Conditions: Gastroesophageal Reflux
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 256
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the effect of vonoprazan compared to esomeprazole for preventing heartburn symptoms over a 4-week treatment period in participants who have a partial response to treatment with esomeprazole.

Detailed description:
The drug being tested in this study is called vonoprazan. Vonoprazan is being tested to treat people who have symptomatic gastroesophageal reflux disease (GERD) with a partial response to treatment with a high dose of esomeprazole. This study will look at improvement in heartburn symptoms in participants who take vonoprazan compared to esomeprazole.

The study will enroll approximately 213 patients. All participants will receive esomeprazole or esomeprazole placebo-matching capsules (this is a capsule that looks like esomeprazole but has no active ingredient) during a 7-week run-in period. Participants will then be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Esomeprazole 40 mg
* Vonoprazan 20 mg
* Vonoprazan 40 mg

All participants will be asked to take one capsule at the same time each day throughout the study. All participants will be asked to record heartburn symptoms in a diary every morning upon waking and every evening before going to sleep.

This multi-center trial will be conducted in Europe. The overall time to participate in this study is 12 weeks. Participants will make multiple visits to the clinic, and will be contacted by telephone 1 week after the last dose of study drug for a follow-up assessment.

Arms:
arm 1: Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by esomeprazole 40 mg, over encapsulated tablets, orally, once daily for 4 weeks during the active treatment period. arm 2: Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 20 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the treatment period. arm 3: Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 40 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the active treatment period.

Interventions: intervention 1: Vonoprazan intervention 2: Esomeprazole intervention 3: Esomeprazole Placebo
Intervention descriptions: intervention 1: Vonoprazan over-encapsulated capsules intervention 2: Esomeprazole over-encapsulated tablets intervention 3: Esomeprazole placebo-matching capsules

Protocol document:
Prot_000.pdf: 


•
Title: A Randomized, Double-Blind, Proof-of-Concept, Phase 2 Study to Evaluate the Efficacy 
and Safety of Once Daily Oral Vonoprazan 20 mg or Vonoprazan 40 mg Compared to 
Esomeprazole 40 mg for the Treatment of Subjects With Symptomatic 
Gastro-Esophageal Reflux Disease Who have a Partial Response Following Treatment with a 
High Dose of Proton Pump Inhibitor
NCT Number: NCT02743949
Protocol Approve Date: 29 March 2016
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


PROTOCOL AMENDMENT
A Randomized, Double-Blind, Proof-of-Concept, Phase 2 Study to Evaluate the Efficacy 
and Safety of Once Daily Oral Vonoprazan 20 mg or Vonoprazan 40 mg Compared to 
Esomeprazole 40 mg for the Treatment of Subjects With Symptomatic 
Gastro-Esophageal Reflux Disease Who have a Partial Response Following Treatment 
with a High Dose of Proton Pump Inhibitor
Comparison of Vonoprazan to Esomeprazole in Subjects with Symptomatic GERD 
Who Responded Partially to a High Dose of PPI
Sponsor:
Takeda Development Centre Europe Ltd.
61 Aldwych
London, WC2B 4AE, UK
Study Number:
Vonoprazan-2001 
IND Number:
NA
EudraCT Number:
2015-001154-14 
Compound:
Vonoprazan (TAK-438)
Date:
29 March 2016
Amendment Number:
02
Amendment History: 
Date
Amendment Number
Amendment Type 
Region
25 November 2015
Initial Protocol
Not applicable
Global*
15 February 2016
01
Non-substantial amendment
Global*
29 March 2016
02
Non-substantial amendment
Global*
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
TDC sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Serious adverse event and pregnancy reporting
Medical Monitor
(medical advice on protocol and compound)
Responsible Medical Officer 
(carries overall responsibility for the conduct of 
the study)
PPD


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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer and other signatories, as applicable can be 
found on the signature page.
Electronic Signatures may be found on the last page of this document.
PPD


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1.3
Protocol Amendment 02 Summary of Changes 
This document describes the changes in reference to the Protocol Incorporating Amendment No. 
02.
The primary purpose of this amendment is to update the protocol to provide minor changes and 
clarification of study procedures.
Full details on changes of text are given in Appendix G. The following is a summary of the 
changes made in the amendment:
1. Addition of additional endpoint of heartburn. This analysis has been included as it includes 
components of both reduction in the number as well as severity of symptoms.
2. Clarification of inclusion criteria No 5 to include patients who have predominant heartburn 
symptoms in the presence of regurgitation. This confirms the patient has GERD and also has 
the appropriate symptoms to perform the required proposed data analysis
3. Correction of schedule of Subject reported Outcome Questionnaires(PSQI and PGIC).
4. Inclusion of blind reporting of serum gastrin and pepsinogen I and II values during double 
blind treatment period to avoid potential unblinding.
5. Clarification of barrier methods for contraception.
6. Clarification of unscheduled visits if necessary.
7. Correction of the condition of storage and shipping of CYP2C19 DNA samples.


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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 02 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Coordinating Investigator.........................................................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Corporate Identification...........................................................................................16
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.2
Rationale for the Proposed Study.............................................................................19
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................20
5.1
Objectives................................................................................................................20
5.1.1
Primary Objective(s) ...................................................................................20
5.1.2
Secondary Objectives..................................................................................20
5.1.3
Additional Objectives..................................................................................20
5.2
Endpoints.................................................................................................................21
5.2.1
Primary Endpoints.......................................................................................21
5.2.2
Secondary Endpoints...................................................................................21
5.2.3
Additional Endpoints ..................................................................................21
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................25
6.1
Study Design ...........................................................................................................25
6.2
Justification for Study Design, Dose, and Endpoints ................................................27
6.3
Premature Termination or Suspension of Study or Investigational Site.....................29
6.3.1
Criteria for Premature Termination or Suspension of the Study...................29
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites ..29
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s).........................................................29
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............30
7.1
Inclusion Criteria .....................................................................................................30
7.2
Exclusion Criteria ....................................................................................................31
7.3
Excluded Medications, Procedures, and Treatments.................................................33


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7.4
Diet, Fluid, Activity Control ....................................................................................34
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................34
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................35
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................36
8.1
Study Medication and Materials...............................................................................36
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................36
8.1.1.1
Investigational drug................................................................................36
8.1.1.2
Rescue Medication .................................................................................37
8.1.1.3
Sponsor-Supplied Drug ..........................................................................37
8.1.2
Storage........................................................................................................37
8.1.3
Dose and Regimen ......................................................................................37
8.1.4
Overdose.....................................................................................................38
8.2
Investigational drug Assignment and Dispensing Procedures...................................39
8.3
Randomization Code Creation and Storage..............................................................39
8.4
Investigational Drug Blind Maintenance ..................................................................40
8.5
Unblinding Procedure..............................................................................................40
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................40
9.0
STUDY PLAN ..............................................................................................................42
9.1
Study Procedures.....................................................................................................42
9.1.1
Informed Consent Procedure.......................................................................42
9.1.1.1
Pharmacogenomic Informed Consent Procedure.....................................42
9.1.2
Demographics, Medical History, and Medication History Procedure...........42
9.1.3
Physical Examination Procedure .................................................................43
9.1.4
Weight and Height ......................................................................................43
9.1.5
Vital Sign Procedure ...................................................................................43
9.1.6
Efficacy Measurement.................................................................................43
9.1.6.1
Reflux Symptom Questionnaire Electronic Diary (RESQ-eD) ................43
9.1.6.2
Subject Reported Outcome Questionnaires .............................................44
9.1.7
Documentation of Concomitant Medications...............................................46
9.1.8
Documentation of Concurrent Medical Conditions......................................46
9.1.9
Procedures for Clinical Laboratory Samples................................................47
9.1.10
Contraception and Pregnancy Avoidance Procedure....................................49
9.1.11
Pregnancy ...................................................................................................50
9.1.12
ECG Procedure ...........................................................................................50
9.1.13
Endoscopy ..................................................................................................51


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9.1.14
Pharmacogenetic Sample Collection For Genotyping (Mandatory)..............51
9.1.15
Pharmacogenomic Sample Collection For Storage (Optional) .....................52
9.1.16
Pharmacokinetic Sample Collection and Analysis .......................................52
9.1.16.1
Bioanlytical Methods..............................................................................53
9.1.17
Documentation of Screen Failure and Run-In Failure..................................53
9.1.18
Documentation of Randomization ...............................................................54
9.2
Monitoring Subject Treatment Compliance..............................................................54
9.3
Schedule of Observations and Procedures................................................................54
9.4
Post Study Care .......................................................................................................55
9.5
Biological Sample Retention and Destruction ..........................................................55
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................56
10.1
Definitions...............................................................................................................56
10.1.1
PTEs...........................................................................................................56
10.1.2
AEs.............................................................................................................56
10.1.3
Additional Points to Consider for PTEs and AEs.........................................56
10.1.4
SAEs...........................................................................................................58
10.1.5
Severity of PTEs and AEs ...........................................................................59
10.1.6
Causality of AEs .........................................................................................59
10.1.7
Relationship to Study Procedures................................................................59
10.1.8
Start Date....................................................................................................60
10.1.9
Stop Date ....................................................................................................60
10.1.10
Frequency ...................................................................................................60
10.1.11
Action Concerning Study Medication..........................................................60
10.1.12
Outcome .....................................................................................................60
10.2
Procedures...............................................................................................................61
10.2.1
Collection and Reporting of AEs.................................................................61
10.2.1.1
PTE and AE Collection Period ...............................................................61
10.2.1.2
PTE and AE Reporting ...........................................................................61
10.2.2
Collection and Reporting of SAEs...............................................................62
10.2.3
Reporting of Abnormal Liver Function Tests as an SAE .............................62
10.3
Follow-up of SAEs ..................................................................................................63
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................63
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................64
12.0
DATA HANDLING AND RECORDKEEPING............................................................65


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12.1
CRFs .......................................................................................................................65
12.2
Record Retention .....................................................................................................65
13.0
STATISTICAL METHODS..........................................................................................67
13.1
Statistical and Analytical Plans ................................................................................67
13.1.1
Analysis Sets...............................................................................................67
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................67
13.1.3
Efficacy Analysis........................................................................................67
13.1.4
Pharmacokinetic Analysis ...........................................................................68
13.1.5
Patient Reported Outcomes Analysis...........................................................69
13.1.6
Other Analysis ............................................................................................69
13.1.7
Safety Analysis ...........................................................................................69
13.2
Interim Analysis and Criteria for Early Termination ................................................69
13.3
Determination of Sample Size..................................................................................69
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................71
14.1
Study-Site Monitoring Visits ...................................................................................71
14.2
Protocol Deviations..................................................................................................71
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................71
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................72
15.1
IRB and/or IEC Approval ........................................................................................72
15.2
Subject Information, Informed Consent, and Subject Authorization .........................73
15.3
Subject Confidentiality ............................................................................................74
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................74
15.4.1
Publication and Disclosure..........................................................................74
15.4.2
Clinical Trial Registration...........................................................................75
15.4.3
Clinical Trial Results Disclosure .................................................................75
15.5
Insurance and Compensation for Injury....................................................................75
16.0
REFERENCES..............................................................................................................76
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medication .........................................................................................33
Table 8.a
Dose and Regimen .............................................................................................38
Table 9.a
Requirements for Subject Diary Entries Regarding Subjective Symptoms..........44
Table 9.b
Clinical Laboratory Tests...................................................................................47


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Table 9.c
Los Angeles (LA) classification for diagnosis and grading of erosive 
esophagitis .........................................................................................................51
Table 9.d
Schedule of Pharmacokinetic Sample Collection................................................53
Table 10.a
Takeda Medically Significant AE List................................................................59
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................26
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................80
Appendix B
Responsibilities of the Investigator.....................................................................83
Appendix C
Elements of the Subject Informed Consent.........................................................85
Appendix D
Investigator Consent to Use of Personal Information..........................................88
Appendix E
Collection, Shipment, and Storage of Pharmacogenomic Samples......................89
Appendix F
Collection, Shipment and Storage of Pharmacokinetic Samples..........................90
Appendix G
Detailed Description of Amendments to Text.....................................................91


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Centre Europe Ltd.
Compound:
Vonoprazan (TAK-438)
Title of Protocol:
A Randomized, Double-Blind, Proof-of-Concept, Phase 2 
Study to Evaluate the Efficacy and Safety of Once Daily 
Oral Vonoprazan 20 mg or Vonoprazan 40 mg Compared to 
Esomeprazole 40 mg for the Treatment of Subjects With 
Symptomatic Gastro-Esophageal Reflux Disease Who have 
a Partial Response Following Treatment with a High Dose 
of Proton Pump Inhibitor
IND No.: N/A
EudraCT No.:
2015-001154-14 
Study Number: Vonoprazan-2001 
Phase: 2
Study Design:
Vonoprazan-2001 is a Phase 2 proof-of-concept (POC) study to compare vonoprazan 20 mg or 40 mg once daily (QD) 
with esomeprazole 40 mg QD in subjects who have a history of predominant heartburn symptoms in the presence of 
regurgitation that are troublesome despite an adequate course of proton pump inhibitor (PPI) treatment and who are 
then confirmed to have a partial response to a 4-week treatment course with esomeprazole 40 mg QD.
Primary Objectives:
To determine the effect of vonoprazan compared to esomeprazole for preventing heartburn symptoms over a 4-week 
treatment period in subjects who have a partial response to treatment with esomeprazole
Secondary Objectives:
To determine the effect of vonoprazan treatment on sustained resolution of heartburn symptoms over a 4-week 
treatment period (at least one 7-day symptom-free period)
Subject Population: Subjects aged 18 years or older who have a documented history of symptoms of both heartburn 
and acid regurgitation prior to entry into the study and of not responding fully to their PPI treatment (at least 8 weeks
of predominant heartburn symptoms in the presence of regurgitation that are troublesome after treatment at the 
standard doses of PPI). Subjects must also have a partial response to treatment with a high dose of esomeprazole 40 
mg QD (defined as having heartburn on 2 to 5 days and regurgitation on at least one day of the last week (Week 4) of 
a 4 week PPI Assessment Period with esomeprazole 40 mg and an increase of at least 2 symptom days of heartburn in 
the last week of a 2 week Off-PPI Assessment Period (4 to 7 symptom days) and at least one symptom day with 
regurgitation compared with the last week of the PPI Assessment Period.
Number of Subjects:
Estimated total: 213 randomized
Per treatment group: Vonoprazan 40 mg:Vonoprazan 
20 mg: Esomeprazole 40 mg =1:1:1 (71 subjects in each 
treatment arm)
Number of Sites: 
Estimated total: Up to 50 sites in Europe 
Dose Level(s):
Vonoprazan 20 mg QD
Vonoprazan 40 mg QD
Esomeprazole 40 mg QD
Route of Administration:
Oral


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Duration of Treatment:
4 weeks double-blind treatment
Period of Evaluation:
Approximate total study duration: 12 weeks
The study consists of 3 periods: a 7-week Run-in 
period (initial 1 week screen period and a 6-week 
single-blind Run-in), a 4-week double blind Treatment 
Period, and a 1-week Safety Follow-up. 
Main Criteria for Inclusion:
Subjects will be eligible for participation in the study if they; have a documented history of symptoms of both 
heartburn and acid regurgitation prior to entry into the study; have a history of predominant heartburn symptoms in the 
presence of regurgitation that are troublesome despite an adequate course of PPI treatment; continue to have 
symptoms of heartburn (and regurgitation) following 4 weeks treatment with a high dose of esomeprazole 40 mg QD 
during the Run-in Period; have symptoms of heartburn which increases following a 2-week Washout Period in the 
presence of regurgitation prior to randomization. Patients with mild (LA grade A) esophagitis are permitted to enter 
the study.
Main Criteria for Exclusion:
Subjects who have hypersensitivity to vonoprazan or related compounds; a history or any coexisting diseases affecting 
the esophagus; ‘alarm features’ in symptomatology pointing to a possible malignant disease of the GI tract; current or 
historical chest pain due to cardiac disease; a history of surgical treatment for GERD; dilation of an esophageal 
stricture or gastric or duodenal surgery. Subjects who have a documented history of functional dyspepsia or irritable 
bowel syndrome or other gastrointestinal diseases which are not acid-related, and therefore, are nonresponsive to 
gastric acid-blocking treatment. Subjects who have levels of AST, ALT or total bilirubin > ULN. In addition, the 
following subjects should be excluded: those who have a documented history of familial adenomatous polyposis, 
active gastric or duodenal ulcers or acute upper gastrointestinal hemorrhage within 30 days prior to screening and any 
other co-morbidities or any significant results from physical examinations, or clinical laboratory results as deemed by 
the investigator. 
Main Criteria for Evaluation and Analyses:
The primary endpoint for this study is the percentage of heartburn free 24 hour periods (day and night) during 4 weeks 
of randomized double-blind treatment.
The secondary endpoint for this study is the proportion of subjects with ≥1 sustained resolution of heartburn (defined 
as ≥7 consecutive days without both daytime and nighttime heartburn any time during the 4-week randomized 
double-blind Treatment Period).
Statistical Considerations:
Analysis Sets:
Full Analysis Set (FAS): This analysis set will include all subjects randomized. Subjects in this set will be analyzed 
according to the original randomization.
Per Protocol Set (PPS): This analysis set is a subset of the FAS. The PPS consists of all subjects who do not violate the 
terms of the protocol in a way that would impact the study output significantly. All decisions to exclude subjects from 
the PPS dataset will be made prior to the unblinding of the study. Analyses using the PPS may be provided as a 
sensitivity analysis.
Safety Set: This analysis set will include all subjects who have received at least 1 dose of study drug. Subjects in this 
set will be analyzed according to the treatment they actually received.
Efficacy Analysis:
For the assessment of the percentage of heartburn-free days, the Wilcoxon-Mann-Whitney Odds estimator with the 
97.5% CI and the Wilcoxon rank-sum test will be used at the 2.5% level of significance for each vonoprazan treatment 
comparison with esomeprazole to control for multiplicity. The Wilcoxon rank-sum test will be used because data from 
a previous vonoprazan trial (TAK-438/CCT-201) showed that the data is unlikely to be normally distributed.


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To assess the secondary endpoint, the proportion of subjects with ≥1 sustained resolution of heartburn, a Pearson 
Chi-square test will be used at the 2.5% level of significance for each vonoprazan treatment comparison with 
esomeprazole to control for multiplicity. All subjects with missing data for determination of endpoint status will be 
considered as a non-responder in the analysis.
Multiplicity will not be adjusted across the remaining additional endpoints. 
The time to sustained resolution of heartburn is defined as the time from the first dose of study drug to the first day of 
the 7 consecutive days free of heartburn and will be analyzed using a product-limit survival analysis with treatment 
group as the stratum. The survivor function will be estimated using the Kaplan-Meier method and the survivor 
functions between vonoprazan and esomeprazole treatment groups will be compared using log-rank tests. The median 
time to sustained resolution of heartburn from the survivor function will be presented by treatment group, along with 
the 95% confidence interval. 
If the assumptions underlying planned inferential methods are not adequately met, methods will be amended as needed 
for appropriate analysis.
Other analysis
All data collected in this study will, where applicable, be summarized by treatment regimen using descriptive 
statistics. For continuous variables mean values, standard deviations, median and lower and upper percentiles will be 
calculated. For categorical variables frequencies and percent will be calculated.
Adverse events (AEs) will be summarized using the safety analysis set. Adverse events collected during the trial will 
be summarized by System Organ Class, treatment regimen and stage of trial (eg, screening and treatment emergent) 
and reported.
Sample Size Justification: 
A total of 213 subjects (71 patients per treatment arm) who have a partial response to treatment with a high dose of 
esomeprazole (40 mg QD for 4 weeks) are planned to be randomized into the study with the expectation that 180 
subjects will complete the study (assuming a 15% drop out rate). The sample size of 60 subjects completing the study 
per treatment group will provide at least 80% power at the 2-sided 0.025 level of significance to detect an absolute 
20% difference between each Vonoprazan dose and esomeprazole in the percentage of heartburn-free 24 hour periods 
(day and night) during 4 weeks of randomized double-blind treatment. The pooled standard deviation was estimated as 
33.61 from prior Dexlansoprazole studies. 
With the expectation that 180 subjects will complete the study, the secondary endpoint; proportion of subjects with 
≥1 sustained resolution of heartburn (defined as ≥7 consecutive days without both daytime and nighttime heartburn 
any time during the 4-week randomized double-blind Treatment Period) has 80% power at the 2-sided 0.025 level of 
significance to detect an absolute 30% difference between each vonoprazan dose and esomeprazole, assuming a 
response rate of 33% for esomeprazole. 


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.


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3.3
List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CK/CPK
Creatine Phosphokinase
Cl
Chloride
Cmax
Maximum observed plasma concentration
CNS
Central nerve system
COX-2
Cyclooxygenase 2
eCRF
Electronic case report form
CRO
contract research organization
CSR
clinical study report
CYP
Cytochrome P450 enzyme
DNA
deoxyribonucleic acid
ECG
Electrocardiogram
EDC
electronic data capture
EE
Erosive esophagitis
EM
Extensive metabolizers
EMA
European Medicines Agency
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCDT
Global Clinical Development Team
GCP
Good Clinical Practice
GGT
-glutamyl transferase
GERD
gastro-esophageal reflux disease
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
H. pylori
Helicobacter pylori
HRQoL
Health-Related Quality of Life
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ID
Identification
IEC
independent ethics committee
INN
International Nonproprietary Name


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INR
international normalized ratio
IRB
institutional review board
IWRS
interactive web response system
LA classification
Los Angeles classification
LDH
Lactate dehydrogenase
LFT
liver function tests
MedDRA
Medical Dictionary for Regulatory Activities
NERD
Non-erosive reflux disease
NSAIDs
Non-steroidal anti-inflammatory drugs
P-CAB
Potassium-competitive acid blockers
PGx
Pharmacogenomics
pH4 HTR
pH4 holding time ratio
PM
Poor metabolizers
PPI
Proton Pump Inhibitor
PPS
Per-protocol analysis set
PTE
pretreatment event
QD
Once daily
QTc
corrected QT interval
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
SNRI
selective norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor.
UGI
upper gastrointestinal
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
3.4
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
Failure of proton pump inhibitor (PPI) treatment is very common, affecting approximately 30% of 
gastro-esophageal reflux disease (GERD) patients [1] and PPI failure is the most common
presentation of GERD in gastrointestinal practice [2]. Most of the GERD patients who are not 
responsive to PPIs have non-erosive reflux disease (NERD), primarily due to their relatively large 
numbers in the GERD population (up to 70%) and low response rate to once daily (QD) PPI [2]. 
Bytzer et al reported that in a post hoc analysis of 5796 patients, partial response to PPI therapy 
occurred in 14% to 20% of GERD patients, more commonly in NERD than in reflux esophagitis 
[3] and El-Serag et al reported that 17–32% of the patients assessed in interventional primary care 
trials continue to experience reflux symptoms despite PPI treatment [4]. More recently 
(2011-2012), a survey was performed in Asia-Pacific (GERD in Asia Pacific Survey, GAPS) [5]. 
A total of 450 patients with GERD participated in the GAPS. Although the respondents generally 
complied with treatment, response to therapy was only partially successful. Most respondents 
indicated that PPIs eliminated pain (72%), took effect within 30 minutes (76%), provided 
sustained relief (73%), and provided nocturnal relief (77%). However, 45% of respondents 
reported limited improvement in nocturnal symptoms and 49% continued to take adjunctive 
therapy to manage their symptoms. After treatment, respondents’ ‘well-being’ had improved.
However, GERD still had a negative impact on well-being for 76% of respondents after treatment, 
compared with 94% before treatment. Asian patients reported a negative impact of GERD on their 
daily lives. Many respondents continued to experience symptoms despite reporting good 
compliance with PPI therapy, emphasizing the shortcomings of currently available therapy for 
GERD.
The European Medicines Agency (EMA) has recognized partial response to a PPI as a medical 
issue. The 2011 revision of the “Guideline on the evaluation of drugs for the treatment of 
Gastro-oesophageal reflux disease” includes recommendations on how to assess PPI partial 
responders (patients with an insufficient response to a PPI) [6]. Although it is likely that the 
majority of patients entered into the proposed study will be NERD patients [2], mild (LA grade A) 
erosive esophagitis (EE) patients will also be included as this is accepted in the EMA guidelines 
when the indication is for the treatment of symptomatic GERD [6].
Varying underlying mechanisms have been proposed for a partial response to PPI treatment 
including residual acid, weakly acidic reflux, and weakly alkaline reflux in GERD patients [7]. 
This may be due to the pharmacodynamic profile of PPIs as therapeutic oral doses of some PPIs
have a slow, cumulative onset of effect, and achieve maximal acid suppression only after 4 to 
5 days of daily dosing [8]. 
Vonoprazan is a novel, orally active small-molecule potassium-competitive acid blocker (PCAB).
Vonoprazan at doses ≥20 mg has been shown in both single and multiple repeat-dosing studies to 
have a rapid onset of action after the first dose and near maximal effect on pH holding time within 
24 hours of dosing, which is maintained with chronic dosing [9].


