TEAEs 
In the tabulation of TEAE frequency, if a subject will have more than 1 episode of the same event, 
the subject should be counted only once for that event. If a subject will have more than 1 episode of 
the same PT, the subject should be counted only once for that PT. If a subject will have more than 
1 TEAE within a SOC, the subject should be counted only once for that SOC. In the tabulation of 
TEAE frequency by intensity, a subject should be counted only once using the highest severity for 
either PT or SOC. 
13.1.4.2 Clinical Laboratory Test Values, ECGs, Vital Signs, Serum Gastrin and Pepsinogen I/II 
Levels 
For continuous variables, the observed values and the changes from the start of the study drug for 
the treatment period will be summarized by treatment group for each visit using descriptive 
statistics. 
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For categorical variables, shift tables (eg, assessment of laboratory measurements and qualitative 
test results) in each category before and after treatment for the treatment period post-baseline visit 
will be provided for each treatment group. 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
The planned sample size is 474 subjects in total, 237 subjects for each group. 
The number of evaluable subjects required for the primary endpoint will be 460 in total, 230 for 
each group. 
Justification of the planned sample size 
In a phase 3 double-blind study of lansoprazole (AG-1749/CCT-206) evaluating the proportion of 
days without heartburn in those given AG-1749 15 mg and placebo, the mean proportion of days 
without heartburn and their standard deviations (SD) were shown to be 51.03%±28.388% in the 
placebo group versus 63.21%±32.200% in the AG-1749 15 mg group. Additionally, in the 
postmarketing study for lansoprazole (AG-1749/CCT-971), the mean proportion of days without 
heartburn and their SD were shown to be 46.83%±32.350% in the placebo group and 
55.36%±34.545% in the AG-1749 15 mg group. In a phase 3 double-blind study of TAK-438 
(TAK-438/CCT-201), the mean proportion of days without heartburn and their SD were shown to 
be 22.63%±28.202% in the placebo group and 28.89%±34.853% in the TAK-438 10 mg group. 
Assuming that, based on these results and assessment method of heartburn in this study, the 
difference between the TAK-438 10 mg group and the placebo group will be 10% with a common 
SD of 32%, 230 subjects per treatment group will be required to ensure 90% power of the 
Wilcoxon rank sum test with a significance level of 5%. Thus, it is appropriate that 237 subjects 
will be required for each treatment group, taking into account some dropouts, 3%, after 
randomization. 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study drug, subject medical records, informed consent documentation, documentation of subject 
authorization to use personal health information (if separate from the informed consent forms), 
and review of eCRFs and associated source documents. It is important that the investigator and 
other study personnel are available during the monitoring visits and that sufficient time is devoted 
to the process. 
14.2 
Protocol Deviations 
The investigator can deviate and change from the protocol for any medically unavoidable reasons, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the principal 
investigator should notify the sponsor and the head of the site of the deviation or change as well as 
its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the site as soon as possible and an approval from IRB should be obtained. 
The investigator should document all protocol deviations. Significant deviations should be 
recorded on the eCRFs and then confirmed by the sponsor or its designee. Significant deviations 
include, but are not limited to, those that involve fraud or misconduct, increase the health risk to 
the subject, or confound interpretation of primary study assessment. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1. 
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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 
IRB Approval 
IRBs must be constituted according to the applicable local requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of members 
who make up the respective IRB. If any member of the IRB has direct participation in this study, 
written notification regarding his or her abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements and 
other documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB for approval. The IRB’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study specific screening activity). The IRB 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, informed consent form) reviewed; and state the approval date. The 
sponsor will notify site once the sponsor has confirmed the adequacy of site regulatory 
documentation. Until the site receives notification no protocol activities, including screening may 
occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor. 
Regarding pharmacogenomic investigation using collected and stored specimens, analysis will be 
carried out at the time when detail is determined. The sponsor will create a research protocol for 
pharmacogenomics investigations. 
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15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form describes the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
The informed consent form will detail the requirements of the participant and the fact that he or she 
is free to withdraw at any time without giving a reason and without prejudice to his or her further 
medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form. The informed consent form must be approved by both the IRB and the sponsor prior 
to use. 
The informed consent form must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB. 
The subject must be given ample opportunity to: (1) inquire about details of the study and (2) 
decide whether or not to participate in the study. If the subject, determines he or she will 
participate in the study, then the informed consent form must be signed and dated by the subject at 
the time of consent and prior to the subject entering into the study. The subject should be instructed 
to sign using their legal names, not nicknames, using blue or black ballpoint ink. The investigator 
must also sign and date the informed consent form at the time of consent and prior to subject 
entering into the study. 
Once signed, the original informed consent form will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form. 
The informed consent form for phamacogenomic sample collection in the clinical study of 
TAK-438 will be used to explain pharmacogenomic analysis to only subjects who provided 
consent to study participation. Pharmacogenomic samples are to be collected from only subjects 
who provided consent to both study participation and pharmacogenomic sampling. 
When subjects request disposal of a stored sample, follow the procedures described in Section 9.4. 
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15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results is the 
sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. 
The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association. 
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. 
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15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov and other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee. 
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16.0 
REFERENCES 
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