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Phase 2 clinical data in Japanese subjects with EE demonstrated that vonoprazan was effective at 
healing EE after 4 weeks of treatment and was non-inferior to lansoprazole 30 mg. In addition, EE 
healing rates with the higher doses of vonoprazan (20 and 40 mg) were higher than lansoprazole 
30 mg at Week 2 and higher for more severe grades of EE at Week 4 [8]. Recently, vonoprazan at 
a dose of 20 mg has been shown in large phase 3 studies to be effective for the treatment of erosive 
EE [10], maintenance of EE healing [11], Gastric and Duodenal ulcer treatment [data on file], 
prevention of aspirin-induced and non-steroidal anti-inflammatory-induced peptic ulcers [12.13] 
and the eradication of H pylori in conjunction with antibiotics [14].
An extensive pre-clinical program has been conducted with vonoprazan including PK and PD 
studies in rats and dogs as well as single/repeat-dose toxicology studies, genotoxicity studies, 
carcinogenicity studies (rata/mice) and reproductive toxicity studies (rats and rabbits) [15].
In addition, the safety of vonoprazan has been closely monitored in an extensive clinical program. 
In 14 completed phase 3 studies conducted in Japan across multiple indications, 3397 patients
were exposed to vonoprazan 5 to 40 mg once daily (QD) for up to 104 weeks (actual maximum 
exposure: 684 days). Vonoprazan treatment was generally well tolerated, with a similar safety 
profile to that of lansoprazole. Incidences of drug-related TEAEs were similar between the 
vonoprazan and lansoprazole treatment groups [15].
In phase 3 clinical studies with vonoprazan, a dose dependent increase of mean levels of serum 
gastrin to vonoprazan was observed and these elevations in serum gastrin were shown to be higher 
compared with lansoprazole. Changes in serum gastrin did not translate to gastric mucosal changes 
as evidenced by biopsies performed in EE studies of up to 52 weeks duration.
There was no pre-clinical safety data and nothing in the safety/tolerability profile observed to date 
that precludes continued clinical investigation of vonoprazan. The overall risk: benefit remains 
positive in both non-Japanese and Japanese healthy subjects and in Japanese patients with 
acid-related diseases. Non-Japanese patients are currently being recruited into EE 
healing/maintenance studies in a number of countries outside Japan. In addition, Takeda received 
approval for vonoprazan in Japan for the treatment of acid-related diseases in December 2014. 
Vonoprazan (TAKECAB®) is currently available in 2 dose strengths of 10 and 20 mg, as 
film-coated tablets, for oral dosing. The indications approved are as follows: treatment of gastric 
and duodenal ulcer; reflux esophagitis; prevention of ulcer recurrence during low-dose aspirin or 
NSAID administration and as an adjunct to H pylori eradication.
Agents that can increase gastric pH faster, to a greater extent, and for longer than is achievable 
with PPIs may offer a clinical advantage for the treatment of patients who have a partial response 
to PPIs and still have GERD symptoms after treatment with a PPI.
Vonoprazan-2001 is a Phase 2 proof-of-concept (POC) study comparing vonoprazan with 
esomeprazole in subjects who have a history of persistent heartburn and regurgitation GERD
symptoms despite an adequate course of PPI treatment and who are then confirmed to have a 
partial response to a 4-week treatment course with esomeprazole 40 mg QD[16,17]. As 
vonoprazan is a strong gastric acid inhibitor, it is considered that esomeprazole 40 mg, which is 


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commonly used in patients not responding to their initial dose of PPI, is an appropriate comparator 
for this indication.
4.2
Rationale for the Proposed Study
Despite PPI treatment with an adapted dosing regimen, defined as use outside the approved labels, 
there is a significant patient population who do not achieve adequate symptom relief.
Upon once daily PPI treatment, it has been observed that the majority of GERD patients (70–75%) 
also have nighttime heartburn at least once a week and approximately 40% of these individuals 
reported that nighttime heartburn disrupted their sleep [18]. It is therefore possible that once daily 
PPI use may not alleviate all of the nighttime symptoms experienced by GERD patients.
Varying underlying mechanisms have been proposed for a partial response to PPI treatment,
including their short duration of pharmacological activity [19], which leaves GERD patients 
exposed to residual acid and increase their susceptibility to weakly acidic reflux, and weakly 
alkaline reflux [7]. This may be due to the PD profile of PPIs, as therapeutic oral doses of some 
PPIs have a short half life (1–2 hours) and require an intermediate complex formation prior to 
acting on the parietal cells. Consequently, these PPIs have a slow, cumulative onset of effect, and 
achieve maximal acid suppression only after 4–5 days of daily dosing [8].
Unlike PPIs, Vonoprazan has a long-half-life (9 hours) and does not require intermediate complex 
formation, thus achieving a faster onset of action with greater duration of effect to control both 
daytime and nighttime symptoms [15]. 
This study is therefore designed to test the hypothesis that the fast onset, potency and long duration 
of action of Vonoprazan will provide superior symptom control compared with esomeprazole, 
during both daytime and nighttime, in a population of patients with a partial acid-related symptom 
response to a PPI.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective(s) 
To determine the effect of vonoprazan compared to esomeprazole for preventing heartburn 
symptoms over a 4-week treatment period in subjects who have a partial response to treatment 
with esomeprazole.
5.1.2
Secondary Objectives
To determine the effect of vonoprazan treatment on sustained resolution of heartburn symptoms 
over a 4 week treatment period (at least one 7-day symptom-free period).
5.1.3
Additional Objectives
!
To determine the effect of vonoprazan compared with esomeprazole on GERD-related 
endpoints, including:
–
Preventing heartburn at night over a 4 week treatment period.
–
Sustained resolution of heartburn during the final week of treatment.
–
Preventing regurgitation during 24-hour periods, over a 4 week treatment period.
–
Preventing regurgitation at night over a 4 week treatment period.
–
Preventing heartburn and/or regurgitation during 24-hour periods over a 4 week treatment 
period.
–
Complete prevention of regurgitation (response rate) during the final week of treatment. 
–
Evaluation of the effect of vonoprazan on the use of rescue medication over 4 weeks of 
treatment.
–
Evaluation of the effect of vonoprazan on GERD quality of sleep over 4 weeks of 
treatment.
–
Evaluation of the effect of vonoprazan on Health Related Quality of Life (HRQL) over 4 
weeks of treatment.
!
To evaluate the pharmacokinetics of vonoprazan in patients.
!
To determine the safety and tolerability of vonoprazan in this population.
!
To evaluate the pharmacokinetics and clinical efficacy of vonoprazan in patients identified as 
CYP2C19 poor or extensive metabolizers (PM/EM).
!
CCI


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5.2
Endpoints
5.2.1
Primary Endpoints
!
Percentage of heartburn-free 24 hour periods (day and night) during 4 weeks of randomized 
double-blind treatment.
5.2.2
Secondary Endpoints
!
Proportion of subjects with ≥1 sustained resolution of heartburn (defined as ≥7 consecutive 
days without both daytime and nighttime heartburn any time during the 4-week randomized 
double-blind Treatment Period). 
5.2.3
Additional Endpoints
Heartburn Endpoint
!
Change from baseline in percentage of heartburn-free 24 hour periods (day and night) during 
4 weeks of randomized double-blind treatment, where baseline is defined as the 4 weeks run-in 
period on esomeprazole.
!
Change from baseline in proportion of subjects with ≥1 sustained resolution of heartburn, 
where baseline is defined as the 4 weeks run-in period on esomeprazole
!
Percentage of heartburn-free nights during 4 weeks of randomized double-blind treatment.
!
Percentage of heartburn-free days after 4 weeks of randomized double-blind treatment.
!
Proportion of patients with no nighttime heartburn symptoms during the last week of 
treatment.
!
Proportion of patients with no daytime heartburn symptoms during the last week of treatment.
!
Proportion of patients with no daytime and nighttime heartburn symptoms during the last week 
of treatment.
!
Percentage of subjects with ≥80% heartburn free days and nights during 4 weeks of 
randomized double-blind treatment.
!
Percentage of subjects with ≥80% heartburn free nights during 4 weeks of randomized 
double-blind treatment.
!
Percentage of subjects with ≥80% heartburn free days during 4 weeks of randomized 
double-blind treatment.
CCI


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
Percentage of heartburn free 24 hour periods (day and night) during weeks 1, 2 and week 3 of 
randomized double-blind treatment.

Time to first sustained resolution (defined as 7 consecutive days without daytime and 
nighttime heartburn).

Proportion of subjects who achieve sustained resolution of heartburn (defined as 
≥7 consecutive days without daytime and nighttime heartburn) with an onset within 3 days of 
starting randomized double-blind treatment.

Proportion of subjects with resolution of symptoms with an onset within 3 days of starting 
randomized double-blind treatment and continuing out to the end of week 2 and end of week 4.

Maintenance of heartburn-free period – duration of heartburn symptom-free days and nights 
(24-hour periods) following the first 24-hour period when no symptoms were recorded until 
the next time symptoms were recorded.

Heartburn severity (severity of the most intense episode will be assessed for daytime and 
nighttime).

Percentage of responders, where a responder is defined as having at least 3 more days of not 
more than mild heartburn symptoms on average per week during the whole double blind 
treatment period compared to baseline, where baseline is defined as the 1 week run-in period 
on placebo prior to randomization.
Regurgitation Endpoint

Percentage of regurgitation-free nights during 4 weeks of randomized double-blind treatment.

Percentage of regurgitation-free days after 4 weeks of randomized double-blind treatment.

Percentage of regurgitation-free 24 hour periods during 4 weeks of randomized double-blind 
treatment.

Percentage of subjects with ≥80% regurgitation-free days and nights during 4 weeks of 
randomized double-blind treatment.

Percentage of subjects free from regurgitation (“no regurgitation”) during week 1, 2 and 3 of 
randomized double-blind treatment.

Time to first sustained resolution (defined as 7 consecutive days without daytime and 
nighttime regurgitation).

Proportion of subjects who achieve sustained resolution of regurgitation (defined as ≥7 
consecutive days without daytime and nighttime heartburn) with an onset within 3 days of 
starting randomized double-blind treatment.


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
Proportion of subjects with resolution of regurgitation symptoms with an onset within 3 days 
of starting randomized double-blind treatment and continuing out to the end of week 2 and the 
end of week 4.

Proportion of patients with no daytime and nighttime regurgitation symptoms during the last 
week of treatment.

Maintenance of regurgitation-free period – duration of regurgitation symptom-free days and 
nights (24-hour periods) following the first 24-hour period when no symptoms were recorded.

Regurgitation severity (severity of the most intense episode and will be assessed for daytime 
and nighttime).
Heartburn and Regurgitation Endpoint

Percentage of heartburn and/or regurgitation-free 24 hour periods (day and night) during 4 
weeks of randomized double-blind treatment.
Rescue medication Endpoint

Percentage of days without using rescue medication.

Percentage of nights without using rescue medication.

Percentage of days and nights without using rescue medication.
GERD Sleep quality measure

Change from baseline in measured scores. 

Proportion of subjects with clinically significant improvement on sleep disturbance measures.
HRQoL

HRQoL will be assessed using patient reported outcome questionnaires at patient visit and the 
following endpoints will be used for analysis:
–
Change from baseline in HRQoL scores. 
–
Proportion of subjects with clinically significant improvement on HRQoL measures.
Other Additional Endpoints

Summary statistics of plasma concentrations of Vonoprazan at the Week 2 and 4 visit and 
summary pharmacokinetic parameters where available: maximum observed plasma 
concentration (Cmax), time to reach Cmax (tmax), area under the plasma concentration-time curve 
from time 0 to tau (AUCτ).

Summary statistics of plasma concentrations of Vonoprazan at the Week 2 and 4 visit for 
CYP2C19 poor or extensive metabolizers (PM/EM) and summary pharmacokinetic 
parameters where available: maximum observed plasma concentration (Cmax), time to reach 
Cmax (tmax), area under the plasma concentration-time curve from time 0 to tau (AUCτ).


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
Summary statistics of plasma concentrations of esomeprazole at the Week 4 visit.

Safety parameters examined will include AEs, serious adverse events (SAEs), vital signs, 
results of standard laboratory tests.


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 2, randomized, double-blind, parallel-group, 3-arm PoC study with a 4-week active 
Treatment Period. This study will evaluate the safety and efficacy of vonoprazan 20 mg QD and 
40 mg QD compared with esomeprazole 40 mg QD when administered as an oral daily dose in the 
morning, at least 1 hour before the first meal of the day, for 4 weeks of treatment in subjects with 
symptomatic GERD who have a partial response to treatment with a high dose of esomeprazole. 
This study will be conducted at a total of up to 50 sites in Europe. A total of 213 subjects will be 
randomized in a 1:1:1 ratio of Vonoprazan 40 mg to Vonoprazan 20 mg to Esomeprazole 40 mg 
(71 per treatment arm).
Subjects will be eligible for participation in the study if they: have a documented history of 
symptoms of both heartburn and acid regurgitation prior to entry into the study; have a history of 
predominant heartburn symptoms in the presence of regurgitation that are troublesome despite an 
adequate course of PPI treatment; continue to have symptoms of heartburn and regurgitation 
following 4 weeks treatment with a high dose of esomeprazole 40 mg QD during the Run-in 
Period; have symptoms of heartburn which increases following a 2-week Washout Period in the 
presence of regurgitation prior to randomization; and meet all of the inclusion criteria and none of 
the exclusion criteria. Patients with mild (LA grade A) esophagitis are also permitted to enter the 
study. To confirm LA grade, endoscopy will be performed at screening, or historical data of 
endoscopy up to one year prior to screening may be permitted. The study will consist of 3 periods: 
a 7-week Run-in period (initial 1 week screening period and a 6-week single-blind Run-in), a 
4-week double blind Treatment Period, and a 1-week Safety Follow-up. The Run-in includes a 
1-week general Screening Period during which the subject will remain on their prescribed PPI 
(Day-49 to Day -42); followed by a 4-week single-blind PPI assessment period with blinded 
esomeprazole 40 mg QD (Day -42 to Day -14); and then a 2-week single-blind placebo Off-PPI 
Assessment period (Day -14 to Day-1). Subjects who remain symptomatic and compliant will be 
randomized to the 4-week Treatment Period followed by a one week safety Follow-up Call. 
Certain medications will require washout prior to entry into the study and will not be permitted 
during the study as outlined in Table 7.a.
The Screening Period will take up to 49 days. After providing informed consent and meeting the 
appropriate study entry criteria during the Initial Screening Visit (Visit 1), subjects will be taken 
off their prescribed PPI and be given esomeprazole 40 mg QD, be provided with an electronic 
diary (Visit 2), and trained in how to complete it. They will return 4 weeks later to assess treatment 
compliance, completion of the e-Diary and assessment of the PPI Treatment Period (Day -21 to 
-14). If the subject is still symptomatic, he or she will receive single-blinded placebo medication 
for a 2-week PPI Washout Period and their Off-PPI Baseline will be assessed during the week 
prior to randomization (Day -8 to -1).
It is estimated that approximately 426 subjects will be screened to ensure that a total of 
213 subjects who meet the symptomatic GERD entry criteria for a partial response to PPI (defined 
as having heartburn following 4 weeks of treatment with esomeprazole 40 mg and an increase of at 


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least 2 symptom days of heartburn (and/or regurgitation) in the last week of the Off-PPI 
assessment period compared with the last week of esomeprazole treatment) are randomized 
equally to 1 of 3 treatments at Visit 4 (vonoprazan 20 mg QD, vonoprazan 40 mg QD or 
esomeprazole 40 mg QD for 4 weeks). A 50% screen failure rate is higher than for standard GERD 
studies and has been estimated based on the duration of the run-in, inclusion of a 2 week placebo 
washout period and the symptom criteria to be met prior to randomization. Patients will take their 
first dose of study drug on the morning after Visit 4 and be treated on an outpatient basis, complete 
their e-Diary twice daily and will return to the clinic at Weeks 2 (Visit 5) and Week 4 (Visit 6) of 
the Treatment Period. 
A Safety Follow-up call will be made approximately 1 week after completion of the 4-week 
Treatment Period. If possible, subjects who prematurely withdraw from the study will be seen for a 
withdrawal visit as soon as possible after discontinuation, and also will be contacted for Safety 
Follow-up approximately 1 week after withdrawal.
Rescue antacid medication will be provided for all subjects at the Initial Screening Visit and as 
required throughout the study.
From the Initial Screening Visit to the End-of-Treatment Visit, there will be 6 subject visits and a 
phone call during the Follow-up period. 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


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6.2
Justification for Study Design, Dose, and Endpoints
Vonoprazan-2001 is a phase 2, randomized, double-blind, parallel-group, 3-arm PoC study with a 
4-week Treatment Period. The study is designed to assess a maximum clinical dose of vonoprazan
(40 mg QD) and a lower clinical dose (20 mg QD) vs. the maximum approved dose of 
esomeprazole (40 mg QD for the treatment of erosive esophagitis), to identify if vonoprazan offers 
a clinically meaningful benefit for the treatment of symptomatic GERD in patients who have a 
partial response to a high dose of PPI. A total of 213 subjects will be randomized in the study, in a 
1:1:1 ratio of Vonoprazan 40 mg to Vonoprazan 20 mg to Esomeprazole 40 mg.
This study aims to recruit subjects who have a documented history of symptoms of both heartburn 
and acid regurgitation prior to entry into the study and of not responding fully to their PPI 
treatment (at least 8 weeks of predominant heartburn symptoms in the presence of regurgitation
that are troublesome after treatment at the standard doses of PPI) and who have a partial response 
to treatment with a high dose of esomeprazole 40 mg QD (defined as having heartburn on 2 to 5 
days and regurgitation on at least one day of the last week [Week 4] of a 4 week Run-in with 
esomeprazole 40 mg). To further confirm that their heartburn is acid-related, subjects also have to 
have an increase of at least 2 symptom days of heartburn) in the last week of a 2-week Off-PPI 
Assessment Period (4 to 7 symptom days) and at least one symptom day with regurgitation 
compared with the last week of the PPI Assessment Period. Having the Washout after PPI 
treatment will result in a higher pre-randomization baseline heartburn frequency allowing the 
effects of both treatments as well as the treatment difference to be estimated. Symptomatic patients 
with mild EE (LA Grade A) will be permitted to enter the study as the presence of EE is a good 
indicator of the patient suffering from an acid-related problem and the study treatments are being 
used at doses which have been shown to effectively treat EE. Two doses of vonoprazan (20 mg and 
40 mg) have been selected for this study. Vonoprazan 20 mg has been included, as this is the 
clinical dose recommended in Japan for the treatment of EE. Experience with PPIs indicate that for 
patients with a partial response to approved once daily therapy, tailored therapy is often given 
off-label with adjustment of dose, dose timing and/or twice daily dosing [20]. Therefore, 
vonoprazan 20 mg may be expected to be a minimally effective clinical dose in this difficult to 
treat population. As such, a higher dose of vonoprazan 40 mg has also been selected as a 
potentially appropriate dose for this population of patients. Using vonoprazan 20 mg and 40 mg 
therefore allows for a comparison of dose effect and to select the appropriate dose of vonoprazan
to take forward in to Phase 3. Esomeprazole is considered as the current gold standard PPI for the 
treatment of GERD and 40 mg is the most appropriate dose for this difficult to treat population.
All subjects will receive blinded esomeprazole 40 mg QD for 4 weeks during the PPI assessment 
Run-in Period at the licensed dose for the treatment of erosive esophagitis in the EU and US 
[16,17]. This standard 4-week PPI assessment Run-in Period allows for PPI exposure to be 
consistent across subjects. Subjects having heartburn symptoms on 2 to 5 days and regurgitation 
on at least one day of the last week of the PPI Assessment Run-in Period (Week 4 of this period) 
are therefore having a partial response to their PPI treatment. A Washout of 2 weeks prior to
Randomization, where subjects receive blinded placebo, will be of sufficient duration to observe 
an increase in the frequency of heartburn of 2 or more symptom-days off-PPI and together with at 


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least one symptom day of regurgitation will confirm that subjects have symptomatic acid-related 
disease. In addition, 2 weeks should be an acceptable length of time for subjects to stop PPI 
treatment without risking their withdrawal from the study. Compliance with taking medication and 
completing their e-Diary also will be monitored during the Run-in Period and has been set at ≥85% 
for both ensuring that the subject’s historical partial response to a PPI is not due to lack of 
treatment compliance.
Vonoprazan has been given at doses of up to 40 mg QD for 7 days in both healthy Caucasian and 
Japanese subjects and its pharmacodynamic (PD) profile suggests that it has a quick onset of 
action, strong PD effect, and a long (> 24 hours) duration of action [21]. In addition, vonoprazan at 
doses up to 40 mg QD for 8 weeks has been shown to be beneficial for the treatment of EE in 
Japanese subjects with EE [9] and more recently, vonoprazan 20 mg has been shown in large phase 
3 studies to be effective for the treatment of EE [10], maintenance of EE healing [11], 
aspirin-induced and non-steroidal anti-inflammatory induced peptic ulcers [12,13] and the 
eradication of H. pylori in conjunction with antibiotics [14].
Vonoprazan can increase gastric pH faster, to a greater extent, and for a longer duration than that 
achievable with PPIs and therefore may offer a clinical advantage for the treatment of acid-related 
diseases. As heartburn is often considered the most frequent and troublesome symptom for 
subjects and the goal of treatment is to prevent heartburn throughout the whole day and night, the 
percentage of heartburn-free days and nights (in 24-hour periods) during 4 weeks of randomized 
double-blind treatment has been selected as the primary endpoint. The secondary endpoint will be 
the percentage of subjects with ≥1 sustained resolution of heartburn (defined as ≥7 consecutive 
days without daytime and nighttime heartburn any time during the 4-week randomized 
double-blind Treatment Period). Other additional endpoints include the following: Percentage of 
heartburn -free nights during 4 weeks of randomized double-blind treatment; Percentage of 
regurgitation-free nights during 4 weeks of randomized double-blind treatment; Percentage of 
patients with no daytime and nighttime heartburn symptoms during the last week of treatment;
Percentage of patients with no daytime and nighttime regurgitation symptoms during the last week 
of treatment and change from baseline in the primary and secondary endpoints, where baseline is 
defined as the 4 week run-in period on esomeprazole. These endpoints are believed to be 
appropriate for an effective and long-acting gastric acid blocker and are also goals for treatment in 
this difficult to treat population of patients who have a partial response to a PPI.
A 4-week Treatment Period has been proposed for this Phase 2 proof-of-concept study as it will 
allow both vonoprazan and esomeprazole to have reached steady-state in plasma and to have 
plateaued in terms of their respective efficacy. The cardinal symptom of interest in this study is 
heartburn as the presence of this symptom suggests there is a gastric acid related issue and we are 
comparing two gastric-acid blocking treatments. A number of other symptom-based endpoints 
also will be investigated at Week 4.
Although the influence of 2C19 PM/EM status is expected to have minimal impact on the exposure 
to vonoprazan, the effect of metabolizer status on vonoprazan pharmacokinetics/clinical efficacy 
will be evaluated in this study.


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The general study design, subject number, dose selection, choice of active comparator, treatment 
period, and endpoints are believed to be appropriate to determine if there is a clinically meaningful 
treatment difference between vonoprazan (vonoprazan 20 mg and 40 mg QD) and esomeprazole 
(40 mg QD) in subjects with a partial response to PPI treatment.
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication
that indicates a change in the known risk/benefit profile for the compound, such that the risk
/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures. 
3. The subject is a man or a woman and ≥18 years of age, at the time of the Screening visit. 
4. The subject has a documented history of symptoms of both heartburn (burning pain) and acid 
regurgitation prior to entry into the study.
5. The subject has a medical history of ≥8 weeks of persistent heartburn symptoms in the 
presence of regurgitation symptoms (persistent heartburn  symptoms defined as heartburn 
symptoms on ≥2 days a week) that are troublesome despite appropriate and correctly 
performed treatment with a PPI at standard doses.
6. The subject is ≥85% compliant at taking their Run-in medication and completing their e-Diary.
Compliance for taking the Run-in medication is defined as the medication provided 
(esomeprazole and placebo) taken for 85% of the 6 weeks Run-in Period (or on 36 of 42 days 
of the Run-in Period).
Compliance for the e-Diary is defined as the percentage of scheduled assessments that are 
completed based on 2 assessments per day (daytime and nighttime). For randomization, 85% 
compliance is required and is defined as 12 of 14 assessments completed over the 7-day period
(Day -21 to Day-14) prior to the single blind Placebo Run-in Period.
7. The subject has a partial response to a PPI defined as having heartburn on 2 to 5 days and 
regurgitation on at least one day of the last week (Week 4) of a 4 week PPI Run-In Period with 
esomeprazole 40 mg and an increase of at least 2 symptom days of heartburn in the last week of 
a 2 week Placebo Run-In Period (4 to 7 symptom days) and at least one symptom day with 
regurgitation compared with the last week of the PPI Run-In Period.
8. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
throughout the duration of the study and for 4 weeks after last dose of the study medication.
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.10 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.11 Pregnancy.


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7.2
Exclusion Criteria
A 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 30 days prior to the Screening 
Visit.
2. The subject has received vonoprazan in a previous clinical study. 
3. The subject is an immediate family member, study site employee, 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 have consented under duress. 
4. The subject has, in the judgment of the investigator, clinically significant abnormal 
hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening. 
5. The subject has a history of erosive esophagitis of Los Angeles (LA) Classification Grade B 
severity or worse prior to screening or at Screening endoscopy.
6. The subject has a history of or any coexisting diseases affecting the esophagus (eg, Barrett’s
esophagus, eosinophilic esophagitis, esophageal varices, scleroderma, viral or fungal 
infection, or esophageal stricture), history of radiation therapy or cryotherapy to the 
esophagus, caustic trauma, or physiochemical trauma such as sclerotherapy to the esophagus. 
7. The subject has “alarm features” in symptomatology, including odynophagia, severe
dysphagia, bleeding, weight loss, anemia, and blood in stool, pointing to a possible malignant 
disease of the GI tract. Patients displaying “alarm symptoms” in addition to the “typical” 
GERD symptoms may be included based on endoscopic exclusion of malignancy. 
8. The subject has current or historical chest pain due to cardiac diseases (eg, within one year).
9. The subject has had surgical treatment for GERD (eg, cardioplasty), dilation of an esophageal
stricture (other than Schatzki ring) or gastric or duodenal surgery, except simple oversew of an 
ulcer or endoscopic polypectomy of benign polyps.
10. The subject has active gastric or duodenal ulcers which have been confirmed by endoscopy
within 30 days prior to Screening. Gastric or duodenal erosions are not exclusionary, unless 
considered severe and symptomatic by the investigator.
11. The subject has had an acute upper gastrointestinal hemorrhage within 30 days prior to 
Screening.
12. The subject has current or historical evidence of Zollinger-Ellison syndrome or other 
hypersecretory condition.
13. The subject has current or historical evidence of eosinophilic esophagitis (evidence may be 
based on the following: missing response to acid suppressive therapy, the presence of 
eosinophilia in histological probes of the esophageal mucosa, a normal pH profile of the distal
esophagus, symptoms of dysphagia and food impaction). The exclusion of patients based on a 
predominance of the “typical” eosinophilic esophagitis symptoms only (as above) is 


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considered acceptable. However, in patients with a predominance of “typical” symptoms and 
co-existing significant dysphagia and food impaction, the syndrome should be excluded by 
endoscopy with biopsy.
14. The subject has a documented history (within 6 months prior to screening) of functional 
dyspepsia (suggested by the presence of one or more of the following symptoms: epigastric 
pain, postprandial fullness or early satiety), or irritable bowel syndrome or other 
gastrointestinal diseases which are not acid-related, and therefore, are nonresponsive to gastric 
acid-blocking treatment.
15. The patient has a documented history of familial adenomatous polyposis.
16. The subject has known intolerance, hypersensitivity or allergies to any PPI or their 
components (including lansoprazole, dexlansoprazole, omeprazole, rabeprazole, pantoprazole, 
or esomeprazole), any component of vonoprazan, or antacid(s) selected as rescue medication 
for this study.
17. The subject has a history of alcohol abuse, illegal drug use, or drug addiction within the 
12 months prior to Screening, or regularly consumes >21 units of alcohol (1 unit = 
12 oz/300 mL beer, 1.5 oz/25 mL hard liquor/spirits, or 5 oz/100 mL wine) per week. Subjects 
must have a negative drug screen at Screening. 
18. The subject has evidence of a serious uncontrolled concomitant disease including: clinically 
significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, 
systemic, or endocrine disease or other abnormality (other than the disease being studied), 
which may impact the ability of the subject to participate or potentially confound the study 
results.
19. The subject has planned, or is likely to require, in-patient surgery during the course of the 
study.
20. The subject has a history of cancer (except basal cell carcinoma of the skin) within 3 years 
prior to Screening.
21. The subject is known to have acquired immunodeficiency syndrome or chronic hepatitis due to 
any etiology.
22. The subject has abnormal laboratory values at Screening that suggest a clinically significant 
underlying disease or condition that may prevent the subject from completing the study. 
23. The subject has an ALT, AST or T-bilirubin level which exceeds ULN set by the testing 
laboratory at the Screening. 
24. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after participating in this study; or intending to donate ova during such time 
period.


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25. The subject is required to take excluded medications or it is anticipated that the subject will 
require treatment with at least 1 of the disallowed concomitant medications during the study 
please refer to Excluded Medication listed in Section 7.3).
26. The subject who, in the opinion of the investigator, is unable to comply with the requirements 
of the study or is unsuitable for any reason.
7.3
Excluded Medications, Procedures, and Treatments
Medications that are not permitted prior to or during the study are shown in Table 7.a below, 
including the time periods during which they must be withdrawn.
Table 7.a
Excluded Medication
Pre-screening
(Days)
Run-In Period
(Days)
Randomization
(Day)
Treatment
(Days)
Excluded Medication
-90
-60
-49
-42
-14
-1
1-28
Drugs that may be affected by increase in stomach 
pH (eg itraconazole)
X
X
X
X
X
High dose methotrexate 
X
X
X
X
X
X
X
Bisphosphonates
X
X
X
X
X
Antacids (a)
X
X
X
X
X
Strong CYP3A4 inhibitors (eg, clarithromycin)
X
X
X
X
X
Strong CYP2C19 inhibitors (eg, fluconazole)
X
X
X
X
X
CYP2C19 or CYP3A4 inducers (eg, Rifampin, St. 
John’s Wort, Phenytoin, Mephenytoin)
X
X
X
X
X
CYP2C19 substrates (eg, S-mephenytoin)
X
X
X
X
X
PPIs (b) 
X
X
X
Histamine 2 receptor antagonists 
X
X
X
X
X
Anticoagulant therapy (c) including, but not limited 
to:
Warfarin, Heparin, Clopidogrel, Prasugrel
X
X
X
X
Other agents affecting digestive organs including: 
muscarinic M3 receptor antagonists, prokinetics (eg,
metoclopramide, cisapride, tegaserod), 
anticholinergic agents, prostaglandins, anti-gastrin 
agents or mucosal-protective (eg, sucralfate) agents
X
X
X
X
Oral corticosteroids (d)
X
X
X
X
Drugs with a narrow therapeutic range (eg, Digoxin, 
Warfarin)
X
X
X
X
(a) Study antacid medication provided may be used during the Screening and Treatment Periods. 
(b) Subjects will change their prescribed PPI to esomeprazole 40 mg QD for the 4 week PPI Run-in period. Subjects are not allowed 
to take any other PPIs other than study drug during the Run-in and Treatment Periods.
(c) Aspirin up to 325 mg per day is allowed as anticoagulant therapy. 
(d) A short course taper for the treatment of asthma exacerbations and inhaled corticosteroids are permitted. 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. The investigator should review any additions or 
changes in medications at all visits. All medications should be recorded in the source documents or 
equivalent and then transcribed onto the appropriate electronic case report forms (eCRFs). 


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Concomitant medications should remain at a stable dose during the study unless a change in 
dosage is medically indicated.
7.4
Diet, Fluid, Activity Control
The subject should refrain from excessive drinking and eating, an extreme diet change (eg, Change 
to an extremely high-fat diet) or excessive exercise throughout the study. Vonoprazan 20 mg, 
vonoprazan 40 mg and esomeprazole 40 mg will be administered as an oral daily dose in the 
morning, at least 1 hour before the first meal of the day.
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 
medication should be recorded in the case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.17.
1. Pretreatment event (PTE) or adverse event (AE). The subject has experienced a PTE or AE that 
requires early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE.

Liver Function Test (LFT) Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.9), if the following circumstances occur at any time 
during study medication treatment:
–
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or total bilirubin 
> 2 × upper limit of normal (ULN)
2. Significant protocol deviation. The discovery post-randomization that the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE or lack of efficacy).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.


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6. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.11.
7. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject. 
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
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 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. Discontinued or withdrawn subjects will not be replaced.


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, study medication refers to vonoprazan (20 mg and 40 mg) active, esomeprazole
(40 mg) active and matching placebo capsules defined below. Study medication will be packaged 
in blinded fashion.
8.1.1.1
Investigational drug
Vonoprazan 20 mg and 40 mg Capsules
Vonoprazan study medication will be supplied as 20 mg and 40 mg capsules. The drug product 
will be over-encapsulated into DBAAel Swedish Orange capsules at the contract manufacturing 
organization, Almac UK. Takeda Pharmaceutical Company Ltd., Osaka, Japan, manufactures the 
vonoprazan drug substance and vonoprazan drug product. 
The over-encapsulated vonoprazan 20 mg and 40 mg strengths will be identical in appearance. 
They will be foil/foil blister packaged into 10-day (1 week plus 3 extra days) child-resistant blister 
cards, containing a total of 10 capsules. Dosing consists of 1 capsule daily. 
Each wallet of vonoprazan 20 mg or 40 mg capsules will bear a multilingual booklet or a single 
language label that includes pertinent study information along with caution statement.
Labels will be in the appropriate language where the study medication is being dispensed.
Esomeprazole (40 mg) active and Placebo Capsules
Commercially available 40 mg esomeprazole tablets will be over-encapsulated by Almac, UK, 
hence the product is considered investigational material and Almac Clinical Services becomes the 
manufacturer of active over-encapsulated esomeprazole 40 mg and matching placebo capsules.
The esomeprazole and placebo will be identical in appearance to the vonoprazan 20 mg and 40 mg 
over encapsulated drug product as DBAAel Swedish Orange Capsules, which will be foil/foil 
blister packaged into 10-day (1 week plus 3 extra days) child-resistant blister cards, containing a 
total of 10 capsules. Dosing consists of 1 capsule daily.
Each wallet of either esomeprazole or placebo capsules will bear a multilingual booklet or a single 
language label that includes pertinent study information along with caution statement.
Labels will be in the appropriate language where the study medication is being dispensed.


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8.1.1.2
Rescue Medication
During the study period including the screening period, antacids such as Gelusil (main ingredients 
are aluminium hydroxide, magnesium hydroxide and simethicone) or other bicarbonate based 
medication, if available in the participating countries, can be used as the rescue medication if the 
symptoms caused by acid reflux cannot be tolerated by the subjects.
A guideline of commonly used medications which may be used as rescue medications in each of
the countries will be provided. If the listed rescue medications in the guideline are not available, 
CRO/Takeda medical monitor may provide guidance of available brand to investigators. The 
administration of rescue medication shall be in accordance to the package insert approved in the 
corresponding countries. For aluminum based medications, an interval of at least 2 hours must be 
maintained between administration of study medication (Vonoprazan or esomeprazole) and rescue 
medication. Subjects shall contact the investigators if they would like to take the rescue medication 
at a dose higher than the approved ones in the local insert package.
When rescue medication has been taken for more than 7 consecutive days in the randomization 
treatment period, the investigator should discuss the case with the CRO/sponsor medical monitor
and consider whether to withdraw the subject.
The use of rescue medication shall be recorded in the subject electronic diary. The sponsor will 
reimburse the investigational sites for the cost of supplying rescue medication drugs to subjects. 
8.1.1.3
Sponsor-Supplied Drug
Over-encapsulated vonoprazan (20 mg and 40 mg) active as well as over-encapsulated 
esomeprazole (40 mg) active and matching placebo capsules will be supplied by the sponsor.
8.1.2
Storage
Vonoprazan, esomeprazole and matching placebo capsules should be stored in blister at or below 
25°C. Investigational drug must be kept in an appropriate, limited-access, secure place until it is 
used or returned to the sponsor or designee for destruction. Investigational 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.
Temperature excursion must be reported to the sponsor or designee.
8.1.3
Dose and Regimen
PPI Run-In period (Days -42 to -14)
Subjects will be dispensed 4 blister cards containing 10 capsules of esomeprazole 40 mg.
Subjects will be instructed to take one capsule at least 1 hour before the first meal of the day. The
subject will also be reminded to bring the study medication blister cards (including any unused 
study medication) to the following study visit.


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Single blind Placebo Run-In period (Days -14 to -1)
Subjects will be dispensed two blister cards containing 10 capsules of Placebo.
Subjects will be instructed to take one capsule at least 1 hour before the first meal of the day. The
subject will also be reminded to bring the study medication blister card (including any unused 
study medication) to the following study visit.
Treatment Day 1 – Randomization and Treatment Period visits
Each subject who meets all the inclusion criteria and none of the exclusion criteria will be 
randomly assigned to receive either once daily vonoprazan or esomeprazole via the IWRS. 
After randomization subjects will be dispensed two blister cards containing 10 capsules of either 
vonoprazan 20 mg or 40 mg or esomeprazole 40 mg.
Subjects will be instructed to take one capsule at least 1 hour before the first meal of the day. The
subject will also be reminded to bring the study medication blister card (including any unused 
study medication) to the following study visit. A further two blister cards will be dispensed at visit 
5 (week 2) so that the subjects will receive study drug for 4 weeks of treatment, thereafter they will 
move into the follow-up phase (with a phone call follow-up completed 1 week after the last dose).
Table 8.a describes the dose and tablet count that will be provided to each group.
Table 8.a
Dose and Regimen
Treatment 
Group
Dose
Treatment Description
Treatment Dose
PPI Run-in QD
Esomeprazole 40 mg capsule
One 40 mg esomeprazole capsule
Placebo Run-in QD
Zero active capsule
One placebo capsule
A
20 mg vonoprazan QD
Vonoprazan 20 mg capsule
One capsule from vonoprazan 20 mg 
blister card
B
40 mg vonoprazan QD
Vonoprazan 40 mg capsule
One capsule from vonoprazan 40 mg 
blister card
C
40 mg esomeprazole QD
Esomeprazole 40 mg capsule
One capsule from esomeprazole 
40 mg blister card 
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
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, Pretreatment Events 
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Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Investigational drug Assignment and Dispensing Procedures
Subjects will be assigned to receive their treatment according to the schedule allocated to each 
study site.
The investigator or investigator’s designee will access the IWRS to obtain the subject number at 
screening. The IWRS will be accessed at Day -42 (Visit 2) to enroll the subject into the PPI Run-in 
period of the study and at Day -14 (Visit 3) to enroll them into single-blind placebo run-in period 
of the study. The investigator or the investigator’s designee will utilize the IWRS to randomize the 
subject into the study (visit 4). During this contact, the investigator or designee will provide the 
necessary subject-identifying information, including the subject number assigned at screening. At 
subsequent drug-dispensing visits (visit 5), the investigator or designee will again contact the 
IWRS to request additional investigational drug for a subject. The medication identification (Med 
ID) number of the investigational drug to be dispensed will then be provided by the IWRS.
If sponsor-supplied drug (vonoprazan 20 mg or 40 mg capsule or esomeprazole 40 mg capsule or 
placebo capsule) is lost or damaged, the site can request a replacement from IWRS. (Refer to 
IWRS manual provided separately.)
The subject will take the first dose of study medication at Visit 2 after completion of all 
assessments but before leaving the clinic. At all subsequent study visits during the Treatment 
phase the subject should be instructed to present to the clinic for the study visit without taking the 
study medication. The daily dose of the study medication on those days will be taken by the subject 
after completion of assessments.
Subjects should be instructed that all doses of study medication (vonoprazan, esomeprazole or 
placebo) should be taken 1 hour before breakfast except on study visit dates where it will be taken 
after completion of the visit assessments. Study drug is to be kept in the blister cards provided until 
the dose is to be taken. Subjects should also be instructed that if any dose is missed inadvertently it 
is acceptable for that dose to be taken within 12 hours of the time that it was due. If longer than 
12 hours have passed since the dose was due, it should not be taken but noted instead in the 
subject’s diary that the dose was missed.
8.3
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule 
prior to the start of this study. All randomization information will be stored in a secured area, 
accessible only by authorized personnel.
At the Randomization Visit, Day 1 (Visit 4), all qualified subjects will be randomized to one of 3 
treatment groups in a 1:1:1 ratio to vonoprazan 20 mg, 40 mg and esomeprazole 40 mg using the 
IWRS.


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8.4
Investigational Drug Blind Maintenance 
The investigational drug blind will be maintained using the IWRS.
8.5
Unblinding Procedure 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. In the 
event of a medical emergency, the investigator will be able to access the IWRS to determine the 
patient’s treatment group assignment. The investigator will, whenever possible, discuss options 
with the medical monitor before unblinding. The sponsor must be notified as soon as possible if 
the investigational drug blind is broken. The date, time, and reason the blind is broken must be 
recorded in the source documents and the same information (except the time) must be recorded on 
the eCRF.
If any site personnel are unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study.
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee or, where appropriate destroyed at the site according to local procedures
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug, vonoprazan (20 mg and 40 mg), esomeprazole 40 mg and placebo, the 
investigator or designee must maintain records of all sponsor-supplied drug delivery to the site, 
site inventory, dispensation and use by each subject, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment by recording in IWRS. If there are any 
discrepancies between the packing list versus the actual product received, Takeda must be 
contacted to resolve the issue. The packing list should be filed in the investigator’s essential 
document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the Med ID number used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.


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If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drugs
(vonoprazan 20 mg and 40 mg, esomeprazole 40 mg and placebo) on a sponsor-approved drug 
accountability log. The following information will be recorded at a minimum: protocol number 
and title, name of investigator, site identifier and number, description of sponsor-supplied drugs,
expiry and/or retest date, date and amount dispensed including initials or signature of the person 
dispensing the drug, and the date and amount returned to the site by the subject, including the 
initials or signature of the person receiving the sponsor-supplied drug. The log should include all 
required information as a separate entry for each subject to whom sponsor-supplied drug is 
dispensed.
All study drugs that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.
In the event of expiry date extension of sponsor-supplied drug already at the study site, 
sponsor-supplied drugs may be relabelled with the new expiry date at that site. In such cases, 
Takeda or its designee will prepare additional labels, certificates of analyses, and all necessary 
documentation for completion of the procedure at the sites.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.1.1
Pharmacogenomic Informed Consent Procedure
The sampling of whole blood for CYP2C19 genotyping analysis is mandatory; every subject must 
sign the informed consent in order to participate in this study. The informed consent for the 
CYP2C19 genotyping analysis is a component of the overall study informed consent.
A separate PGx informed consent form pertaining to storage of the sample must be obtained in 
order to store the sample after the study related PGx analysis described in the protocol is 
completed. The provision of consent to store the sample for future analysis is independent of 
consent to the other aspects of the study. The requirements are described in Section 15.2.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth (or age for the countries which 
don’t allow to collect the date of birth), sex, race as described by the subject, and employment 
status, smoking status, history of use alcohol and history of caffeine-containing drinks, night 
sweats within the past 1 month, weight change within the past 1 year, history of H. pylori
eradication therapy (eg, triple therapy with PPI + amoxicillin + clarithromycin) and date of 
completion of such therapy (within the past 1 year/more than 1 year) of the subject at Screening. 
Medical history including inflammatory disorder, chronic pain conditions and diabetes mellitus to 
be obtained will include determining whether the subject has any significant conditions or diseases
relevant to the disease under study that stopped at or prior to signing of informed consent. Ongoing 
conditions are considered concurrent medical conditions (see Section 9.1.8).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 90 days prior to signing of informed 
consent.


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9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of investigational 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; 
(7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other. 
All subsequent physical examinations should assess clinically significant changes from the 
assessment from the baseline examination.
9.1.4
Weight and Height
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off.
Height will be collected at Visit 1 in centimeters without decimal places.
Weight will be measured at Visit 1, Visit 4 (Randomization) and Visit 6 (or early withdrawal). 
Weight will be collected in kilograms to 1 decimal place. BMI is calculated by sponsor or its 
designee using metric units with the formula provided below.
BMI = weight (kg)/height (m)2
9.1.5
Vital Sign Procedure
Vital signs will include body temperature (oral or tympanic measurement), sitting blood pressure 
(resting more than 5 minutes), and pulse (bpm).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw.
Vital signs will be measured at Visit 1, Visit 4 (Randomization) and Visit 6 (or early termination).
9.1.6
Efficacy Measurement 
9.1.6.1
Reflux Symptom Questionnaire Electronic Diary (RESQ-eD)
RESQ-eD is an electronic diary that Astra Zeneca developed and validated in patients with partial 
response to PPI [22]. Subjects will be given and trained on the use of the study e-Diary at Visit 2 
and re-trained at Visit 3 if necessary once initial eligibility criteria have been confirmed at Visit 3. 
Subjects will be instructed to complete the e-Diary every morning upon waking and every evening 
before going to sleep.
Throughout the Run-in Period and Treatment Period, subjects will document the presence of 
daytime and nighttime heartburn and regurgitation, as well as the use of rescue medication. Any 
subjective symptoms experienced should be entered in accordance with the descriptions given in 
Table 9.a, throughout the study, describing in the diary the severity of all heartburn or 
regurgitation symptoms.


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Subjects will complete the e-Diary during the Run-in Period for at least 42 days prior to
Randomization and during the 4-week Treatment Period. 
Table 9.a
Requirements for Subject Diary Entries Regarding Subjective Symptoms
Subjective symptom
Description of symptom
Entry requirements
Heartburn
A burning feeling behind your breastbone, pain behind 
your breastbone, a burning feeling in the center of the 
upper stomach, a pain in the center of the upper 
stomach 
Since waking today/ During the 
nighttime, how would you rate 
the intensity of…?
Regurgitation
An acid or sour taste in your mouth, A bitter taste in 
your mouth, Unpleasant movement of material 
upwards from the stomach or stomach contents (liquid 
or food) moving upwards to your throat or mouth
Since waking today/ During the 
nighttime, how would you rate 
the intensity of…?
Items are scored for intensity on a 6-point scale (0=did not have; 1=very mild; 2=mild; 3=moderate; 4=moderately 
severe; 5=severe).
9.1.6.2
Subject Reported Outcome Questionnaires
Sleep
Nighttime awakenings (eDiary)
Question that will be included in the morning evaluation of the eDiary are tabulated as follows:
Did you wake up during night (=usual sleeping time)? 
1 Yes
2 No
Fatigue (eDiary)
Questions that will be included in the evening evaluation of the eDiary are tabulated as follows
(both rated on 5-point Likert scale):
1. How much physical fatigue have you experienced today?
0 = none, 1 = slight, 2 = medium, 3 = a lot, 4 = severe
2. How much intellectual fatigue have you experienced today?
0 = none, 1 = slight, 2 = medium, 3 = a lot, 4 = severe
Quality of Sleep
Quality of sleep will be assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire
[23]. The PSQI questionnaire is a 19-item validated questionnaire completed by patients regarding 
the previous 1-month period. Items are grouped into seven component scores: subjective sleep 


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quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping 
medication, and daytime dysfunction. Each component score is weighted equally on a 0–3 scale, 
with 3 representing the worse effect, then summed to yield a global PSQI score, which could range 
from 0 to 21. Patients with a global score >5 are considered to have poor sleep quality. Patients will 
complete the questionnaire at the Visit 2, Visit 3, Visit4 and Visit 6 (or early termination).
HRQoL
Health-Related Quality of Life (HRQL) will be assessed at Visit 2, Visit 3, Visit 4 and Visit 6 (or 
early termination) using generic and disease specific PRO instruments. 
The EuroQol-5 dimensions (EQ-5D-5L) is a validated and reliable generic instrument [24,25] that 
was developed as a standardized non-disease-specific instrument describing and evaluating 
HRQL. It was intended to complement other forms of HRQL measures and have the capacity to 
generate cross-national comparisons for health care evaluations. EQ-5D-5L is used to calculate 
quality-adjusted life years (QALYs) for pharmaco-economic studies [26,27,28]. The questionnaire 
includes 5 domain items: mobility, self-care, usual activities (UA), pain/discomfort (P/D), and 
anxiety/depression (A/D). Subjects choose the level of health problems they currently have on 
each item as “None”, “Slightly”, “Moderate”, “Severe”, or “Unable” and are scored a 1, 2, or 3, 
respectively. The 5 items allow the calculation of a utility index ranging between 0 (the worst) and 
1 (the best). The questionnaire also uses a Visual Analog Scale (VAS). The EQ-5D-5L VAS score 
is a self-assigned rating of overall health using a 20 cm visual, vertical scale, with a score of 0 as 
the worst and 100 as best possible health. A decrease of ≥0.08 points in the EQ-5D-5L index score 
represents a meaningful improvement in patient’s HRQoL [25]. The EQ-5D-5L has a recall period 
of one day and will be provided in the Study Manual. 
An upper-GI (UGI)-disorder specific questionnaire PAGI-QOL (Patient Assessment of Upper 
Gastrointestinal Disorders Quality-of-Life Index) will be used in order to evaluate with more 
sensitivity the treatment-induced changes in HRQoL. The PAGI-QOL is a validated and reliable 
instrument used to measure QOL in patients with UGI disorders including GERD, dyspepsia, and 
gastroparesis [29]. 
Changes in UGI symptoms
Changes in UGI symptoms will be measured with the PAGI-SYM (Patient Assessment of Upper 
Gastrointestinal Disorders Symptom Severity Index), a validated and reliable instrument used to 
measure symptom severity in patients with UGI disorders including GERD, dyspepsia, and gastro 
paresis [30,27]. The PAGI-SYM measures UGI symptom severity over the 2 weeks preceding the 
visit. PAGI-SYM will be used to identify patient that are more likely to be functional patients. 
PAGI-SYM will also be used to identify meaningful change in RESQ-eD. Patients will complete 
the questionnaire at the Visit 2, Visit 3, Visit 4 and Visit 6 (or early termination).
Patient Global Impression of Change
The Patient Global Impression of Change (PGIC) is a patient-rated instrument that measures 
change in patient’s GERD-related symptoms on a 7-point scale ranging from 1 (very much 


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improved) to 7 (very much worse) [31]. Higher scores indicate a change for the worse. For this 
study, subjects will be asked to rate their symptoms relative to their previous past 4-weeks or 
2-weeks. The PGIC item will be assessed at visit 3, visit 4 and visit 6 (Early termination). The 
PGIC will be used to further document the ability RESQ-eD to detect change as well as clinical 
meaningfulness of change. 
Mood
Studies showed that in patients who are referred for a diagnostic work-up for GERD, increased 
anxiety levels were observed most often in patients in whom complaints were owing to a 
functional disorder such as functional heartburn or functional dyspepsia [32,33]. High ratings 
suggestive of depression or an anxiety disorder measured with the Hospital Depression and 
Anxiety scale (HADS) have been shown to be associated with poorer PPI response [34].
The presence of anxiety levels and depression levels will be assessed using the HADS and 
treatment group efficacy outcomes and HADS scores will be assessed [35]. The HADS is a widely 
used scale that was designed for detecting depression and anxiety in an out-patient clinic setting, 
HADS part A (HADS-A) focuses on anxiety and HADS part D (HADS-D) focuses on depression.
HADS-A and HADS-D are 7-item subscales that measure the presence and severity of anxiety and 
depression symptoms, respectively, on a scale of 0 to 3. Total scores ≤ 7 indicate no clinically 
relevant symptoms, 8 to 10 mild symptoms, 11 to 14 moderate symptoms, and ≥15 (maximum 21) 
indicate more severe symptoms. HADS will be assessed at visit 2, visit 3, visit 4 and visit 6(or 
early termination).
Questionnaires should be completed by the subject prior to dosing at appropriate clinic visits and 
questionnaires completeness should be checked prior to the subject leaving the site.
9.1.7
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF.
9.1.8
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, electrocardiogram 
(ECG), or physical examination abnormalities noted at baseline examination. The condition (ie, 
diagnosis) should be described.


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9.1.9
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 55 mL, and the approximate total volume of 
blood for the study is 100 ml or 125 mL depending on the assigned PK assessment group. Details 
of these procedures and required safety monitoring will be given in the laboratory manual.
Table 9.b lists the laboratory tests that will be required by the protocol. Laboratory samples will be 
taken at the time points stipulated in the Schedule of Study Procedures (Appendix A).
Table 9.b
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Hematocrit
Hemoglobin
Platelet count
RBC count
Reticulocyte count
WBC count (with differential) 
Erythrocyte indices (MCV, MCH, 
MCHC) 
Coagulation Tests
Prothrombin time
Partial thromboplastin time
International normalized ratio
ALT
Albumin
Alkaline phosphatase
Amylase
AST
Blood urea nitrogen
Calcium
Chloride
Cholesterol
CK 
C-reactive protein (CRP) (a)
Gastrin tests (b)
γ-Glutamyl transferase
Glucose
Lactate dehydrogenase
Magnesium
Pepsinogen I/II(c)
Potassium
Phosphate
Serum creatinine
Sodium
Standard iron panel (serum iron, TIBC, serum 
ferritin) (d)
Total bilirubin
Direct bilirubin (e)
Total protein
Triglycerides
Uric acid
Appearance
Color
Bilirubin
Glucose
Hemoglobin
Ketones
Leucocytes
Nitrites
pH
Protein
Specific gravity
Urobilinogen
Microscopy for 
abnormal urinalysis 
result (RBCs, WBCs, 
casts, crystals, 
organisms, and 
epithelial cells)


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Table 9.b
Clinical Laboratory Tests (continued)
Other:
Serum
Urine
Breath
Hepatitis panel, including HBsAg and 
anti-HCV
Thyroid-stimulating hormones (TSH)(f)
Female subjects only
hCCGI (for pregnancy, female subjects of 
childbearing potential)
All subjects
Drug screen including: amphetamines 
(including methamphetamine), barbiturates, 
benzodiazepines, cannabinoids, cocaine, 
opiates, methadone and phencyclidine (h)
Helicobacter pylori (i)
Female subjects only
Beta hCG (for pregnancy, female 
subjects of childbearing potential)
Follicle-stimulating hormone (FSH) if 
menopause is suspected (g)
MCH=mean corpuscular hemoglobin, MCHC=mean corpuscular hemoglobin concentration, MCV= mean 
corpuscular volume, RBC=red blood cell, TIBC= total iron binding capacity, WBC=white blood cell. 
(a) CRP will be collected at Visit 4 and Visit 6(or Early termination). 
(b) Gastrin and Gastrin-17 will be performed.
(c) This includes pepsinogen I, pepsinogen II and pepsinogen I/II ratio.
(d) Standard iron panel will be collected at Visit 1 and Visit 6(or Early termination). 
(e) Assess direct bilirubin only if total bilirubin >1.5×ULN. 
(f) TSH will be checked at Visit 4 and Visit 6(or Early termination).
(g) Follicle-stimulating hormone will be conducted at investigator’s discretion to determine the postmenopausal 
status of women whose duration of (consecutive) amenorrhea is borderline or open to doubt and where the 
investigator believes the subject to be menopausal by history. 
(h) The central laboratory will confirm any positive drug screen results.
(i) Helicobacter pylori breath test will be performed at Randomization via a urea breath test (C13 or C14 urea test) at 
a local laboratory. A stool test may be performed at those centers which do not have the facilities to perform a H. pylori
breath test procedure.
The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results.
If subjects experience an increase in any one of either ALT, AST or total bilirubin >2×ULN then 
trial medication should be stopped due to the criteria for discontinuation has been met (please refer 
to section 7.5 for discontinuation criteria). Follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) to monitor recovery should be 
performed within a maximum of 7 days and preferably within 48-72 hours after the abnormality 
was noted.
Please refer to Section 10.2.3 for the appropriate guidance on Reporting of Abnormal Liver 
Function Tests.
CCI


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The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used.
To obtain information on H. pylori infection that reportedly could affect the onset of erosive 
esophagitis, H. pylori infection status will be measured at Randomization. To establish H. pylori
infection status a 13C or 14C urea breath test will be performed. Exhaled air samples will be taken 
in accordance with instructions for use of locally available testing kits for H. pylori infection status 
determination. A stool test to measure the infection of H. pylori may be performed at those centers 
which do not have the facilities to perform a H. pylori breath test procedure.
9.1.10 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 4 weeks after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as at least 1 year since last regular menses with an FSH >40 IU/L or at least 5 years since last 
regular menses, confirmed before any study medication is implemented).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, the only acceptable methods of contraception are: 
Barrier methods (each time the subject has 
intercourse):
Intrauterine devices (IUDs):
!
Cap (plus spermicidal cream or jelly) PLUS 
male condom.
!
Diaphragm (plus spermicidal cream or jelly) 
PLUS male condom.
!
Copper T.
*Barrier methods is only applicable in countries where spermicide is commercially available.
Subjects can continue to use contraceptive medications and/or devices as long as they use 
additional contraceptive precautions as highlighted above. Subjects will be provided with 
information on acceptable methods of contraception as part of the subject informed consent 
process and will be asked to sign a consent form stating that they understand the requirements for 
avoidance of pregnancy, donation of ova during the course of the study.
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During the course of the study, regular serum or urine human chorionic gonadotropin (hCG) 
pregnancy tests will be performed only for women of childbearing potential and subjects will 
receive continued guidance with respect to the avoidance of pregnancy as part of the study 
procedures (Appendix A). In addition to a negative hCG pregnancy test at Screening, subjects also 
must have a negative hCG pregnancy test at Randomization prior to receiving first dose of double 
blind investigational drug. 
9.1.11 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (vonoprazan active and placebo tablets, esomeprazole and matching 
placebo) should be immediately discontinued. 
If the pregnancy occurs during administration of active study medication, eg, after Visit 4 
(Randomization) or within 4 weeks of the last dose of active study medication, the pregnancy 
should be reported immediately, using a pregnancy notification form, to the contact listed in 
Section 1.0.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time 
she became pregnant and provide details of treatment the subject received (blinded or unblinded, 
as applicable).
All pregnancies in subjects on active study drug including comparator will be followed up to final 
outcome, using the pregnancy form. Pregnancies will remain blinded to the study team. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.
9.1.12 ECG Procedure
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The 
following parameters will be recorded on the eCRF from the subject’s ECG trace: heart rate, PR 
interval, QT interval and QRS interval.
ECG will be recorded at Visit 1(screening), Visit 4(Randomization) and Visit 6(or early 
termination). A copy of the ECG trace should be kept with the subject’s notes. For ECG results 
printed on thermal paper, non-thermal paper copies should be made to avoid degradation of trace 
over time.


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9.1.13
Endoscopy
Endoscopy to check the stomach and esophagus will be performed at screening, or historical data 
of endoscopy checking stomach and esophagus up to one year prior to screening may be permitted. 
Subjects are fasted for 10 hours according to the usual practice of the institution (ie, in regards to 
pre-medications or concomitant therapies as long as they are not prohibited in Section 7.3 of this 
protocol) prior to the endoscopy. The purpose of the endoscopy is to confirm erosive esophagitis 
status and exclude esophageal and gastric malignancies. During endoscopy, the investigator or
designee should ensure that gastric and esophageal mucosa is observed for a sufficient duration 
that the subject’s eligibility is confirmed and/or ensure that accurate classification of the grade of 
any erosive esophagitis observed can be made. Digital images of the current esophageal erosions 
will be captured and stored at the investigational site which has a method of storage.
Table 9.c
Los Angeles (LA) classification for diagnosis and grading of erosive 
esophagitis 
Grade
Description
Grade 0
No mucosal breaks
Grade A
One or more mucosal breaks no longer than 5 mm, none of which extends between 
the tops of the mucosal folds
Grade B
One or more mucosal breaks more than 5 mm long, none of which extends between 
the tops of two mucosal folds
Grade C
Mucosal breaks that extend between the tops of two or more mucosal folds, but 
which involve less than 75% of esophageal circumference
Grade D
Mucosal breaks which involve at least 75% of esophageal circumference
Source : [36]
9.1.14
Pharmacogenetic Sample Collection For Genotyping (Mandatory)
The sampling of whole blood for CYP2C19 genotyping analysis is mandatory; every subject must 
sign the informed consent in order to participate in this study.
One 6 mL whole blood sample for deoxyribonucleic acid (DNA) isolation will be collected before 
dosing on visit 4 (randomization) from each subject in the study, into plastic K2 
ethylenediamine-tetraacetic acid (EDTA) spray-coated tubes, and stored under frozen conditions. 
If necessary and feasible, a second aliquot of blood may be taken if isolation of DNA from the first
sample was not successful or possible.
The DNA sample collected from each subject will be used for CYP2C19 genotyping analysis.
Genetic variation in the CYP2C19 gene may lead to changes in metabolic activity of the CYP2C19 
enzyme that may contribute to the variability in the PK/clinical efficacy of Vonoprazan.
Investigators will be blinded to CYP2C19 metabolic status to ensure that assessments of efficacy 
and tolerability are unbiased by knowledge of metabolic status. After the study ends, the 
CYP2C19 metabolic status information may be provided to investigators and the subject based on 
subject or the legal representative request.


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9.1.15 Pharmacogenomic Sample Collection For Storage (Optional)
A separate PGx informed consent form must be obtained in order to store the remaining DNA 
sample from the CYP2C19 genotyping and to collect additional blood samples for ribonucleic acid 
(RNA) isolation. The provision of consent to store the sample for future analysis is independent of 
consent to the other aspects of the study.
Two whole blood samples (2.5 mL per sample) for ribonucleic acid (RNA) isolation will be 
collected from each subject predose at visit 4 (randomization), into a PaxGene TM tube and stored 
under frozen conditions. 
DNA forms the basis for the genes that make the body produce proteins such as enzymes, drug 
transporters or drug targets, and may be evaluated for the genetic contribution how the drug is 
broken down, or how the drug affects the body. This is called a “Pharmacogenomics research 
study.” Specific purposes of this study include:

Identifying genetic reasons why certain people respond differently to vonoprazan.

Finding out more information about how vonoprazan works.

Generating information needed for research, development, and regulatory approval of tests to 
predict response to vonoprazan.

Identifying variations in genes related to the biological target of vonoprazan.
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of vonoprazan and other study medications, understanding of disease/condition being 
studied and for improving the efficiency, design and study methods of future research studies.
Each pharmacogenomic sample for a study subject should be identifiable on the requisition form 
with a subject ID.
The samples will be stored for no longer than 15 years after completion of the study and/or until 
the drug development of vonoprazan is no longer actively pursued by Takeda or its collaborators. 
No samples will be stored for longer than permitted by the applicable law and samples will be 
destroyed upon notification from Takeda. “Stored samples” are defined as samples that are 
key-coded (the samples are stripped of all personal identifying information but a key links the 
samples to the clinical data collected from the sample donor) and are used in the analysis of 
investigational drug or related drugs.
Detailed instructions for the handling and shipping of samples are provided in Appendix E.
9.1.16 Pharmacokinetic Sample Collection and Analysis 
Subjects will be assigned to one of two sub PK groups.
Subjects in Group 1 (minimum 15 subjects per treatment arm) will be asked to arrive at the clinic 
prior to taking the daily dose at Visit 5 (Week 2) and Visit 6 (Week 4). A predose sample will be 
collected, followed by drug administration. One post dose sample will be taken at a time after 


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1 hour post dose at Visit 5 and 5 post-dose plasma samples will be taken at time point 0.5, 2, 5, 6 
and 8 hours post dose at Visit 6.
The remaining subjects in each treatment arm will be assigned to Group 2 (minimum 45 subjects 
per treatment arm). Subjects will be asked to arrive at the clinic prior to taking the daily dose at 
Visit 5 (Week 2) and Visit 6 (Week 4). A predose sample will be collected, followed by drug 
administration. Additional plasma samples will be taken at a time after 1 hour post dose.
Table 9.d
Schedule of Pharmacokinetic Sample Collection
Group
Sample collection time
Visit 5
Visit 6
Group 1
Predose / >1 hr post dose
Predose / 0.5, 2, 5, 6 and 8 hr post dose
Group 2
Predose / >1 hr post dose
Predose / >1 hr post dose
All subjects will provide a blood sample in order to maintain the blind; however, only samples 
from subjects receiving vonoprazan will be analyzed for all groups and visits. Samples from 
subjects receiving esomeprazole may be analyzed, but will be reported separately. The plasma 
samples will be analyzed for plasma concentration of vonoprazan and esomeprazole (if required)
by validated methods.
For the final pharmacokinetic analysis, it is important that the date and time of administration of
the previous study drug dose before collection of the pharmacokinetic sample (PK dose), and the
dose before that, be accurately recorded in the source documents and eCRF at Visit 5 and Visit 6.
Similarly, it is important that the date and time that each blood sample is drawn is accurately 
recorded in the eCRF.
9.1.16.1 Bioanlytical Methods
Plasma concentrations of Vonoprazan and esomeprazole (if required) will be analyzed using 
separate validated LC/MS/MS methods.
9.1.17 Documentation of Screen Failure and Run-In Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible at the screening visit or prior to Run-in period, the 
investigator should complete the eCRF. The IWRS should be contacted as a notification of screen 
failure.
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The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria.

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal <specify reason>.

Study termination.

Other <specify reason>.
Subject numbers assigned to subjects who fail screening should not be reused.
If the subject has begun the PPI Run-in study medication or single-blind placebo Run-in study 
medication and they are found to not be eligible for randomization, they are considered a run-in 
failure. The investigator or designee should complete appropriate eCRFs and register the subjects 
as a run-in failure in the IWRS.
9.1.18 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 phase. IWRS will be contacted for treatment assignment and 
this information should be captured on the appropriate eCRF.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study medication containers/unused medications to each 
dispensing site visit regardless of whether the study medication container is empty. Compliance 
with the study drug regimen will be documented throughout the study and must be calculated from 
counts of returned tablets and capsules.
If a subject is persistently noncompliant with the study medication (< 75% or >133% of the 
allocated medication for 2 consecutive 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 evaluations is shown in Appendix A.
Assessments should be completed at the designated visit/time point(s).


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Visit windows should be calculated from the day of randomization. Visit windows are listed in 
Appendix A. Unscheduled non-study visits can be held, if in the opinion of the investigator a 
closer follow-up regime is required for the subject.
9.4
Post Study Care
Unless required by law, the study medication will not be available upon completion of the 
subject’s participation in the study. The subject should be returned to the care of a physician and 
standard therapies as required.
9.5
Biological Sample Retention and Destruction 
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.14 
. The genetic material will be stored initially at
 and then if consent has been 
provided to store the samples for future analysis, the samples will be preserved and retained at the 
designated laboratory for up to but not longer than 15 years or as required by applicable law. The 
sponsor has put into place a system to protect the subjects’ personal information to ensure optimal 
confidentiality and defined standard processes for sample and data collection, storage, analysis, 
and destruction.
The sponsor and researchers working with the sponsor will have access to the samples collected 
and any test results. All samples collected during the study will be stored securely with limited 
access and the sponsor will require anyone who works with the samples to agree to hold the 
research information and any results in confidence.
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided a pharmacogenomic samples for DNA analysis can 
withdraw their consent and request disposal of a stored sample at any time. Notify sponsor of 
consent withdrawal.
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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/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 a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 


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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 a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.


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Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.
The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death if it 
were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is 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.


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
Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6 Causality of AEs
The relationship of each AE to study medication(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 cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs 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 drugs and concurrent treatments.
10.1.7 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.


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The relationship 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 relationship should be assessed 
as Not Related. 
10.1.8 Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.9
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with
sequelae or the subject died.
10.1.10
Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.11
Action Concerning Study Medication

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study medication was stopped for a reason other than the particular AE eg,
the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE.

Dose Interrupted – the dose was interrupted due to the particular AE.
10.1.12
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.


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
Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death. 

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication (Visit 
2, Day -42) or until screen failure. For subjects who discontinue prior to study medication
administration, PTEs are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication (Visit 2, Day -42). Routine collection of AEs will continue until 1 week after 
completion or withdrawal from the study (safety follow-up call).
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date.
3. Severity.


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4. Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (related or not related) (not completed for PTEs).
5. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
6. Action concerning study medication (not applicable for PTEs).
7. Outcome of event.
8. Seriousness.
Patient diary and questionnaire will not be used as a primary means to collect AEs. However, 
should the investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the patient for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s)

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal Liver Function Tests as an SAE
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 


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other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.9 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
transmit it immediately within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators and IRBs or IECs, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first awareness 
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be 
submitted 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 an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial. The investigational site also will forward a 
copy of all expedited reports to his or her IRB or IEC in accordance with national regulations.


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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary.
12.1
CRFs 
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. 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.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, 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, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 


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retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address study objectives. 
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess subject evaluability and the appropriateness of the planned statistical 
methods.
13.1.1 Analysis Sets
Full Analysis Set: this analysis set will include all subjects randomized. Subjects in this set will be 
analyzed according to the original randomization.
Per Protocol Set: this analysis set is a subset of the FAS. The PPS consists of all subjects who do 
not violate the terms of the protocol in a way that would impact the study output significantly. All 
decisions to exclude subjects from the PPS dataset will be made prior to the unblinding of the 
study. Analyses using the PPS may be provided as a sensitivity analysis.
Safety Set: this analysis set will include all subjects who have received at least 1 dose of study 
drug. Subjects in this set will be analyzed according to the treatment they actually received.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by each treatment group and 
overall. Summary statistics (N, mean, SD, median, minimum, and maximum) will be generated for 
continuous variables (eg, age and weight) and the number and percentage of subjects within each 
category will be presented for categorical variables (eg, sex, ethnicity, and race). Individual 
subject demographic and baseline characteristics data will be listed.
13.1.3 Efficacy Analysis
For the assessment of the percentage of heartburn-free days, the Wilcoxon-Mann-Whitney Odds 
estimator with the 97.5% CI and the Wilcoxon rank-sum test will be used at the 2.5% level of 
significance for each vonoprazan treatment comparison with esomeprazole to control for 
multiplicity. The Wilcoxon rank-sum test will be used because data from a previous Vonoprazan
trial (TAK-438/CCT-201 [37]) showed that the data is unlikely to be normally distributed. This 
endpoint will be analyzed for both the FAS and PPS. The FAS analysis will be considered the 
primary analysis and the PPS analysis as a sensitivity analysis.
The percentage of days with neither daytime nor nighttime heartburn will be calculated for each 
subject who has at least one daytime or nighttime heartburn result (yes or no) during treatment by 
calculating the days that are heartburn-free out of the total number of days for which either a 


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daytime or nighttime result is marked. Thus, days missing diary results for both daytime and 
nighttime will be excluded from the numerator and denominator.
To assess the secondary endpoint, proportion of subjects with ≥1 sustained resolution of heartburn
(defined as ≥7 consecutive days without both daytime and nighttime heartburn any time during the 
4-week randomized double-blind Treatment Period) a Pearson Chi-square test will be used at the 
2.5% level of significance for each Vonoprazan treatment comparison with esomeprazole to 
control for multiplicity. All subjects with missing data for determination of endpoint status will be 
considered as a non-responder in the analysis. The difference in proportion and odds ratio for each 
Vonoprazan treatment comparison with esomeprazole will be estimated and presented with 97.5% 
confidence intervals. This endpoint will be analyzed for both the FAS and PPS. The FAS analysis 
will be considered the primary analysis and the PPS analysis as a sensitivity analysis.
Additional Endpoints
All additional endpoints will be analyzed for the FAS only and tested at the 5% level of 
significance for each Vonoprazan treatment comparison with esomeprazole. 95% confidence 
levels will also be presented. Multiplicity will not be adjusted across the remaining endpoints. 
If the assumptions underlying planned inferential methods are not adequately met, methods will be 
amended as needed for appropriate analysis. 
The time to first sustained resolution of heartburn is defined as the time from the first dose of study 
drug to the first day of the 7 consecutive days free of heartburn and will be analyzed using a 
product-limit survival analysis with treatment group as the stratum. The survivor function will be 
estimated using the Kaplan-Meier method and the survivor functions between Vonoprazan and 
Esomeprazole treatment groups will be compared using log-rank tests. The median time to 
sustained resolution of heartburn from the survivor function will be presented by treatment group, 
along with the 95% confidence interval. Time to first sustained resolution of regurgitation will be 
similarly analyzed.
The analysis of the remaining additional endpoints will be described in the SAP.
13.1.4 Pharmacokinetic Analysis 
Vonoprazan
Listings of all Vonoprazan concentration data will be provided in the clinical study report. The 
plasma concentration-time data for Vonoprazan will be summarized using descriptive statistics 
including geometric mean and CV%. Full details of the analysis will be included in the study SAP. 
Data from the subset of patients with full PK sampling will be performed by traditional NCA as 
outlined in the CPAP and results of this analysis will be reported in the CSR. 
Concentration-time data will be analyzed using population PK approach. A detailed description of 
the pharmacokinetic analysis methodology to be followed will be given in the population PK/PD 
analysis plan. This will be a standalone document and will not be included in the CSR.


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Esomeprazole
If esomeprazole concentration data is required, listings of all esomeprazole concentration data will 
be provided in a separate report to this clinical study report. The plasma concentration-time data 
for esomeprazole will be summarized using descriptive statistics including geometric mean and 
CV%. 
13.1.5 Patient Reported Outcomes Analysis
The scores of the PRO questionnaires will be summarized descriptively at each visit including 
changes from baseline “off-PPI” (visit 4) and changes from baseline PPI response (visit 3) by each 
treatment group. Absolute values and changes from baseline will be summarized per treatment 
arm.
 
13.1.6 Other Analysis
All data collected in this study will, where applicable, be summarised by treatment regimen using 
descriptive statistics. For continuous variables mean values, standard deviations, median and 
lower and upper percentiles will be calculated. For categorical variables frequencies and percent 
will be calculated.
13.1.7 Safety Analysis
Adverse events (AEs) will be summarized using the safety analysis set. 
Adverse events collected during the trial will be summarised by System Organ Class, treatment 
regimen and stage of trial (eg, screening and treatment emergent) and reported.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
It is estimated that approximately 426 subjects will be screened from which a total of 213 subjects 
(71 per treatment arm) who have a partial response to treatment with a high dose of esomeprazole 
(40 mg QD for 4 weeks) are planned to be randomised into the study with the expectation that 
180 subjects will complete the study (assuming a 15% dropout rate). The sample size of 
60 subjects per treatment group will provide at least 80% power at the 2-sided 0.025 level of 
significance to detect an absolute 20% difference between each vonoprazan dose and 
esomeprazole 40 mg for the percentage of heartburn free 24 hour periods (day and night) during 
4 weeks of randomized double-blind treatment. The pooled standard deviation was estimated as 
33.61 from prior Dexlansoprazole (T-GD04-082, T-GD04-083, T-EE04-084, T-EE04-085) and 
vonoprazan (CCT-201) studies (Data on file). The sample size was calculated using the Wilcoxon 
rank-sum test in EAST version 6.0.
CCI


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With the expectation that 180 subjects will complete the study, the secondary endpoint; proportion 
of subjects with ≥1 sustained resolution of heartburn (defined as ≥7 consecutive days without both 
daytime and nighttime heartburn any time during the 4-week randomized double-blind Treatment 
Period) has 80% power at the 2-sided 0.025 level of significance to detect an absolute 30% 
difference between each vonoprazan dose and esomeprazole, assuming a response rate of 33% for 
esomeprazole. The sample size was calculated using the Fisher’s exact test in EAST version 6.0.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). 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. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol. 
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will {ship drug/notify site once} the sponsor 
has confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor 
has received permission from competent authority to begin the trial. Until the site receives 
[drug/notification] no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During 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, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.


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15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for America’s investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or 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
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inhibitors based on the patient's CYP2C19 genotype an effective management strategy? 
Internal Medicine, 54(2), 97-105. doi: 10.2169/internalmedicine.54.3412. Epub 2015 Jan 15
35. Zigmond AS, Snaith RP.The hospital anxiety and depression scale. Acta Psychiatr Scand,
1983;Jun: 67(6),361-370.


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36. Lundell LR1, Dent J, Bennett JR, Blum AL, Armstrong D, Galmiche JP, et al. Endoscopic 
assessment of oesophagitis: clinical and functional correlates and further validation of the Los 
Angeles classification. See comment in PubMed Commons below. Gut.
1999;Aug;45(2):172-80.
37. A Phase 3, Randomized, double-blind, placebo control, multicenter study to evaluate the 
efficacy and safety of TAK-438 (10 and 20 mg once-daily) in patients with non-erosive 
gastroesophageal reflux disease. CCT-20 data on file.


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Appendix A
Schedule of Study Procedures
Run-In Period
Treatment Period
Visit:
Screen Visit
PPI
Run-In Period
4 weeks
Placebo Run-In
Period
2 weeks (a)
Randomization
Week 2
Week 4
End of Treatment Visit 
or Early Termination 
Visit (b)
Safety Follow-
up (c)
Week 5
PPI assessment
Off-PPI 
assessment
Visit Number:
1
2
3
4
5
6
7
Day:
Max Day -49 
Day -42
Day -14
Day 1
Day 14
Day 28
Day 35
Visit Windows:
-
± 3 days
± 3 days
0
3 days
3 days
3 days
Informed consent
X
Inclusion/exclusion criteria
X
X
X
X
Demographics, medical history, smoking 
status, alcohol and caffeine consumption and 
medication history
X
Physical examination 
X
X
X
Vital signs, height and weight (d)
X
X
X
Clinical laboratory tests and urinalysis(e)
X (e)
X (e)
X 
X (e)
Fasting serum gastrin, Pepsinogen I/II(f)
X
X
X
Mandatory Pgx sample for genotyping (g)
X
Optional Pgx sample for storage (h)
X
PK sampling (i)
X
X
12-lead ECG
X
X
X
Pregnancy test (j) – Serum/Urine
X
X
X
Endoscopy (k)
X
H. pylori breath test (l)
X
Dispense e-Diary/Review compliance (m)
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
AE/PTE assessment
X
X
X
X
X
X
X
Contact IWRS
X
X
X
X
X
X
Dispense PPI Run-in medication
X
Dispense Single blind Placebo Run-in
X
Dispense Double blind study medication
X (n)
X
Drug accountability
X
X
X
X


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Appendix A
Schedule of Study Procedures (continued)
Run-In Period
Treatment Period
Visit:
Screen Visit
PPI
Run-In Period
4 weeks
Placebo Run-In
Period
2 weeks (a)
Randomization
Week 2
Week 4
End of Treatment Visit 
or Early Termination 
Visit (b)
Safety Follow-
up (c)
Week 5
PPI assessment
Off-PPI 
assessment
Visit Number:
1
2
3
4
5
6
7
Day:
Max Day -49 
Day -42
Day -14
Day 1
Day 14
Day 28
Day 35
Visit Windows:
-
± 3 days
± 3 days
0
3 days
3 days
3 days
Dispense rescue (antacid) medication
X
X
X
Accountability of rescue medication (o)
X
X
X
Questionnaires(p): PSQI/ HADS/ PGIC(q)/ 
EQ-5D-5L/ PAGI-QOL/ PAGI-SYM
X
X
X
X
Footnotes are on the following page.


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(a) All subjects will receive esomeprazole 40 mg QD during the PPI Run-in period to assess their response to a high dose of PPI. The subject must have a partial response to a PPI 
defined as having heartburn on 2-5 days of the last week of a 4 week PPI Run-In Period with esomeprazole 40 mg and an increase of at least 2 symptom days of heartburn (and/or 
regurgitation) in the last week of a 2 week Off-PPI Assessment Period (4-7 symptom days) compared with the last week of the esomeprazole Treatment Period. Total screening 
including run-in period is max 49 days.
(b) Subjects who prematurely discontinue from the Treatment Period should undergo early termination Visit procedures. 
(c) The subjects will be contacted for a safety follow up call approximately 1 week after last dose of study drug. Subjects who withdraw their consent should still be contacted for a 
Safety Follow-up but the contact should only be recorded in the medical records (and not in the eCRF), according to data protection regulations. 
(d) Vital signs include body temperature. Vital sign, weight and height at Screening, vital signs and weight at Randomization and Visit 6(or early termination).
(e) Standard iron panel to be collected only at Visit 1 and Visit 6(or early termination). TSH and CRP samples to be collected at Visit 4 and Visit 6(or early termination).Urine drug 
screening and hepatitis test only at Visit 1.
(f) Subjects should be fasting for a minimum of 12 hours prior to the collection at Randomization, Visit 5 (Week 2) and Visit 6 (Week 4) or early termination. At the visits, subjects 
should be instructed to take their dose of study medication on the morning of their visit with a sip of water. Actual value of serum gastrin and serum pepsinogen I and II will be 
reported to investigators at Visit 4. In order to maintain blinding of study treatment, investigators will be blinded to serum gastrin and serum pepsinogen I and II values at Visit 5 and 
Visit 6. After the study ends, the level of serum gastrin and pepsinogen I and II at Visit 5 and Visit 6 may be provided to investigators.
(g) One 6 mL whole blood sample for DNA CYP2C19 genotyping collected at visit 4 prior to the dose administration (mandatory).
(h) Two whole blood samples (2.5 mL per sample) for ribonucleic acid (RNA) isolation to be collected at visit 4 prior to the dose administration (optional).
(i) For group 1 (a minimum of 15 subjects per treatment arm), plasma samples will be taken at time points 0 (predose) and 1 hour postdose at Visit 5 and 0 (predose), 0.5, 2, 5, 6, and 
8 hours postdose at Visit 6. For group 2 (the remaining subjects in each treatment arm), plasma samples will be taken at predose and at 1 hour postdose at Visit 5 and Visit 6.
(j) Pregnancy test is only performed for women of child-bearing potential. In this group of women, the serum pregnancy testing must be done at Screening and at Week 4 (or early 
termination). A urine pregnancy test will be performed at Randomization.
(k) Endoscopy – For assessment of EE status and to exclude esophageal and gastric malignancies. Historical data up to one year prior to Screening is permitted. Only NERD or 
Grade A EE subjects are permitted to continue in the study.
(l) Helicobacter pylori breath test will be performed via a urea breath test (C13 or C14 urea test) at a local laboratory. A stool test may be performed at those centers which do not 
have the facilities to perform a H pylori breath test procedure.
(m) Subjects will complete the e-Diary during the Screening Period for at least 42 days prior to randomization and during the 4-week Treatment Period. Subjects should complete the 
diary every morning (for nighttime symptoms) and every evening (for daytime symptoms) on each day of the study. Instruct the subject to continue to complete the diary every 
morning upon waking and evening before bedtime.
(n) Study drug will be dispensed at randomization visit (Day 1) after the subject has completed all of the Screening Period procedures and subject has met all inclusion/exclusion 
criteria for the study including the baseline PPI insufficient responder criteria. Following randomization, the first dose of study medication will be administered at the clinic and be 
continued on a daily basis for 4 weeks. A 2 weeks supply of randomized treatment will be given at Visits 4 and Visit 5.
(o) Rescue medication will be dispensed at Screening and may be dispensed at Study Day 1, Week 2 and Week 4 if needed. Subjects should not take more doses than stipulated in the 
patient information leaflet.
(p) Questionnaires will be completed electronically on e-diary device by the subject prior to dosing and questionnaires completeness should be check prior to the subject leaving the 
site.
(q) PGIC questionnaire will be completed only at Visit 3, Visit 4 and Visit 6.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations.
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
(e)CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied
drugs, and return all unused sponsor-supplied drugs to the sponsor.


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12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that is experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.


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19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and


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e) that the subject’s identity will remain confidential in the event that study results are 
published.
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening throughout the duration of the study. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study medication will be discontinued and the investigator 
will offer the subject the choice to receive unblinded treatment information.
26. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix E
Collection, Shipment, and Storage of Pharmacogenomic Samples 
Sample Collection
1. Mandatory Collection for CYP2C19 Genotyping: 
One 6 mL whole blood sample for DNA isolation and genotyping will be collected from each 
subject at Visit 4 after randomization and prior to dosing, into a plastic tube spray coated with 
K2 ethylenediamine-tetraacetic acid (EDTA).
2. Optional Collection for storage of the sample for future use:
Two whole blood samples (2.5 mL per sample) for RNA isolation will be collected at Visit 4 
prior to dose administration from each subject in the study, into a PaxGene TM tube. 
Sample Shipment
1. CYP2C19 DNA samples will be shipped ambient after collection and RNA pharmacogenomic 
samples will be shipped frozen at -20°C after collection.
2. The laboratory must confirm arrival of the shipped samples. Store CYP2C19 samples at 
ambient and optional RNA samples at -20°C or colder at the site prior to shipping.
3. For instructions on shipping, both ambient and frozen, and packing follow the laboratory
manual and shipping instructions provided by the central laboratory.
4. Before shipping, ensure the sample tubes are tightly sealed. Ship samples to the Central 
Laboratory Services. Shipping information can be found in the lab manual.
Sample Storage
 will initially store the DNA and RNA samples in a secure storage space with 
adequate measures to protect confidentiality. The samples that have consent for storage and future 
use will be retained at the designated laboratory for up to but not longer than 15 years or as 
required by applicable law.
CCI


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Appendix F
Collection, Shipment and Storage of Pharmacokinetic Samples
Vonoprazan and/or Esomeprazole (if required) Sample Collection and Processing
1. Using sample collection kits provided by the Central Laboratory, collect 6 mL of venous blood 
into a chilled Becton-Dickinson Vacutainer®. For all Vonoprazan or esomeprazole samples, 
blood samples should be collected into chilled vacutainers containing sodium heparin.
2. Gently invert the Vacutainer several times to mix the additive with the collected blood prior to 
centrifugation and place immediately on ice or stored at room temperature.
3. Centrifuge the Vacutainers for 10 minutes at approximately 1100 to 1300 (RCF) at room 
temperature or approximately 4°C in a refrigerated centrifuge. If using a collection device 
other than Becton-Dickinson, refer to manufacturer’s instruction for proper centrifugation 
force and time.
4. Immediately following centrifugation, gently remove plasma from the packed cells. To ensure 
a more homogeneous sample, all plasma should first be transferred into 1 aliquot. From there, 
split the plasma evenly between the 2 aliquots. A minimum of 1.0 mL needs to be obtained for 
each sample. Labeling will include protocol number, matrix (ie, plasma), analyte (vonoprazan 
or esomeprazole), subject number, visit number, accession number, PK blood draw 
[ie, Predose PK 1, Predose PK 2, PK (0.5-1 hr) Post, or PK(2-5 hr) Post] and either “SET 1” 
(for original sample) or “SET 2” (for duplicate sample). Refer to Central Laboratory 
Instruction manual for detailed sample collection, processing, packaging & shipping 
guidelines.
5. Cap the labeled storage tubes and freeze the plasma samples immediately at approximately 
-20°C or lower. No more than 60 minutes will elapse between blood collection and freezing the 
plasma sample.
6. Keep samples frozen at approximately -20°C or lower until shipment to Central laboratory. 
SET 1 samples will be shipped first on dry ice, followed by shipment of duplicate SET 2 
samples after SET 1 samples have been received by the Central laboratory.
Sample Handling and Shipping
1. Biological samples (ie, plasma) should be shipped on dry ice to prevent thawing during transit. 
Ship samples only on Monday, Tuesday or Wednesday, and at least 2 days prior to a national 
holiday, to minimize the possibility of samples in transit over a weekend or holiday. If 
duplicate samples are to be shipped, send SET 1 samples and await confirmation of arrival 
before shipping the duplicate SET 2 samples. Before shipping, make sure the sample tubes are 
tightly sealed. Separate each subject’s samples as follows:
2. Separate the duplicate SET 2 samples from the SET 1 samples.
3. Follow Central Laboratory Manual for shipping samples.


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Appendix G
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 02.
Section 2.0 Study Summary, Page 11
Existing text
Study Design:Vonoprazan-2001 is a Phase 2 proof-of-concept (POC) study to compare 
vonoprazan 20 mg or 40 mg once daily (QD) with esomeprazole 40 mg QD in subjects who have a 
history of persistent heartburn and/or regurgitation symptoms that are troublesome despite an 
adequate course of proton pump inhibitor (PPI) treatment and who are then confirmed to have a 
partial response to a 4-week treatment course with esomeprazole 40 mg QD.
(……………….)
Subject Population: Subjects aged 18 years or older who have a documented history of symptoms 
of both heartburn and acid regurgitation prior to entry into the study and of not responding fully to 
their PPI treatment (at least 8 weeks of persistent heartburn and/or regurgitation symptoms that are 
troublesome after treatment at the standard doses of PPI).
(……………….)
Main Criteria for Inclusion: Subjects will be eligible for participation in the study if they; have a 
documented history of symptoms of both heartburn and acid regurgitation prior to entry into the 
study; have a history of persistent heartburn and/or regurgitation symptoms that are troublesome 
despite an adequate course of PPI treatment; continue to have symptoms of heartburn (and 
regurgitation) following 4 weeks treatment with a high dose of esomeprazole 40 mg QD during the 
Run-in Period; have symptoms of heartburn which increases following a 2-week Washout Period 
in the presence of regurgitation prior to randomization. Patients with mild (LA grade A) 
esophagitis are permitted to enter the study.
Revised text
Study Design: Vonoprazan-2001 is a Phase 2 proof-of-concept (POC) study to compare 
vonoprazan 20 mg or 40 mg once daily (QD) with esomeprazole 40 mg QD in subjects who have a 
history of predominant heartburn symptoms in the presence of regurgitation that are 
troublesome despite an adequate course of proton pump inhibitor (PPI) treatment and who are then 
confirmed to have a partial response to a 4-week treatment course with esomeprazole 40 mg QD.
(……………….)
Subject Population: Subjects aged 18 years or older who have a documented history of symptoms 
of both heartburn and acid regurgitation prior to entry into the study and of not responding fully to 
their PPI treatment (at least 8 weeks of predominant heartburn symptoms in the presence of 
regurgitation that are troublesome after treatment at the standard doses of PPI).


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(……………….)
Main Criteria for Inclusion: Subjects will be eligible for participation in the study if they; have a 
documented history of symptoms of both heartburn and acid regurgitation prior to entry into the 
study; have a history of predominant heartburn symptoms in the presence of regurgitation
that are troublesome despite an adequate course of PPI treatment; continue to have symptoms of 
heartburn (and regurgitation) following 4 weeks treatment with a high dose of esomeprazole 40 
mg QD during the Run-in Period; have symptoms of heartburn which increases following a 
2-week Washout Period in the presence of regurgitation prior to randomization. Patients with mild 
(LA grade A) esophagitis are permitted to enter the study.
Rationale for Amendment
Updated to reflect the change of inclusion criteria No 5. The inclusion criteria has been clarified to 
include patients who have predominant heartburn symptoms in the presence of regurgitation.
Section 4.1 Background, Paragraph 7, Page 18
Existing Text
Vonoprazan-2001 is a Phase 2 proof-of-concept (POC) study comparing vonoprazan with 
esomeprazole in subjects who have a history of persistent heartburn and/or regurgitation GERD 
symptoms despite an adequate course of PPI treatment and who are then confirmed to have a 
partial response to a 4-week treatment course with esomeprazole 40 mg QD[16,17]. As 
vonoprazan is a strong gastric acid inhibitor, it is considered that esomeprazole 40 mg, which is 
commonly used in patients not responding to their initial dose of PPI, is an appropriate comparator 
for this indication.
Revised Text
Vonoprazan-2001 is a Phase 2 proof-of-concept (POC) study comparing vonoprazan with 
esomeprazole in subjects who have a history of persistent heartburn and regurgitation GERD 
symptoms despite an adequate course of PPI treatment and who are then confirmed to have a 
partial response to a 4-week treatment course with esomeprazole 40 mg QD[16,17]. As 
vonoprazan is a strong gastric acid inhibitor, it is considered that esomeprazole 40 mg, which is 
commonly used in patients not responding to their initial dose of PPI, is an appropriate comparator 
for this indication.
Rationale for Amendment
Updated to reflect the change of inclusion criteria No 5. The inclusion criteria has been clarified to 
include patients who have predominant heartburn symptoms in the presence of regurgitation.


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Section 5.2.3 Additional Endpoints, Page 22
Existing Text
None
Revised Text

Percentage of responders, where a responder is defined as having at least 3 more days of 
not more than mild heartburn symptoms on average per week during the whole double 
blind treatment period compared to baseline, where baseline is defined as the 1 week 
run-in period on placebo prior to randomization.
Rationale for Amendment
The additional analysis is being included as this was one of the primary endpoints derived from 
RESQ-eD data in a previous study which enrolled GERD Patients with partial response to PPI 
(NCT01005251). This analysis has been included as it includes components of both reduction in 
the number as well as severity of symptoms.
Section 6.1 Study Design, Paragraph 2, Page 25
Existing Text
Subjects will be eligible for participation in the study if they: have a documented history of 
symptoms of both heartburn and acid regurgitation prior to entry into the study; have a history of 
persistent heartburn and/or regurgitation symptoms that are troublesome despite an adequate 
course of PPI treatment; continue to have symptoms of heartburn (and/or regurgitation) following 
4 weeks treatment with a high dose of esomeprazole 40 mg QD during the Run-in Period; have 
symptoms of heartburn which increases following a 2-week Washout Period in the presence of 
regurgitation prior to randomization; and meet all of the inclusion criteria and none of the 
exclusion criteria. Patients with mild (LA grade A) esophagitis are also permitted to enter the 
study. To confirm LA grade, endoscopy will be performed at screening, or historical data of 
endoscopy up to one year prior to screening may be permitted. The study will consist of 3 periods: 
a 7-week Run-in period (initial 1 week screening period and a 6-week single-blind Run-in), a 
4-week double blind Treatment Period, and a 1-week Safety Follow-up. The Run-in includes a 
1-week general Screening Period during which the subject will remain on their prescribed PPI 
(Day-49 to Day -42); followed by a 4-week single-blind PPI assessment period with blinded 
esomeprazole 40 mg QD (Day -42 to Day -14); and then a 2-week single-blind placebo Off-PPI 
Assessment period (Day -14 to Day-1). Subjects who remain symptomatic and compliant will be 
randomized to the 4-week Treatment Period followed by a one week safety Follow-up Call. 
Certain medications will require washout prior to entry into the study and will not be permitted 
during the study as outlined in Table 7.a.
Revised Text
Subjects will be eligible for participation in the study if they: have a documented history of 
symptoms of both heartburn and acid regurgitation prior to entry into the study; have a history of 


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Study No. Vonoprazan-2001 
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CONFIDENTIAL
predominant heartburn symptoms in the presence of regurgitation that are troublesome 
despite an adequate course of PPI treatment; continue to have symptoms of heartburn and
regurgitation following 4 weeks treatment with a high dose of esomeprazole 40 mg QD during the 
Run-in Period; have symptoms of heartburn which increases following a 2-week Washout Period 
in the presence of regurgitation prior to randomization; and meet all of the inclusion criteria and 
none of the exclusion criteria. Patients with mild (LA grade A) esophagitis are also permitted to 
enter the study. To confirm LA grade, endoscopy will be performed at screening, or historical data 
of endoscopy up to one year prior to screening may be permitted. The study will consist of 3 
periods: a 7-week Run-in period (initial 1 week screening period and a 6-week single-blind 
Run-in), a 4-week double blind Treatment Period, and a 1-week Safety Follow-up. The Run-in 
includes a 1-week general Screening Period during which the subject will remain on their 
prescribed PPI (Day-49 to Day -42); followed by a 4-week single-blind PPI assessment period 
with blinded esomeprazole 40 mg QD (Day -42 to Day -14); and then a 2-week single-blind 
placebo Off-PPI Assessment period (Day -14 to Day-1). Subjects who remain symptomatic and 
compliant will be randomized to the 4-week Treatment Period followed by a one week safety 
Follow-up Call. Certain medications will require washout prior to entry into the study and will not 
be permitted during the study as outlined in Table 7.a.
Rationale for Amendment
Updated to reflect the change of inclusion criteria No 5. The inclusion criteria has been clarified to 
include patients who have predominant heartburn symptoms in the presence of regurgitation.
Section 6.2 Justification for Study Design, Dose, and Endpoints, Paragraph 2, Page 27
Existing Text
This study aims to recruit subjects who have a documented history of symptoms of both heartburn 
and acid regurgitation prior to entry into the study and of not responding fully to their PPI 
treatment (at least 8 weeks of persistent heartburn and/or regurgitations symptoms that are 
troublesome after treatment at the standard doses of PPI) and who have a partial response to 
treatment with a high dose of esomeprazole 40 mg QD (defined as having heartburn on 2 to 5 days 
and regurgitation on at least one day of the last week [Week 4] of a 4 week Run-in with 
esomeprazole 40 mg). To further confirm that their heartburn is acid-related, subjects also have to 
have an increase of at least 2 symptom days of heartburn) in the last week of a 2-week Off-PPI 
Assessment Period (4 to 7 symptom days) and at least one symptom day with regurgitation 
compared with the last week of the PPI Assessment Period. Having the Washout after PPI 
treatment will result in a higher pre-randomization baseline heartburn frequency allowing the 
effects of both treatments as well as the treatment difference to be estimated. Symptomatic patients 
with mild EE (LA Grade A) will be permitted to enter the study as the presence of EE is a good 
indicator of the patient suffering from an acid-related problem and the study treatments are being 
used at doses which have been shown to effectively treat EE. Two doses of vonoprazan (20 mg and 
40 mg) have been selected for this study. Vonoprazan 20 mg has been included, as this is the 
clinical dose recommended in Japan for the treatment of EE. Experience with PPIs indicate that for 


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Study No. Vonoprazan-2001 
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CONFIDENTIAL
patients with a partial response to approved once daily therapy, tailored therapy is often given 
off-label with adjustment of dose, dose timing and/or twice daily dosing [20]. Therefore, 
vonoprazan 20 mg may be expected to be a minimally effective clinical dose in this difficult to 
treat population. As such, a higher dose of vonoprazan 40 mg has also been selected as a 
potentially appropriate dose for this population of patients. Using vonoprazan 20 mg and 40 mg 
therefore allows for a comparison of dose effect and to select the appropriate dose of vonoprazan
to take forward in to Phase 3. Esomeprazole is considered as the current gold standard PPI for the 
treatment of GERD and 40 mg is the most appropriate dose for this difficult to treat population.
Revised Text
This study aims to recruit subjects who have a documented history of symptoms of both heartburn 
and acid regurgitation prior to entry into the study and of not responding fully to their PPI 
treatment (at least 8 weeks of predominant heartburn symptoms in the presence of 
regurgitation that are troublesome after treatment at the standard doses of PPI) and who have a 
partial response to treatment with a high dose of esomeprazole 40 mg QD (defined as having 
heartburn on 2 to 5 days and regurgitation on at least one day of the last week [Week 4] of a 4 week 
Run-in with esomeprazole 40 mg). To further confirm that their heartburn is acid-related, subjects 
also have to have an increase of at least 2 symptom days of heartburn) in the last week of a 2-week 
Off-PPI Assessment Period (4 to 7 symptom days) and at least one symptom day with 
regurgitation compared with the last week of the PPI Assessment Period. Having the Washout 
after PPI treatment will result in a higher pre-randomization baseline heartburn frequency 
allowing the effects of both treatments as well as the treatment difference to be estimated. 
Symptomatic patients with mild EE (LA Grade A) will be permitted to enter the study as the 
presence of EE is a good indicator of the patient suffering from an acid-related problem and the 
study treatments are being used at doses which have been shown to effectively treat EE. Two doses 
of vonoprazan (20 mg and 40 mg) have been selected for this study. Vonoprazan 20 mg has been 
included, as this is the clinical dose recommended in Japan for the treatment of EE. Experience 
with PPIs indicate that for patients with a partial response to approved once daily therapy, tailored 
therapy is often given off-label with adjustment of dose, dose timing and/or twice daily dosing
[20]. Therefore, vonoprazan 20 mg may be expected to be a minimally effective clinical dose in 
this difficult to treat population. As such, a higher dose of vonoprazan 40 mg has also been 
selected as a potentially appropriate dose for this population of patients. Using vonoprazan 20 mg 
and 40 mg therefore allows for a comparison of dose effect and to select the appropriate dose of 
vonoprazan to take forward in to Phase 3. Esomeprazole is considered as the current gold standard 
PPI for the treatment of GERD and 40 mg is the most appropriate dose for this difficult to treat 
population.


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Study No. Vonoprazan-2001 
Page 96 of 102
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29 March 2016
CONFIDENTIAL
Rationale for Amendment
Updated to reflect the change of inclusion criteria No 5. The inclusion criteria has been clarified to 
include patients who have predominant heartburn symptoms in the presence of regurgitation.
Section 7.1 Inclusion Criteria, Page 30
Existing Text
5. The subject has a medical history of ≥8 weeks of persistent heartburn and/or regurgitation
symptoms (persistent heartburn and/or regurgitation symptoms defined as symptoms on ≥2 
days a week) that are troublesome despite appropriate and correctly performed treatment with 
a PPI at standard doses.
Revised Text
5. The subject has a medical history of ≥8 weeks of persistent heartburn symptoms in the 
presence of regurgitation symptoms (persistent heartburn symptoms defined as heartburn
symptoms on ≥2 days a week) that are troublesome despite appropriate and correctly 
performed treatment with a PPI at standard doses.
Rationale for Amendment
The inclusion criteria has been clarified to include patients who have predominant heartburn 
symptoms in the presence of regurgitation. This confirms the patient has GERD and also has the 
appropriate symptoms to perform the required proposed data analysis.
Section 8.1.1.2 Rescue Medication, Page 37
Existing Text
A guideline of commonly used medications which may be used as rescue medications in each of
the countries will be provided. If the listed rescue medications in the guideline are not available, 
CRO/Takeda medical monitor may provide guidance of available brand to investigators. The 
administration of rescue medication shall be in accordance to the package insert approved in the 
corresponding countries. When rescue medication is administered, subjects should be instructed to 
take rescue medication only after consultation with the investigator. For aluminum based 
medications, an interval of at least 2 hours must be maintained between administration of study 
medication (Vonoprazan or esomeprazole) and rescue medication. Subjects shall contact the 
investigators if they would like to take the rescue medication at a dose higher than the approved 
ones in the local insert package.
Revised Text
A guideline of commonly used medications which may be used as rescue medications in each of
the countries will be provided. If the listed rescue medications in the guideline are not available, 
CRO/Takeda medical monitor may provide guidance of available brand to investigators. The 
administration of rescue medication shall be in accordance to the package insert approved in the 


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Study No. Vonoprazan-2001 
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29 March 2016
CONFIDENTIAL
corresponding countries. For aluminum based medications, an interval of at least 2 hours must be 
maintained between administration of study medication (Vonoprazan or esomeprazole) and rescue 
medication. Subjects shall contact the investigators if they would like to take the rescue medication 
at a dose higher than the approved ones in the local insert package.
Rationale for Amendment
Removal of the instruction for subjects to contact the investigators when rescue medication is 
administered as this is not practical.
Section 9.1.6.2 Subject Reported Outcome Questionnaires, Quality of Sleep, Page 45
Existing Text
Quality of sleep will be assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire
[23]. The PSQI questionnaire is a 19-item validated questionnaire completed by patients regarding 
the previous 1-month period. Items are grouped into seven component scores: subjective sleep 
quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping 
medication, and daytime dysfunction. Each component score is weighted equally on a 0–3 scale, 
with 3 representing the worse effect, then summed to yield a global PSQI score, which could range 
from 0 to 21. Patients with a global score >5 are considered to have poor sleep quality. Patients will 
complete the questionnaire at the Visit 4 and Visit 6 (or early termination).
Revised Text
Quality of sleep will be assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire
[23]. The PSQI questionnaire is a 19-item validated questionnaire completed by patients regarding 
the previous 1-month period. Items are grouped into seven component scores: subjective sleep 
quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping 
medication, and daytime dysfunction. Each component score is weighted equally on a 0–3 scale, 
with 3 representing the worse effect, then summed to yield a global PSQI score, which could range 
from 0 to 21. Patients with a global score >5 are considered to have poor sleep quality. Patients will 
complete the questionnaire at the Visit 2, Visit 3, Visit 4 and Visit 6 (or early termination).
Rationale for Amendment
Correction of inconsistencies with appendix A. schedule of study procedures.
Section 9.1.6.2 Subject Reported Outcome Questionnaires, Patient Global Impression of 
Change, Page 45
Existing Text
The Patient Global Impression of Change (PGIC) is a patient-rated instrument that measures 
change in patient’s GERD-related symptoms on a 7-point scale ranging from 1 (very much 
improved) to 7 (very much worse) [31]. Higher scores indicate a change for the worse. For this 
study, subjects will be asked to rate their symptoms relative to their previous past 4-weeks or 
2-weeks. The PGIC item will be assessed at visit 2, visit 3, visit 4 and visit 6 (Early termination).


TAK-438 
Study No. Vonoprazan-2001 
Page 98 of 102
Protocol Incorporating Amendment No. 02
29 March 2016
CONFIDENTIAL
The PGIC will be used to further document the ability RESQ-eD to detect change as well as 
clinical meaningfulness of change. 
Revised Text
The Patient Global Impression of Change (PGIC) is a patient-rated instrument that measures 
change in patient’s GERD-related symptoms on a 7-point scale ranging from 1 (very much 
improved) to 7 (very much worse) [31]. Higher scores indicate a change for the worse. For this 
study, subjects will be asked to rate their symptoms relative to their previous past 4-weeks or 
2-weeks. The PGIC item will be assessed at visit 3, visit 4 and visit 6 (Early termination). The 
PGIC will be used to further document the ability RESQ-eD to detect change as well as clinical 
meaningfulness of change.
Rationale for Amendment
Correction of schedule of PGIC assessment due to an error of the original protocol.
Section 9.1.9 Procedures for Clinical Laboratory Samples, Table 9.b, Page 47
Existing Text
Urinalysis
Bilirubin
Glucose
Hemoglobin
Ketones
Leucocytes
Nitrites
pH
Protein
Specific gravity
Urobilinogen
Revised Text
Urinalysis
Appearance
Color
Bilirubin
Glucose
Hemoglobin
Ketones
Leucocytes
Nitrites
pH
Protein
Specific gravity
Urobilinogen
Rationale for Amendment
Missing of urine appearance and color from the original protocol. 


TAK-438 
Study No. Vonoprazan-2001 
Page 99 of 102
Protocol Incorporating Amendment No. 02
29 March 2016
CONFIDENTIAL
Section 9.1.9 Procedures for Clinical Laboratory Samples, Paragraph 5, Page 48
Existing Text
 
Revised Text
Rationale for Amendment
Section 9.1.10 Contraception and Pregnancy Avoidance Procedure, Paragraph 4, Page 49
Existing Text
Barrier methods (each time the subject has 
intercourse):
Intrauterine devices (IUDs):
!
Cap (plus spermicidal cream or jelly) PLUS 
male condom and spermicide.
!
Diaphragm (plus spermicidal cream or jelly) 
PLUS male condom and spermicide.
!
Copper T.
Revised Text
Barrier methods (each time the subject has 
intercourse):
Intrauterine devices (IUDs):
!
Cap (plus spermicidal cream or jelly) PLUS 
male condom.
!
Diaphragm (plus spermicidal cream or jelly) 
PLUS male condom.
!
Copper T.
Rationale for Amendment
Duplication of spermicide is not required.
CCI
CCI
CCI


TAK-438 
Study No. Vonoprazan-2001 
Page 100 of 102
Protocol Incorporating Amendment No. 02
29 March 2016
CONFIDENTIAL
Section 9.3 Schedule of observations and Procedures, Page 55
Existing Text
The schedule for all study-related procedures for all evaluations is shown in Appendix A.
Assessments should be completed at the designated visit/time point(s).
Visit windows should be calculated from the day of randomization. Visit windows are listed in 
Appendix A. 
Revised Text
The schedule for all study-related procedures for all evaluations is shown in Appendix A.
Assessments should be completed at the designated visit/time point(s).
Visit windows should be calculated from the day of randomization. Visit windows are listed in 
Appendix A. Unscheduled non-study visits can be held, if in the opinion of the investigator a 
closer follow-up regime is required for the subject.
Rationale for Amendment
Clarification of unscheduled non-study visits which may be held, if  necessary.
Section Appendix A Schedule of Study Procedures, Page 81
Existing Text
Visit:
Screen Visit
PPI
Run-In Period
4 weeks
Placebo Run-In Period
2 weeks (a)
PPI assessment
Off-PPI assessment
Visit Number:
1
2
3
Day:
Max Day -49 
Day -42
Day -14
Visit Windows:
-
± 3 days
± 3 days
Questionnaires(p): PSQI/ HADS/ PGIC/ EQ-5D-5L/ 
PAGI-QOL/ PAGI-SYM
X
X
(a) All subjects will receive esomeprazole 40 mg QD during the PPI Run-in period to assess their response to a high dose of PPI. 
The subject must have a partial response to a PPI defined as having heartburn on 2-5 days of the last week of a 4 week PPI Run-In 
Period with esomeprazole 40 mg and an increase of at least 2 symptom days of heartburn (and/or regurgitation) in the last week of 
a 2 week Off-PPI Assessment Period (4-7 symptom days) compared with the last week of the esomeprazole Treatment Period.
(…………..)
(f) Subjects should be fasting for a minimum of 12 hours prior to the collection at Randomization, Visit 5 (Week 2) and Visit 6
(Week 4) or early termination. At the visits, subjects should be instructed to take their dose of study medication on the morning of 
their visit with a sip of water.
(…………..)
(p) Questionnaires should be completed by the subject prior to dosing and questionnaires completeness should be check prior to the
subject leaving the site.


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Study No. Vonoprazan-2001 
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29 March 2016
CONFIDENTIAL
Revised Text
Visit:
Screen Visit
PPI
Run-In Period
4 weeks
Placebo Run-In Period
2 weeks (a)
PPI assessment
Off-PPI assessment
Visit Number:
1
2
3
Day:
Max Day -49 
Day -42
Day -14
Visit Windows:
-
± 3 days
± 3 days
Questionnaires(p): PSQI/ HADS/ PGIC(q)/ EQ-5D-5L/ 
PAGI-QOL/ PAGI-SYM
X
X
(a) All subjects will receive esomeprazole 40 mg QD during the PPI Run-in period to assess their response to a high dose of PPI. 
The subject must have a partial response to a PPI defined as having heartburn on 2-5 days of the last week of a 4 week PPI Run-In 
Period with esomeprazole 40 mg and an increase of at least 2 symptom days of heartburn (and/or regurgitation) in the last week of 
a 2 week Off-PPI Assessment Period (4-7 symptom days) compared with the last week of the esomeprazole Treatment Period.
Total screening including run-in period is max 49 days.
(…………..)
(f) Subjects should be fasting for a minimum of 12 hours prior to the collection at Randomization, Visit 5 (Week 2) and Visit 6
(Week 4) or early termination. At the visits, subjects should be instructed to take their dose of study medication on the morning of 
their visit with a sip of water. Actual value of serum gastrin and serum pepsinogen I and II will be reported to investigators at 
Visit 4. In order to maintain blinding of study treatment, investigators will be blinded to serum gastrin and serum 
pepsinogen I and II values at Visit 5 and Visit 6. After the study ends, the level of serum gastrin and pepsinogen I and II at 
Visit 5 and Visit 6 may be provided to investigators.
(…………..)
(p) Questionnaires will be completed electronically on e-diary device by the subject prior to dosing and questionnaires 
completeness should be check prior to the subject leaving the site.
(q) PGIC questionnaire will be completed only at Visit 3, Visit 4 and Visit 6.
Rationale for Amendment
Clarification of total screening period including PPI/Placebo run-in. Clarification of completion of 
questionnaires electronically. Correction of schedule of PGIC assessment due to error of the 
original protocol.
Section Appendix E Collection, Shipment, and Storage of Pharmacogenomic Samples, 
Page 89
Existing Text
Sample Shipment
1. DNA and RNA pharmacogenomic samples will be shipped frozen at -20°C after collection.
2. Ship samples only on Monday, Tuesday, or Wednesday, and at least 2 days prior to a 
national holiday, to minimize the possibility of samples in transit over a weekend or 
holiday. 
3. The laboratory must confirm arrival of the shipped samples. Storage at the site prior to 
shipping must be at -20°C or colder.


TAK-438 
Study No. Vonoprazan-2001 
Page 102 of 102
Protocol Incorporating Amendment No. 02
29 March 2016
CONFIDENTIAL
6. For instructions on shipping, both ambient and refrigerated, and packing follow the 
laboratory manual and shipping instructions provided by the central laboratory.
7. Before shipping, ensure the sample tubes are tightly sealed. Ship samples to the Central 
Laboratory Services. Shipping information can be found in the pharmacogenomic lab 
manual.
Revised Text
Sample Shipment
1. CYP2C19 DNA samples will be shipped ambient after collection and RNA 
pharmacogenomic samples will be shipped frozen at -20°C after collection.
2. The laboratory must confirm arrival of the shipped samples. Store CYP2C19 samples at 
ambient and optional RNA samples at -20°C or colder at the site prior to shipping .
3. For instructions on shipping, both ambient and frozen, and packing follow the laboratory
manual and shipping instructions provided by the central laboratory.
4. Before shipping, ensure the sample tubes are tightly sealed. Ship samples to the Central 
Laboratory Services. Shipping information can be found in the pharmacogenomic lab 
manual.
Rationale for Amendment
Correction of sample storage and shipping condition of CYP2C19 DNA samples.


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SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, Double-Blind, Proof-of-Concept, Phase 2 Study to Evaluate the Efficacy and 
Safety of Once Daily Oral Vonoprazan 20 mg or Vonoprazan 40 mg Compared to Esomeprazole 40 
mg for the Treatment of Subjects With Symptomatic Gastro-Esophageal Reflux Disease Who have a 
Partial Response Following Treatment with a High Dose of Proton Pump Inhibitor
NCT Number: NCT02743949
SAP Approve Date:  15 January 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information or 
company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


CROSS-REGIONAL TEMPLATE
Template Number:
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Page:
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Version Number:
1.2
Effective Date:
14 Sep 2015
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C-SOP-DO-800
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Printed or downloaded documents must be verified against the effective version.
CONFIDENTIAL INFORMATION
Do not distribute outside of Takeda without a confidentiality agreement.
TAKEDA DEVELOPMENT CENTER
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: VONOPRAZAN-2001
A Randomized, Double-Blind, Proof-of-Concept, Phase 2 Study to Evaluate the Efficacy
and Safety of Once Daily Oral Vonoprazan 20 mg or Vonoprazan 40 mg Compared to
Esomeprazole 40 mg for the Treatment of Subjects With Symptomatic
Gastro-Esophageal Reflux Disease Who have a Partial Response Following Treatment
with a High Dose of Proton Pump Inhibitor
PHASE 2
Version: 1
Date: 15 January 2019
Prepared by:
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


CROSS-REGIONAL TEMPLATE
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Page:
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Version Number:
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Effective Date:
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This version replaces:
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Parent Document:
C-SOP-DO-800
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Printed or downloaded documents must be verified against the effective version.
CONFIDENTIAL INFORMATION
Do not distribute outside of Takeda without a confidentiality agreement.
1.0
APPROVAL SIGNATURES
Electronic signatures can be found on the last page of this document.
Study Title:
A Randomized, Double-Blind, Proof-of-Concept, Phase 2 Study to Evaluate 
the Efficacy and Safety of Once Daily Oral Vonoprazan 20 mg or 
Vonoprazan 40 mg Compared to Esomeprazole 40 mg for the Treatment of 
Subjects With Symptomatic Gastro-Esophageal Reflux Disease Who have a 
Partial Response Following Treatment with a High Dose of Proton Pump 
Inhibitor
TDC Approvals:
PPD


CROSS-REGIONAL TEMPLATE
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Page:
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Version Number:
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C-SOP-DO-800
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Printed or downloaded documents must be verified against the effective version.
CONFIDENTIAL INFORMATION
Do not distribute outside of Takeda without a confidentiality agreement.
2.0
TABLE OF CONTENTS
1.0
APPROVAL SIGNATURES........................................................................................................2
2.0
TABLE OF CONTENTS..............................................................................................................3
3.0
LIST OF ABBREVIATIONS........................................................................................................5
4.0
OBJECTIVES.............................................................................................................................7
4.1
PRIMARY OBJECTIVES.................................................................................................7
4.2
SECONDARY OBJECTIVES............................................................................................7
4.3
ADDITIONAL OBJECTIVES.............................................................................................7
4.4
STUDY DESIGN ..........................................................................................................8
5.0
ANALYSIS ENDPOINTS .......................................................................................................... 11
6.0
DETERMINATION OF SAMPLE SIZE ...................................................................................... 14
7.0
METHODS OF ANALYSIS AND PRESENTATION................................................................... 15
7.1
GENERAL PRINCIPLES............................................................................................... 15
7.2
ANALYSIS SETS........................................................................................................ 16
7.3
DISPOSITION OF SUBJECTS........................................................................................ 16
7.4
DEMOGRAPHIC AND BASELINE CHARACTERISTICS........................................................17
7.5
MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS........................................ 17
7.6
MEDICATION HISTORY AND CONCOMITANT MEDICATIONS ............................................. 18
7.7
STUDY DRUG EXPOSURE AND COMPLIANCE ................................................................18
7.8
EFFICACY ANALYSIS ................................................................................................. 20
7.8.1
Primary Efficacy Endpoint....................................................................................... 22
7.8.2
Secondary Efficacy Endpoint.................................................................................. 23
7.8.3
Additional Efficacy Endpoint(s) ............................................................................... 23
7.9
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS......................................................26
7.10
OTHER OUTCOMES................................................................................................... 27
7.11
SAFETY ANALYSIS .................................................................................................... 30
7.11.1
Adverse Events...................................................................................................... 31
7.11.2
Clinical Laboratory Evaluations............................................................................... 32
7.11.3
Vital Signs.............................................................................................................. 33
7.11.4
12-Lead ECGs ....................................................................................................... 34
7.11.5
Other Observations Related to Safety..................................................................... 35
7.12
INTERIM ANALYSIS.................................................................................................... 35
7.13
CHANGES IN THE STATISTICAL ANALYSIS PLAN ............................................................35


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8.0
REFERENCES ......................................................................................................................... 36
9.0
APPENDIX ............................................................................................................................... 37
9.1
CLINICAL LABORATORY TESTS .......................................................................... 37
9.2
CRITERIA FOR MARKEDLY ABNORMAL VALUES ............................................... 39


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUCτ
area under the curve from time zero to tau
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval
Cmax
maximum observed plasma concentration
CPK
creatine phosphokinase
eCRF
electronic case report form
ECG
electrocardiogram
EM
extensive metabolizer
EOT
end of treatment
EQ-5D-5L
EuroQol-5 dimension-5 levels
ESS
enrolled subjects set
FAS
full analysis set
GERD
gastro-esophageal reflux disease
GGT
-glutamyl transferase
GI
gastrointestinal
HADS
hospital depression and anxiety scale
HIV
human immunodeficiency virus
H pylori
helicobacter pylori
HRQoL
health related quality of life
ICH
International Conference on Harmonisation
IVRS
interactive voice response system
LA
Los Angeles
LDH
lactate dehydrogenase
LLN
lower limit of normal
LOCF
last observation carried forward
MAV
markedly abnormal values
MedDRA
Medical Dictionary for Regulatory Activities
PAGI-QOL
Patient Assessment of Upper Gastrointestinal Disorders Quality-of-Life Index
PAGI-SYM
Patient Assessment of Upper Gastrointestinal Disorders Symptom Severity Index
PD
pharmacodynamics
PGIC
patient global impression of change
PK
pharmacokinetics


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PM
poor metabolizer
PPI
proton pump inhibitor
PPS
per protocol set
PRO
patient-reported outcome
PSQI
Pittsburgh sleep quality index
PT
preferred term
PTE
pre-treatment event
QD
quaque die (once a day)
QOL
quality-of-life
QTcF
corrected QT using the Fredericia correction
RESQ-eD
reflux symptom questionnaire e-Diary
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SD
standard deviation
SDB
standard database
SE
standard error
SOC
system organ class
TAU
therapeutic area unit
TEAE
treatment emergent adverse event
TLGs
tables, listings, and graphs
tmax
time to Cmax
UGI
upper gastrointestinal
ULN
upper limit of normal
VAS
visual analogue scale
WHODrug
World Health Organization Drug Dictionary


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4.0
OBJECTIVES
4.1 PRIMARY OBJECTIVES
To determine the effect of vonoprazan compared to esomeprazole for preventing heartburn 
symptoms over a 4-week treatment period in subjects who have a partial response to treatment 
with esomeprazole.
4.2 SECONDARY OBJECTIVES
To determine the effect of vonoprazan treatment on sustained resolution of heartburn symptoms 
over a 4 week treatment period (at least one 7-day symptom-free period).
4.3 ADDITIONAL OBJECTIVES
To determine the effect of vonoprazan compared with esomeprazole on GERD-related endpoints, 
including:
–
Preventing heartburn at night over a 4 week treatment period.
–
Sustained resolution of heartburn during the final week of treatment.
–
Preventing regurgitation during 24-hour periods, over a 4 week treatment period.
–
Preventing regurgitation at night over a 4 week treatment period.
–
Preventing heartburn and/or regurgitation during 24-hour periods over a 4 week treatment 
period.
–
Complete prevention of regurgitation (response rate) during the final week of treatment.
–
Evaluation of the effect of vonoprazan on the use of rescue medication over 4 weeks of 
treatment.
–
Evaluation of the effect of vonoprazan on GERD quality of sleep over 4 weeks of 
treatment.
–
Evaluation of the effect of vonoprazan on Health Related Quality of Life (HRQoL) over 
4 weeks of treatment.
To evaluate the pharmacokinetics of vonoprazan in patients.
To determine the safety and tolerability of vonoprazan in this population.
To evaluate the pharmacokinetics and clinical efficacy of vonoprazan in patients identified as 
CYP2C19 poor or extensive metabolizers (PM/EM).
In this study, samples for pharmacogenomics will be collected where possible and stored for 
possible exploratory investigation of drug response or disease. In this study, using Vonoprazan, 
or in a set of clinical trials, if variability is seen in responsiveness to study medication and it is 


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suspected to be attributable to gene polymorphism, pharmacogenomics analyses may be 
conducted to explore gene polymorphism relationships, as indicated by the observations.
4.4 STUDY DESIGN
This is a phase 2, randomized, double-blind, parallel-group, 3-arm Proof of Concept study with a 
4-week active Treatment Period. This study will evaluate the safety and efficacy of vonoprazan 
20 mg once daily (QD) and 40 mg QD compared with esomeprazole 40 mg QD when 
administered as an oral daily dose in the morning, at least 1 hour before the first meal of the day, 
for 4 weeks of treatment in subjects with symptomatic GERD who have a partial response to 
treatment with a high dose of esomeprazole. This study will be conducted at a total of up to 
50 sites in Europe. A total of 213 subjects will be randomized in a 1:1:1 ratio of Vonoprazan 
40 mg to Vonoprazan 20 mg to Esomeprazole 40 mg (71 per treatment arm). 
Subjects will be eligible for participation in the study if they: have a documented history of 
symptoms of both heartburn and acid regurgitation prior to entry into the study; have a history of 
persistent heartburn and/or regurgitation symptoms that are troublesome despite an adequate 
course of proton pump inhibitor (PPI) treatment; continue to have symptoms of heartburn (and/or 
regurgitation) following 4 weeks treatment with a high dose of esomeprazole 40 mg QD during 
the Run-in Period; have symptoms of heartburn which increases following a 2-week Washout 
Period in the presence of regurgitation prior to randomization; and meet all of the inclusion 
criteria and none of the exclusion criteria. Patients with mild (LA grade A) esophagitis are also 
permitted to enter the study. To confirm LA grade, endoscopy will be performed at screening, or 
historical data of endoscopy up to one year prior to screening may be permitted. The study will 
consist of 3 periods: a 7-week Run-in period (initial 1 week screening period and a 6-week 
single-blind Run-in), a 4-week double blind Treatment Period, and a 1-week Safety Follow-up. 
The Run-in includes a 1-week general Screening Period during which the subject will remain on 
their prescribed PPI (Day-49 to Day -42); followed by a 4-week single-blind PPI assessment 
period with blinded esomeprazole 40 mg QD (Day -42 to Day -14); and then a 2-week 
single-blind placebo Off-PPI Assessment period (Day -14 to Day-1). Subjects who remain 
symptomatic and compliant will be randomized to the 4-week Treatment Period followed by a 
one week safety Follow-up Call. Certain medications will require washout prior to entry into the 
study and will not be permitted during the study.
The Screening Period will take up to 49 days. After providing informed consent and meeting the 
appropriate study entry criteria during the Initial Screening Visit (Visit 1), subjects will be taken 
off their prescribed PPI and be given esomeprazole 40 mg QD, be provided with an electronic 
diary (Visit 2), and trained in how to complete it. They will return 4 weeks later to assess 
treatment compliance, completion of the e-Diary and assessment of the PPI Treatment Period 
(Day -21 to -14). If the subject is still symptomatic, he or she will receive single-blinded placebo 
medication for a 2-week PPI Washout Period and their Off-PPI Baseline will be assessed during 
the week prior to randomization (Day -8 to -1). 


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It is estimated that approximately 426 subjects will be screened to ensure that a total of 
213 subjects who meet the symptomatic GERD entry criteria for a partial response to PPI 
(defined as having heartburn following 4 weeks of treatment with esomeprazole 40 mg and an 
increase of at least 2 symptom days of heartburn (and/or regurgitation) in the last week of the 
Off-PPI assessment period compared with the last week of esomeprazole treatment) are 
randomized equally to 1 of 3 treatments at Visit 4 (vonoprazan 20 mg QD, vonoprazan 40 mg 
QD or esomeprazole 40 mg QD for 4 weeks). A 50% screen failure rate is higher than for 
standard GERD studies and has been estimated based on the duration of the run-in, inclusion of a 
2 week placebo washout period and the symptom criteria to be met prior to randomization. 
Patients will take their first dose of study drug on the morning after Visit 4 and be treated on an 
outpatient basis, complete their e-Diary twice daily and will return to the clinic at Weeks 2 
(Visit 5) and Week 4 (Visit 6) of the Treatment Period.
A Safety Follow-up call will be made approximately 1 week after completion of the 4-week 
Treatment Period. If possible, subjects who prematurely withdraw from the study will be seen for 
a withdrawal visit as soon as possible after discontinuation, and also will be contacted for Safety 
Follow-up approximately 1 week after withdrawal. 
Rescue antacid medication will be provided for all subjects at the Initial Screening Visit and as 
required throughout the study.
From the Initial Screening Visit to the End-of-Treatment Visit, there will be 6 subject visits and a 
phone call during the Follow-up period. A schematic of the study design is included as Figure 1.


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Figure 1 
Schematic of Study Design


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5.0
ANALYSIS ENDPOINTS
Primary Endpoints
Percentage of heartburn-free 24 hour periods (day and night) during 4 weeks of randomized 
double-blind treatment.
Secondary Endpoints
Proportion of subjects with ≥1 sustained resolution of heartburn (defined as ≥7 consecutive days 
without both daytime and nighttime heartburn any time during the 4-week randomized 
double-blind Treatment Period).
Additional Endpoints
Heartburn Endpoints
Change from baseline in percentage of heartburn-free 24 hour periods (day and night) during 
4 weeks of randomized double-blind treatment, where baseline is defined as the 4 weeks run-in 
period on esomeprazole.
Change from baseline in proportion of subjects with ≥1 sustained resolution of heartburn, where 
baseline is defined as the 4 weeks run-in period on esomeprazole
Percentage of heartburn-free nights during 4 weeks of randomized double-blind treatment.
Percentage of heartburn-free days after 4 weeks of randomized double-blind treatment.
Proportion of patients with no nighttime heartburn symptoms during the last week of treatment.
Proportion of patients with no daytime heartburn symptoms during the last week of treatment.
Proportion of patients with no daytime and nighttime heartburn symptoms during the last week 
of treatment.
Percentage of subjects with ≥80% heartburn free days and nights during 4 weeks of randomized 
double-blind treatment.
Percentage of subjects with ≥80% heartburn free nights during 4 weeks of randomized 
double-blind treatment.
Percentage of subjects with ≥80% heartburn free days during 4 weeks of randomized 
double-blind treatment.
Percentage of heartburn free 24 hour periods (day and night) during weeks 1, 2 and week 3 of 
randomized double-blind treatment.
Time to first sustained resolution (defined as 7 consecutive days without daytime and nighttime 
heartburn).


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Proportion of subjects who achieve sustained resolution of heartburn (defined as ≥7 consecutive 
days without daytime and nighttime heartburn) with an onset within 3 days of starting 
randomized double-blind treatment.
Proportion of subjects with resolution of symptoms with an onset within 3 days of starting 
randomized double-blind treatment and continuing out to the end of week 2 and end of week 4.
Maintenance of heartburn-free period – duration of heartburn symptom-free days and nights 
(24-hour periods) following the first 24-hour period when no symptoms were recorded until the 
next time symptoms were recorded.
Heartburn severity (severity of the most intense episode will be assessed for daytime and 
nighttime).
Percentage of responders, where a responder is defined as having at least 3 more days of not 
more than mild heartburn symptoms on average per week during the whole double blind 
treatment period compared to baseline, where baseline is defined as the 1 week run-in period on 
placebo prior to randomization.
Regurgitation Endpoints
Percentage of regurgitation-free nights during 4 weeks of randomized double-blind treatment.
Percentage of regurgitation-free days after 4 weeks of randomized double-blind treatment.
Percentage of regurgitation-free 24 hour periods during 4 weeks of randomized double-blind 
treatment.
Percentage of subjects with ≥80% regurgitation-free days and nights during 4 weeks of 
randomized double-blind treatment.
Percentage of subjects free from regurgitation (“no regurgitation”) during week 1, 2 and 3 of 
randomized double-blind treatment.
Time to first sustained resolution (defined as 7 consecutive days without daytime and nighttime 
regurgitation).
Proportion of subjects who achieve sustained resolution of regurgitation (defined as 
≥7 consecutive days without daytime and nighttime heartburn) with an onset within 3 days of 
starting randomized double-blind treatment.
Proportion of subjects with resolution of regurgitation symptoms with an onset within 3 days of 
starting randomized double-blind treatment and continuing out to the end of week 2 and the end 
of week 4.
Proportion of patients with no daytime and nighttime regurgitation symptoms during the last 
week of treatment.


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Maintenance of regurgitation-free period – duration of regurgitation symptom-free days and 
nights (24-hour periods) following the first 24-hour period when no symptoms were recorded.
Regurgitation severity (severity of the most intense episode and will be assessed for daytime and 
nighttime).
Heartburn and Regurgitation Endpoint
Percentage of heartburn and/or regurgitation-free 24 hour periods (day and night) during 4 weeks 
of randomized double-blind treatment.
Rescue medication Endpoint
Percentage of days without using rescue medication.
Percentage of nights without using rescue medication.
Percentage of days and nights without using rescue medication.
GERD Sleep quality measure
Change from baseline in measured scores.
Proportion of subjects with clinically significant improvement on sleep disturbance measures.
HRQoL
HRQoL will be assessed using patient reported outcome questionnaires at patient visit and the 
following endpoints will be used for analysis:
– Change from baseline in HRQoL scores.
– Proportion of subjects with clinically significant improvement on HRQoL measures.
Other Additional Endpoints
Summary statistics of plasma concentrations of Vonoprazan at the Week 2 and 4 visit and 
summary pharmacokinetic parameters where available: maximum observed plasma 
concentration (Cmax), time to reach Cmax (tmax), area under the plasma concentration-time curve 
from time 0 to tau (AUCτ).
Summary statistics of plasma concentrations of Vonoprazan at the Week 2 and 4 visit for 
CYP2C19 poor or extensive metabolizers (PM/EM) and summary pharmacokinetic parameters 
where available: maximum observed plasma concentration (Cmax), time to reach Cmax (tmax), area 
under the plasma concentration-time curve from time 0 to tau (AUCτ).
Summary statistics of plasma concentrations of esomeprazole at the Week 4 visit.
Safety parameters examined will include AEs, serious adverse events (SAEs), vital signs, results 
of standard laboratory tests.


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6.0
DETERMINATION OF SAMPLE SIZE
It is estimated that approximately 426 subjects will be screened from which a total of 
213 subjects (71 per treatment arm) who have a partial response to treatment with a high dose of 
esomeprazole (40 mg QD for 4 weeks) are planned to be randomized into the study with the 
expectation that 180 subjects will complete the study (assuming a 15% dropout rate). The sample 
size of 60 subjects per treatment group will provide at least 80% power at the 2-sided 0.025 level 
of significance to detect an absolute 20% difference between each vonoprazan dose and 
esomeprazole 40 mg for the percentage of heartburn free 24 hour periods (day and night) during 
4 weeks of randomized double-blind treatment. The pooled standard deviation was estimated as 
33.61 from prior Dexlansoprazole (T-GD04-082, T-GD04-083, T-EE04-084, T-EE04-085) and 
vonoprazan (CCT-201) studies (Data on file). The sample size was calculated using the 
Wilcoxon rank-sum test in EAST version 6.0.
With the expectation that 180 subjects will complete the study, the secondary endpoint; 
proportion of subjects with ≥1 sustained resolution of heartburn (defined as ≥7 consecutive days 
without both daytime and nighttime heartburn any time during the 4-week randomized 
double-blind Treatment Period) has 80% power at the 2-sided 0.025 level of significance to 
detect an absolute 30% difference between each vonoprazan dose and esomeprazole, assuming a 
response rate of 33% for esomeprazole. The sample size was calculated using the Fisher’s exact 
test in EAST version 6.0.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1 GENERAL PRINCIPLES
There are four baselines defined for the study. 

Change in the primary and secondary endpoint from baseline, where baseline is defined as 
the 4 weeks run-in period on esomeprazole.

Change in the PRO questionnaire scores from baseline, where baseline is the score at visit 3 
(“baseline PPI response”).

Change in the PRO questionnaire scores from baseline, where baseline is the score at visit 4 
(“baseline off-PPI response”).

Change in ECG, vital signs, laboratory results, physical examination, where baseline is 
defined as the last assessment prior to first dose of study drug on Day 1 (visit 4).
Note that in addition to change from baseline assessments, change from Screening will also be 
presented for parameters measured at Screening and later visits. 
Continuous data will be summarized using number of subjects (N), mean, standard deviation 
(SD), median, minimum, and maximum. Summary statistics for continuous data will only 
include subjects with a non-missing value for the data being summarized.
Geometric mean and geometric coefficient of variation will be produced in addition to the above 
for pharmacokinetic (PK) data (concentrations and parameters) where appropriate.
Categorical data will be summarized using the number and percent of subjects for each category 
where appropriate. Missing categories will be used for categorical data when missing data is 
present. The calculation of percentages will take into account missing responses.
All confidence intervals, statistical tests, and resulting p-values will be reported as 2-sided unless 
otherwise stated. P-values (when rounded to three decimals) less than or equal to α are reported 
as “statistically significant”.
Means, LS means, and medians will be presented to 1 more decimal place than the recorded data. 
Where presented, SDs and standard errors (SEs) will be presented to 2 more decimal places than 
the recorded data. Confidence intervals for parameter estimates will be presented using the same 
number of decimal places as those recorded for the parameter point estimate. 
Alternative methods of analysis of the data may be considered prior to un-blinding should some 
of the assumptions underlying the proposed analyses not be met. However, the reasons for any 
departures from the planned approach and methods will be documented fully.


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7.2 ANALYSIS SETS
All Subjects: this analysis set will include all subjects who provided informed consent and will 
include screen fails. This analysis set will be used for reporting of summary data and for data 
listings.
Enrolled Subjects Set (ESS): this analysis set will include all subjects were enrolled into the PPI 
run-in period. This analysis set will be used for reporting of summary data.
Full Analysis Set (FAS): this analysis set will include all subjects randomized. Subjects in this 
set will be analyzed according to the original randomization. The FAS will be the main efficacy 
analysis set.
Per Protocol Set (PPS): this analysis set is a subset of the FAS. The PPS consists of all subjects 
who do not violate the terms of the protocol in a way that would impact the study output 
significantly. All decisions to exclude subjects from the PPS dataset will be made prior to the 
unblinding of the study. Subjects in this set will be analyzed according to the treatment they 
actually received. The PPS is an efficacy analysis set and as such exclusion of subjects from the 
PPS will focus on the effect of violations on the validity of the subject’s efficacy data. The PPS 
analyses will act as a sensitivity analysis to the FAS analyses.
Safety Analysis Set (SAF): this analysis set will include all subjects who have received at least 
1 dose of randomized study drug. Subjects in this set will be analyzed according to the treatment 
they actually received. All safety analyses will be based on the SAF. 
The PK set: this set will include all subjects who received randomized treatment and provided at 
least one PK sample. Subjects in this set will be presented according to the treatment they 
actually received.
The number of subjects within each analysis set will be summarised by treatment and total.
7.3 DISPOSITION OF SUBJECTS
Disposition will be presented separately for screen failures and for those randomised to the 
double-blind period. Disposition of all screened subjects (denominator) will be tabulated (count 
and percent); there will be no inferential analysis of subject disposition data.
Summary of screen failures will be presented for All Subjects. Numbers of subjects failing, and 
reason for failure, where captured, or continuing into each phase (Screening, PPI run-in, Placebo 
run-in, double blind randomised phase) and will be presented. 
Disposition of all subjects will be tabulated by randomized treatment. The categories will 
include:

All randomized subjects (denominator) by site and treatment group.

Subjects who were randomized but not treated with double-blind study drug, if applicable.


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
All subjects who completed double-blind study by site and treatment group.

All subjects who prematurely discontinued (permanently) study drug by site and treatment 
group.
Primary reasons for discontinuation of study will be tabulated by treatment and visit
Significant protocol deviations for the FAS will be summarized according to the category of 
deviation, by site and treatment group.
7.4 DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Demographic and baseline characteristics will include age (years) at date of informed consent, 
race, employment status, smoking status, alcohol use, caffeine consumption, gender, height (cm), 
weight (kg) at Screening, body mass index (BMI) (kg/m2) at Screening, female reproductive 
status, smoking status, weight gain, night sweats, endoscopy findings and H pylori status at 
randomisation.
Demographic and baseline characteristics will be summarized by randomised treatment group 
and total for the ESS. Subjects in the ESS who were screen failures will be included in a ‘Run-in 
Failures’ group for presentation purposes. A total randomised column will also be included.
7.5 MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS
Summaries of medical history (significant conditions or diseases that stopped at or prior to the 
time of informed consent) and concurrent medical conditions (significant ongoing conditions or 
diseases present at the time of informed consent) will be summarized based on the SAF. No 
inferential statistics will be presented.
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA, Version 20 or higher) coding system.
Medical history and concurrent medical conditions will be summarized by system organ class 
(SOC) and preferred term (PT) for each treatment group. The tables will be sorted in alphabetic 
order by SOC and in decreasing frequency based on the total number of reports by preferred 
terms in each SOC. The number and percentage of subjects with any medical history and 
concurrent medical conditions will be summarized for each SOC and preferred term. The 
denominator used for calculating the percentages will be the total number of subjects included in 
each treatment group. For the tables, if a subject reports the same preferred term multiple times, 
then that preferred term will be counted only once for that subject. Similarly, if a subject reports 
multiple conditions within the same SOC, then that SOC will be counted only once for that 
subject in the tables.


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7.6 MEDICATION HISTORY AND CONCOMITANT MEDICATIONS
Summaries of medication history and concomitant medications will be based on the SAF. No
inferential statistics will be presented.
Medication history includes any medication relevant to eligibility criteria. Concomitant 
medications include any medication other than study drug (study drug includes esomeprazole 
administered during the PPI run-in period) taken at any time between the time of informed 
consent through the end of the study. History of therapy for the eradication of H. pylori
(eg, triple therapy with PPI + amoxicillin + clarithromycin) will be summarized separately. Any 
history (Yes/No) and time from completion of such therapy to Screening (within the past 1 
year/more than 1 year) will be summarized for SAF by treatment.
Concomitant medications will be classified as follows:

Medications that started and stopped prior to Visit 4: any medication stopped after time of 
informed consent and prior to the first dose of double-blind study treatment.

Medications that started prior to and were ongoing at Visit 4: any medication that started 
before and was not stopped prior to the first dose of double-blind study treatment.

Medications that started on or after Visit 4: any medication that started at or after the first 
dose of double-blind study treatment.

Medications that were ongoing after Visit 4: any medication that was taken during the 
double-blind period.
Medication history and concomitant medications will be coded using the WHODrug Version 
March 2016 or higher. Each of the 4 concomitant medication classifications will be summarized 
separately.
The tables will present the number and percentage of subjects by therapeutic class and preferred 
term using the total number of subjects in each treatment group as the denominator. Therapeutic 
class will be sorted alphabetically and preferred terms are sorted by decreasing frequency based 
on the total number of subjects.
7.7 STUDY DRUG EXPOSURE AND COMPLIANCE
Study drug exposure and compliance will be summarized by randomised treatment group and 
total for the SAF. No inferential statistics will be presented.
Exposure and compliance will be summarised for both the run-in and double-blind periods 
separately. Exposure during the run-in period will be presented for both esomeprazole 40mg and 
placebo run-in periods separately. Exposure will be summarised as a continuous variable. If any 
drug accountability data for returned medication is missing it will be assumed that all tablets 
were taken (ie, amount returned = 0) unless otherwise indicated elsewhere (eg, comment 
recorded indicating medication lost etc.).


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Duration of exposure to drug (days): date of last dose of study drug - date of first dose of study 
drug + 1. Drug may be esomeprazole run-in, placebo run-in or double blind treatment. If last 
dose of study drug is missing then the date of the End of Treatment/Early Termination Visit will 
be used.
Compliance with the study drug regimen will be documented throughout the study and will be 
calculated from counts of returned tablets and capsules. Study drug compliance for the run-in 
period will be calculated for the total 6 weeks of run-in (esomeprazole and placebo periods 
combined). Compliance during the double blind period will also be presented. Compliance will 
be summarised as a continuous variable and also categorised as follows:
Compliance during the run-in period will be categorised into:

Compliance <85%.

Compliance =>85%.
Whilst compliance in the double blind period will be categorised into:

Compliance <75%.

Compliance >=75% and <=%133%.

Compliance>133%.
Compliance will be calculated using:
The number of capsules taken will be defined as (total number of capsules dispensed – total 
number of capsules returned) for each study medication regimen. The expected number of 
capsules to be taken will be defined as the number of days (last dose day - first dose day + 1) for 
each study medication regimen of each study period. 
Diary compliance will also be summarized. Compliance for the e-Diary is defined as the 
percentage of scheduled assessments that are completed based on 2 assessments per day 
(daytime and nighttime), except for the final day of double blind treatment. For randomization, 
85% compliance is required and is defined as 12 of 14 assessments completed over the 7-day 
period (Day -21 to Day-14) prior to the single blind Placebo Run-in Period. Diary compliance 
will be calculated for the following periods:

Total run-in period (6 weeks – from Visit 2 to Visit 4).

Total PPI run-in period (4 weeks – from Visit 2 to Visit 3).

End of PPI run-in period (1 week – From Day -21 to Day -14).


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
Total double blind period (4 weeks – from Visit 4 to Visit 6).
Diary compliance (by treatment and overall) for each period will be summarised as a continuous 
variable and also categorised into:

Compliance <85%.

Compliance =>85%.
7.8 EFFICACY ANALYSIS
The primary and secondary endpoints will be derived from diary data entered by patients into an 
electronic diary device. The device will present patients with the reflux symptom questionnaire 
e-Diary (RESQ-eD), an electronic questionnaire developed and validated by Astra Zeneca for 
use in patients with partial response to PPI. Subjects will be given and trained on the use of the 
study e-Diary at Visit 2 and re-trained at Visit 3 if necessary once initial eligibility criteria have 
been confirmed at Visit 3. Subjects will be instructed to complete the e-Diary every morning 
upon waking, to capture nighttime symptoms, and every evening before going to sleep, to 
capture daytime symptoms.
Throughout the Run-in Period and Treatment Period, subjects will complete the questionnaire, as 
well as recording the use of rescue medication in the diary.
The RESQ-eD comprises 13 questions to be answered twice daily. Patients answer each question 
by selecting one response from a choice of 6 options (did not have, very mild, mild, moderate, 
moderately severe, and severe).
The 13 questions to be answered regarding daytime symptoms are:
Since waking today, how would you rate the intensity of the burning feeling behind your 
1.
breastbone?
Since waking today, how would you rate the intensity of the pain behind your breastbone?
2.
Since waking today, how would you rate the intensity of the burning feeling in the center of 
3.
the upper stomach?
Since waking today, how would you rate the intensity of the pain in the center of the upper 
4.
stomach?
Since waking today, how would you rate the intensity of the acid or sour taste in your mouth?
5.
Since waking today, how would you rate the intensity of the unpleasant movement of 
6.
material upwards from the stomach?
Since waking today, how would you rate the intensity of your burping (gas coming from the 
7.
stomach through the mouth)?
Since waking today, how would you rate the intensity of your hoarseness?
8.


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Since waking today, how would you rate the intensity of your cough?
9.
Since waking today, how would you rate the intensity of your difficulty swallowing?
10.
Since waking today, how would you rate the intensity of the bitter taste in your mouth?
11.
Since waking today, how would you rate the intensity of the stomach contents (liquid or 
12.
food) moving upwards to your throat or mouth?
Since waking today, how would you rate the intensity of your heartburn?
13.
Questions 1, 2, 3, 4 and 13 relate to heartburn, whilst questions 5, 6, 11 and 12 relate to 
regurgitation.
The 13 questions to be answered regarding nighttime symptoms are:
During the night time, how would you rate the intensity of the burning feeling behind your 
1.
breastbone?
During the nighttime, how would you rate the intensity of the pain behind your breastbone?
2.
During the nighttime, how would you rate the intensity of the burning feeling in the center of 
3.
the upper stomach?
During the nighttime, how would you rate the intensity of the pain in the center of the upper 
4.
stomach?
During the nighttime, how would you rate the intensity of the acid or sour taste in your 
5.
mouth?
During the nighttime, how would you rate the intensity of the unpleasant movement of 
6.
material upwards from the stomach?
During the nighttime, how would you rate the intensity of your burping (gas coming from the 
7.
stomach through the mouth)?
During the nighttime, how would you rate the intensity of your hoarseness?
8.
During the nighttime, how would you rate the intensity of your cough?
9.
During the nighttime, how would you rate the intensity of your difficulty swallowing?
10.
During the nighttime, how would you rate the intensity of the bitter taste in your mouth?
11.
During the nighttime, how would you rate the intensity of the stomach contents (liquid or 
12.
food) moving upwards to your throat or mouth?
During the nighttime, how would you rate the intensity of your heartburn?
13.
Questions 1, 2, 3, 4 and 13 relate to heartburn, whilst questions 5, 6, 11 and 12 relate to 
regurgitation.


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A heartburn-free period is defined as a period during which the patient responds ‘Did not have’ 
to all questions 1, 2, 3, 4 and 13. A regurgitation free period is defined as a period during which 
the patient responds ‘Did not have’ to all questions 5, 6, 11 and 12. For a 24 hour period the 
patient must be free of symptoms for both the day assessment and the following nighttime 
assessment (completed the next morning). For analysis purposes, diary entries will be assigned to 
a study day based on the day the collection interval started for that entry. For example, the Study 
Day 1 diary entries will include the evening diary completed on Study Day 1 (the collection 
interval started when the subject awoke on Study Day 1) and the morning entry completed on 
Study Day 2 (the collection interval started when the subject went to bed on Study Day 1).
For each subject, the percentage of days with neither daytime nor nighttime heartburn during 
treatment will be calculated using all days with at least 1 morning or evening diary entry during
the double blind treatment period (defined as the period starting from Day of first dose of 
randomised treatment to last day of randomised treatment). For example, if a subject completed 
at least 1 diary entry on 24 of 27days, but missed both entries on 4 days, 24 days will be used as 
the denominator in the analysis. On the last day of double blind treatment as the diary will be 
returned to the site diary entries will not be available for the last day following the last dose of 
study treatment. This means that if a subject completes 28 days of randomised treatment there 
should be 27 complete days of diary entries included for consideration for that subject, assuming 
100% diary compliance. A similar approach will be taken for daytime and nighttime endpoints 
and for regurgitation endpoints.
All Efficacy endpoints will be summarised by treatment group and all efficacy data will be listed.
7.8.1 Primary Efficacy Endpoint
Percentage of heartburn-free 24 hour periods (day and night) during 4 weeks of randomized 
double-blind treatment.
For the assessment of the percentage of heartburn-free days, the Wilcoxon-Mann-Whitney Odds 
estimator with the 97.5% CI and the Wilcoxon rank-sum test will be used at the 2.5% level of 
significance for each vonoprazan treatment comparison with esomeprazole to control for 
multiplicity. This endpoint will be analyzed for both the FAS and PPS. The FAS analysis will be 
considered the primary analysis and the PPS analysis as a sensitivity analysis.
The percentage of heartburn-free days will be calculated for each subject. When calculating the 
percentage of heartburn-free days any 24-hour period with no data will be excluded from both 
the numerator and denominator. A boxplot of the primary endpoint will be presented.
A sensitivity analysis using the FAS will be conducted using the van Elteren test with country as 
the stratifying factor. An additional analysis will be conducted where a symptom free day will be 
defined as where both daytime and night time maximum symptom score is very mild for the 
heartburn questions 1, 2, 3, 4 and 13. This will be analyzed as for the primary endpoint.


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Subgroup analyses for the primary efficacy variable will be conducted for the following 
variables. The subgroup analyses will be conducted on the FAS. Summary statistics will be 
presented by subgroup level and treatment group for all subgroups. Pairwise comparisons 
between all treatment groups within each subgroup will be made as for the primary analysis. 

Age (<45, 45-<65, =>65 years old).

Gender (male, female).

BMI (<25, 25 to 30, =>30 kg/m2).

Smoking status (smoker, non-/ex-smoker).

Alcohol use (drinker, non-/ex-drinker).

Caffeine use (caffeine user, non-caffeine user).

H pylori status (positive, negative).

LA grade at Screening.
7.8.2 Secondary Efficacy Endpoint
Proportion of subjects with ≥1 sustained resolution of heartburn (defined as ≥7 consecutive days 
without both daytime and nighttime heartburn any time during the 4-week randomized double-
blind Treatment Period).
To assess the secondary endpoint, proportion of subjects with ≥1 sustained resolution of 
heartburn (defined as ≥7 consecutive days without both daytime and nighttime heartburn any 
time during the 4-week randomized double-blind Treatment Period) a Pearson Chi-square test 
will be used at the 2.5% level of significance for each Vonoprazan treatment comparison with 
esomeprazole to control for multiplicity. All subjects with missing data for determination of 
endpoint status will be considered as a non-responder in the analysis. The difference in 
proportion and odds ratio for each Vonoprazan treatment comparison with esomeprazole will be 
estimated and presented with 97.5% confidence intervals (Miettinen-Nurminen confidence 
intervals). This endpoint will be analyzed for both the FAS and PPS. The FAS analysis will be 
considered the primary analysis and the PPS analysis as a sensitivity analysis. A sensitivity 
analysis using the Cochran-mantel-Haenszel test stratifying by country will be conducted using 
the FAS. A boxplot of the secondary endpoint will be presented.
7.8.3 Additional Efficacy Endpoint(s)
All additional endpoints will be analyzed for the FAS only and tested at the 5% level of 
significance for each Vonoprazan treatment comparison with esomeprazole. 95% confidence 
levels will also be presented. Multiplicity will not be adjusted across the remaining endpoints. 
If the assumptions underlying planned inferential methods are not adequately met, methods will 
be amended as needed for appropriate analysis.


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Heartburn Endpoints
Change from baseline in percentage of heartburn-free 24 hour periods (day and night) during 
1.
4 weeks of randomized double-blind treatment, where baseline is defined as the 4 weeks run-
in period on esomeprazole.
Change from baseline in proportion of subjects with ≥1 sustained resolution of heartburn, 
2.
where baseline is defined as the 4 weeks run-in period on esomeprazole
Percentage of heartburn-free nights during 4 weeks of randomized double-blind treatment.
3.
Percentage of heartburn-free days after 4 weeks of randomized double-blind treatment.
4.
Proportion of patients with no nighttime heartburn symptoms during the last week of 
5.
treatment.
Proportion of patients with no daytime heartburn symptoms during the last week of 
6.
treatment.
Proportion of patients with no daytime and nighttime heartburn symptoms during the last 
7.
week of treatment.
Percentage of subjects with ≥80% heartburn free days and nights during 4 weeks of 
8.
randomized double-blind treatment.
Percentage of subjects with ≥80% heartburn free nights during 4 weeks of randomized 
9.
double-blind treatment.
Percentage of subjects with ≥80% heartburn free days during 4 weeks of randomized 
10.
double-blind treatment.
Percentage of heartburn free 24 hour periods (day and night) during weeks 1, 2 and week 3 of 
11.
randomized double-blind treatment.
Time to first sustained resolution (defined as 7 consecutive days without daytime and 
12.
nighttime heartburn).
Proportion of subjects who achieve sustained resolution of heartburn (defined as 
13.
≥7 consecutive days without daytime and nighttime heartburn) with an onset within 3 days of 
starting randomized double-blind treatment.
Proportion of subjects with resolution of symptoms with an onset within 3 days of starting 
14.
randomized double-blind treatment and continuing out to the end of week 2 and end of week 
4.
Maintenance of heartburn-free period – duration of heartburn symptom-free days and nights 
15.
(24-hour periods) following the first 24-hour period when no symptoms were recorded until 
the next time symptoms were recorded.


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Heartburn severity (severity of the most intense episode will be assessed for daytime and 
16.
nighttime). 
Percentage of responders, where a responder is defined as having at least 3 more days of not 
17.
more than mild heartburn symptoms on average per week during the whole double blind 
treatment period compared to baseline, where baseline is defined as the 1 week run-in period 
on placebo prior to randomization.
Regurgitation Endpoints
Percentage of regurgitation-free nights during 4 weeks of randomized double-blind 
1.
treatment.
Percentage of regurgitation-free days after 4 weeks of randomized double-blind treatment.
2.
Percentage of regurgitation-free 24 hour periods during 4 weeks of randomized double-blind 
3.
treatment.
Percentage of subjects with ≥80% regurgitation-free days and nights during 4 weeks of 
4.
randomized double-blind treatment.
Percentage of subjects free from regurgitation (“no regurgitation”) during week 1, 2 and 3 of 
5.
randomized double-blind treatment.
Time to first sustained resolution (defined as 7 consecutive days without daytime and 
6.
nighttime regurgitation).
Proportion of subjects who achieve sustained resolution of regurgitation (defined as 
7.
≥7 consecutive days without daytime and nighttime heartburn) with an onset within 3 days of 
starting randomized double-blind treatment.
Proportion of subjects with resolution of regurgitation symptoms with an onset within 3 days 
8.
of starting randomized double-blind treatment and continuing out to the end of week 2 and 
the end of week 4.
Proportion of patients with no daytime and nighttime regurgitation symptoms during the last 
9.
week of treatment.
Maintenance of regurgitation-free period – duration of regurgitation symptom-free days and 
10.
nights (24-hour periods) following the first 24-hour period when no symptoms were 
recorded.
Regurgitation severity (severity of the most intense episode and will be assessed for daytime 
11.
and nighttime). 
Heartburn and Regurgitation Endpoints
Percentage of heartburn and/or regurgitation-free 24 hour periods (day and night) during 4 
1.
weeks of randomized double-blind treatment.


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Percentage, change from percentage and duration of symptom-free days additional endpoints will 
be analyzed using the Wilcoxon-Mann-Whitney Odds estimator with the 95% CI and the 
Wilcoxon rank-sum test will be used at the 5% level of significance for each vonoprazan
treatment comparison with esomeprazole. Note that endpoints 8,9,10, 21 and 22 will be analyzed 
as for proportions. Proportion based additional endpoints will be analyzed using a Pearson Chi-
square test at the 5% level of significance for each Vonoprazan treatment comparison with 
esomeprazole. The difference in proportion and odds ratio for each Vonoprazan treatment 
comparison with esomeprazole will be estimated and presented with 95% confidence intervals
(score confidence intervals).
For time to event data (endpoints 12 and 23) the survivor function will be estimated using the 
Kaplan-Meier method and the survivor functions between Vonoprazan and Esomeprazole 
treatment groups will be compared using log-rank tests. A plot of the survivor functions will be 
presented. The median time to sustained resolution of heartburn from the survivor function will
be presented by treatment group, along with the 95% confidence interval.
For severity data the data will be analyzed using the MH chi-square statistic, using standardized 
midrank scores.
Questions 7, 8, 9 and 10 will not be analyzed.
Rescue medication Endpoint
The following endpoints will be summarized per week by treatment group for rescue mediation:

Percentage of days without using rescue medication.

Percentage of nights without using rescue medication.

Percentage of days and nights without using rescue medication.
The rescue medication percentage endpoints will be analyzed using the Wilcoxon-Mann-
Whitney Odds estimator with the 95% CI and the Wilcoxon rank-sum test will be used at the 5% 
level of significance for each vonoprazan treatment comparison with esomeprazole.
7.9 PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS
Summary statistics of plasma concentrations of Vonoprazan at the Week 2 and 4 visits and
summary PK parameters where available: maximum observed plasma concentration (Cmax), time 
to reach Cmax (tmax), area under the plasma concentration-time curve from time 0 to tau (AUCτ).
Additional PK parameters may be presented.
Summary statistics of plasma concentrations of Vonoprazan at the Week 2 and 4 visits for
CYP2C19 poor or extensive metabolizers (PM/EM) and summary pharmacokinetic parameters 
where available: maximum observed plasma concentration (Cmax), time to reach Cmax (tmax), area 
under the plasma concentration-time curve from time 0 to tau (AUCτ). Additional PK parameters 
may be presented.


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7.10
OTHER OUTCOMES
Nighttime awakenings (eDiary)
The eDiary will include the question “Did you wake up during night (=usual sleeping time)?” in 
the morning evaluation. The subject response can be ‘Yes’ or ‘No’. The number of nights per 
week in which the subject woke (response=’Yes’) will be summarized per week. The % of 
patients with ≤2 nights of awakenings per week during the last 2 weeks in the double blind 
treatment period will be reported for each of the 3 treatment arms.
Fatigue (eDiary)
In order to evaluate fatigue, 2 questions will be included in the evening evaluation of the eDiary. 
The response for both questions is rated on 5-point Likert scale (0 = none, 1 = slight, 2 = 
medium, 3 = a lot, 4 = severe). The questions are:
How much physical fatigue have you experienced today?
1.
How much intellectual fatigue have you experienced today?
2.
The number of days per week in which the subject experienced fatigue (response>0) will be 
summarized per week for each type (physical and intellectual). Additionally the mean level of 
fatigue per subject per week will be summarized.
Additional Patient Reported Outcome Questionnaires
PROs are recorded at Visit 2 (Day -42, PPI assessment), Visit 3 (Day -14, Off-PPI assessment), 
Visit 4(Day 1, Randomization) and Visit 6 (Day 28, EOT or early termination). The scores of the 
PRO questionnaires will be summarized descriptively at each visit including changes from 
baseline “off-PPI” (visit 4) and changes from baseline PPI response (visit 3) by each treatment 
group. Data will be assigned to the visit at which it is indicated they were collected in the eCRF.
Absolute values and changes from baseline will be summarized per treatment arm. Additionally, 
the proportion of subjects with clinically significant improvement, when defined for a measure, 
on HRQoL measures will be summarized.
The following PROs will be recorded:
Pittsburgh Sleep Quality Index (PSQI) 
Quality of sleep will be assessed using the PSQI questionnaire. The PSQI questionnaire is a 19-
item validated questionnaire completed by patients regarding the previous 1-month period. Items 
are grouped into seven component scores:

Subjective sleep quality (1 item).

Sleep latency (2 items).

Sleep duration (1 item).

Habitual sleep efficiency (3 items).


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
Sleep disturbances (9 items).

Use of sleep medication (1 item).

Daytime dysfunction (2 items).
Each component score is weighted equally on a 0–3 scale, with 3 representing the worse effect, 
then summed to yield a global PSQI score, which could range from 0 to 21. Component scores as 
well as global PSQI score are calculated only if all items are answered (eg, a missing question 
can result in a missing item and a missing global PSQI score). There are five additional questions 
that are completed by a bed partner if there is one. These are not used in the scoring. Patients 
with a global score >5 are considered to have poor sleep quality. Only the global score will be 
summarised. An additional summary table of patients with a global score<=5 and those with a 
global score >5 at each time point will be presented.
Hospital Depression and Anxiety scale (HADS)
The presence of anxiety levels and depression levels will be assessed using the HADS. The 
HADS is a widely used scale that was designed for detecting depression and anxiety in an 
out-patient clinic setting, HADS part A (HADS-A) focuses on anxiety and HADS part D 
(HADS-D) focuses on depression. HADS-A and HADS-D are 7-item subscales that measure the 
presence and severity of anxiety and depression symptoms, respectively, on a scale of 0 to 3. 
Total scores ≤7 indicate no clinically relevant symptoms, 8 to 10 mild symptoms, 11 to 
14 moderate symptoms, and ≥15 (maximum 21) indicate more severe symptoms.
The developers recommend that in case of a single missing item in any of the subscales, the 
score of the subscale to be inferred by using the mean of the remaining six items. If more than 
one item is missing, then the subscale should be judged as invalid and set to missing. Only the 
total score (treated as a continuous variable) for each part will be summarised.
Patient Global Impression of Change (PGIC) (not at Visit 2)
The PGIC is a patient-rated instrument that measures change in patient’s GERD-related 
symptoms on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). 
Higher scores indicate a change for the worse. For this study, subjects will be asked to rate their 
symptoms relative to their previous past 4-weeks or 2-weeks. The PGIC will be used to further 
document the ability of RESQ-eD to detect change as well as clinical meaningfulness of change.
The PGIC will be summarised as a continuous variable.
EuroQol-5 dimensions 5 levels (EQ-5D-5L)
The EQ-5D-5L is a validated and reliable generic instrument that was developed as a 
standardized non-disease-specific instrument describing and evaluating HRQoL. It was intended 
to complement other forms of HRQoL measures and have the capacity to generate cross-national 
comparisons for health care evaluations. The questionnaire includes 5 domain items: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. Subjects choose the level of 


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health problems they currently have on each item as “None”, “Slightly”, “Moderate”, “Severe”, 
or “Unable” and are scored a 1, 2, or 3, respectively. The 5 items allow the calculation of a utility 
index ranging between -1 (the worst) and 1 (the best). The questionnaire also uses a Visual 
Analog Scale (VAS). The EQ-5D-5L VAS score is a self-assigned rating of overall health using 
a 20 cm visual, vertical scale, with a score of 0 as the worst and 100 as best possible health. An 
increase of ≥0.08 points in the EQ-5D-5L index score represents a meaningful improvement in 
patient’s HRQoL. The EQ-5D-5L has a recall period of one day. The index score (range -1 -1) 
and the VAS score (range 0 to 100) will be summarised as continuous variables. Additionally, 
the proportion of subjects with an increase of ≥0.08 points in the EQ-5D-5L index score at week 
4 from each baseline will be summarised.
Patient Assessment of Upper Gastrointestinal Disorders Quality-of-Life Index 
(PAGI-QOL)
The PAGI-QOl is an upper-GI (UGI)-disorder specific questionnaire and will be used in order to 
evaluate with more sensitivity the treatment-induced changes in HRQoL. The PAGI-QOL is a 
validated and reliable instrument used to measure QOL in patients with UGI disorders including 
GERD, dyspepsia, and gastroparesis. The PAGI-QOL instrument consists of 30 items, each with 
response options based on a 6-point Likert scale ranging from "None of the time" (0) to "All of 
the time (5) and with a recall period of the previous 2 weeks. The items are grouped into 
5 dimensions:

Daily Activities (10 items).

Clothing (2 items).

Diet and Food Habits (7 items).

Relationship (3 items).

Psychological Well-Being and Distress (8 items).
A score per dimension as well as a total score can be calculated. PAGI-QOL subscale scores are 
calculated by taking the mean of the items in each subscale after reversing item scores. PAGI-
QOL subscale scores range from 0 (lowest QoL) to 5 (highest QoL). In case of missing data, the 
half-scale rule is applied (ie, the subscale score is calculated when 50% or less of the items are 
missing for that scale; if more than 50% of the items within a subscale are missing, the score is 
set to missing). The PAGI-QOL total score is calculated by taking the mean of the corresponding 
subscales. If a subscale score is set to missing the PAGI-QOL total score is then set to missing.
Only the total score will be summarised.
Patient Assessment of Upper Gastrointestinal Disorders Symptom Severity Index (PAGI-
SYM)
Changes in UGI symptoms will be measured with the PAGI-SYM, a validated and reliable 
instrument used to measure symptom severity in patients with UGI disorders including GERD, 


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dyspepsia, and gastro paresis. The PAGI-SYM measures UGI symptom severity over the 2 
weeks preceding the visit. The PAGI-SYM contains 20 items, each on a 6-point Likert scale 
ranging from None (0) to Very severe (5). The PAGI-SYM includes 6 subscales:
∀
Heart burn/regurgitation (7 items).
∀
Post-prandial fullness/early satiety (4 items).
∀
Nausea/vomiting (3 items).
∀
Bloating (2 items).
∀
Upper abdominal pain (2 items).
∀
Lower abdominal pain (2 items).
The PAGI-SYM subscale scores are calculated by taking the mean of the items in each subscale; 
the subscale scores vary from 0 (none or absent) to 5 (very severe). The half-scale rule is applied 
for missing data (ie, the subscale score is calculated using the mean of non-missing items; when 
more than 50% of items are missing, the score is set to missing). The total score is calculated by 
taking the mean of the subscales. If a subscale score is missing, the PAGI-SYM total score is set 
to missing. Only the total score will be summarised.
PAGI-SYM will be used to identify patients that are more likely to be functional patients. PAGI-
SYM will also be used to identify meaningful change in RESQ-eD.
Exploratory Analyses
7.11
SAFETY ANALYSIS
Safety analyses include AEs, clinical laboratory values, vital signs, and other safety parameters. 
All safety summaries will be based on the SAF. The analysis of safety data will be restricted to 
descriptive statistics only unless otherwise specified. AE tables will include individual treatment 
columns and a column for both Vonoprazan arms combined (Total Vonoprazan) as well as Total 
over all 3 arms.
CCI


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7.11.1 Adverse Events
See the protocol for definitions of pretreatment events (PTE), adverse events (AEs) and serious 
AEs (SAEs). Treatment-emergent adverse events (TEAEs) will be defined as any AE that occurs 
after the first dose of study drug during the randomized double blind period (for the purposes of 
assigning an AE to this period the start of the randomized double blind period will be from time 
of randomization on Day 1) and up to until 1 week after completion or withdrawal from the 
study (safety follow-up call). PTEs and AEs occurring during the run-in phase will be listed and 
summarized by SOC and PT. 
There are no AEs of special interest defined for the study.
The MedDRA dictionary, version 20 or higher, will be used to code all AEs reported during the 
trial by SOC and PT. 
All TEAE summaries will be arranged in alphabetical order of SOC then by descending 
frequency (subject frequency) of the preferred term (PT) within the Total Vonoprazan treatment 
group.
AEs with missing intensity will be listed as such in the AE listings, however, will be noted with 
an asterisk and summarized as severe in summary tables. If the relationship of an event is 
missing, the relationship for the event will be considered to have been related. In the cases where 
a subject has multiple AEs with the same SOC or PT the AE with the maximum intensity or 
strongest relationship will be summarized. When calculating the frequency and percentage of 
subjects who reported TEAEs, a subject will be counted only once for each SOC or PT when 
multiple TEAEs are coded to the same SOC or preferred term. Thus, if a subject has two distinct 
AEs, each of which corresponds to a distinct preferred term but both of which correspond to the 
same SOC, then that subject will be counted once at that SOC subject-count summary level and 
once at each of the two preferred-term subject-count summary levels.
The number and percentage of subjects with TEAEs will be summarized in several different 
tables:

Overview of TEAEs (including number and percentage of patients and events).

All TEAEs by SOC and PT.

All TEAEs by SOC.

All TEAEs by PT.

Most frequent TEAEs by SOC and PT (occurring in ≥5% of subjects within one treatment 
group).

Most frequent non-serious TEAEs by SOC and PT (occurring in ≥5% of subjects within one 
treatment group).

Relationship of TEAEs to Study Drug by SOC and PT (not related, related).


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
Drug-Related TEAEs by SOC and PT.

Intensity of TEAEs by SOC and PT.

Intensity of Drug-Related TEAEs by SOC and PT.

TEAEs Leading to Study Drug Discontinuation by SOC and PT.

Serious TEAEs by SOC and PT.

Pretreatment Events by SOC and PT.

Pretreatment Serious Events by SOC and PT.

Run-in Adverse Events by SOC and PT.

Serious Run-in Adverse Events by SOC and PT.

Listing of Deaths.
Subject mappings will also be produced for:

TEAEs.

TEAEs leading to study drug discontinuation.

Serious TEAEs.
A list of PTEs by subject number and MedDRA coding will be presented separately. PTEs will 
be summarized by SOC and PT
7.11.2 Clinical Laboratory Evaluations
Clinical laboratory tests and urinalysis will be performed at Screening, Visit 4 (Randomization, 
Day 1), Visit 5 (Day 14) and Visit 6 (EOT or early termination). Laboratory values will be 
summarized, for absolute and change from baseline (Visit 4) values and will be presented by 
parameter and visit for the SAF. Values will be mapped to a scheduled visit by the use of visit 
windows, if a subject has multiple values within a particular visit window, the most extreme 
result will be used for summary. Additionally a final visit summary will be provided, 
summarizing the last recorded values. All laboratory test parameters will be displayed in 
individual subject data listings in standard international (SI) units. Shifts in laboratory test values 
will be presented as cross-tabulations (baseline versus each post-baseline visit) of numbers of 
subjects with low, normal and high values relative to the normal range used at the central 
laboratory. This classification will be based on the low, normal and high alert flags reported by 
the central laboratory. Shift tables will be produced for all clinical laboratory tests with reference 
ranges. Individual results for clinical laboratory tests that meet the predefined criteria for 
markedly abnormal laboratory values (MAV) will be summarized in tables. MAV criteria are 
given in Appendix.


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Visit Windows for Safety Laboratory Parameters
visit
Baseline
Week 2
Week 4/ET
Day
<=1
14
28
window
<=1
2-21
22 - 42
Liver function parameters ALT, AST and total bilirubin will be reported separately. In addition 
to the standard shift table, the number of subjects with AST, ALT and total bilirubin values 
> upper limit of normal (based on the central laboratory defined normal range), >2 ULN and 
>3ULN will also be summarized by visit and overall (double blind period). Additionally the 
number of subjects with AST or ALT >3 ULN and with total bilirubin >2ULN will also be 
summarised by visit and overall (double blind period).
The following tables will be produced:
∀
Summary of Laboratory Test Results and Change from Baseline by Study Visit.
∀
Number and Percent of Subjects in Categories of Urine Laboratory Parameters by Visit.
∀
Summary of Shifts of Laboratory Test Results.
∀
Number and Percent of Subjects With MAVs of Laboratory Parameters.
∀
Number and Percent of Subjects With Elevated Liver Enzyme Laboratory Parameters.
Subject mappings will also be produced for:
∀
The Number and Percent of Subjects With MAVs of Laboratory parameters.
∀
Subjects With Elevated Liver Enzyme Laboratory Parameters.
To obtain information on H. pylori infection status at baseline a 13C or 14C urea breath test will 
be performed at Randomization by the local laboratory. A stool test or blood test to measure the 
infection of H. pylori may be performed at those centers which do not have the facilities to 
perform a H pylori breath test procedure. The results of the H. Pylori tests will be listed 
separately from the other laboratory parameters. A summary of H. Pylori status (number and 
percent of Subjects by H Pylori status) will be included in the baseline and demographic tables.
7.11.3 Vital Signs
Vital signs, including body temperature (°C), sitting blood pressure (mmHg) and pulse (bpm), 
and weight (kg) will be measured at Visit 1 (Screening), Visit 4 (Day 1, Randomization), and 
CCI


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Visit 6 (day 28, End of Treatment) or Early Termination. Height (cm) will also be measured at 
Screening. Measures taken at Visit 4 (Day 1) will be considered as baseline values. Vital signs 
will be summarized by visit and treatment group for the SAF. Change from baseline (Visit 4, 
Day 1) will also be summarized for Visit 6 (Day 28). Data will be assigned to the visit at which it 
is indicated they were collected in the eCRF. No statistical analysis will be performed on vital 
signs data. Individual results for vital signs parameters that meet the predefined criteria for 
MAVs will be summarized in tables. MAV criteria are given in Appendix.
The following tables and subject mappings will be produced:

Summary of Vital Signs Parameters and Change from Baseline by Visit.

Number and Percent of Subjects With MAVs of Vital Signs Parameters.

Subject Mappings for the Number and Percentage of Subjects With MAVs of Vital Signs 
Parameters.
Listings of all vital signs will be provided for all subjects. MAVs will also be flagged in the 
listings.
7.11.4 12-Lead ECGs
12-lead ECG (comprising interpretation (within normal limits, abnormal but not clinically 
significant, or abnormal and clinically significant), heart rate, RR interval, PR interval, QT 
interval and QRS interval) will be measured at Visit 1 (Screening), Visit 4 (Day 1, 
Randomization), and Visit 6 (day 28, End of Treatment) or Early Termination. Measures taken at 
Visit 4(Day 1) will be considered as baseline values. ECG will be summarized by visit and 
treatment group for the SAF. Change from baseline (Visit 4, Day 1) will also be summarized for 
Visit 6 (Day 28). Data will be assigned to the visit at which it is indicated they were collected in 
the eCRF. The corrected QT using the Fredericia correction (QTcF = QT/∛) will also be 
calculated and presented. No statistical analysis will be performed on vital signs data. Individual 
results for ECG parameters that meet the predefined criteria for MAVs will be summarized in 
tables. MAV criteria are given in Appendix.
The following tables and subject mappings will be produced:

Summary of ECG Parameters and Change from Baseline by Visit.

Number and Percent of Subjects With MAVs of 12-lead ECG Parameters.

Number and Percent of Subjects in Various Categories of ECG Parameters.

Subject Mappings for the Number and Percentage of Subjects With MAVs of ECG 
Parameters.

Subject Mappings for the Subjects in Various Categories of ECG Parameters.


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Listings of all vital signs will be provided for all subjects. MAVs will also be flagged in the 
listings.
7.11.5 Other Observations Related to Safety
Weight (kg) will be measured at Visit 1 (Screening), Visit 4 (Day 1, Randomization), and Visit 6 
(day 28, End of Treatment) or Early Termination. Measures taken at Visit 4 (Day 1) will be 
considered as baseline values. Weight will be summarized by visit and treatment group for the 
SAF. Change from baseline (Visit 4, Day 1) will also be summarized for Visit 6 (Day 28). Data 
will be assigned to the visit at which it is indicated they were collected in the eCRF. No 
statistical analysis will be performed. 
The following tables will be produced:

Summary of Weight and Change from Baseline by Visit.
A listing of weight will be provided for all subjects, including height(cm) and BMI (kg/m2) at
Screening.
A physical examination will be conducted at Visit 1 (Screening), Visit 4 (Day 1, 
Randomization), and Visit 6 (day 28, End of Treatment) or Early Termination. The physical 
examination at Visit 4 (occurring prior to first dose of double blind treatment) will be considered 
as baseline. This examination will consist of the following body systems: eyes; ears, nose, throat; 
cardiovascular system; respiratory system; gastrointestinal system; dermatologic system;
extremities; musculoskeletal system; nervous system; lymph nodes; and other. All subsequent 
physical examinations should assess clinically significant changes from the assessment from the 
baseline examination. Physical examination data will only be listed; any clinically significant 
changes are captured and reported as AEs.
7.12
INTERIM ANALYSIS
Not applicable
7.13
CHANGES IN THE STATISTICAL ANALYSIS PLAN
No changes


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8.0
REFERENCES
Study Protocol, dated 25 November 2015
Study Protocol Amendment 1, dated 15 February 2016 (non-substantial)
Study Protocol Amendment 2, dated 26 March 2016 (non-substantial)


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9.0
APPENDIX
9.1 CLINICAL LABORATORY TESTS
Hematology
Serum Chemistry
Urinalysis
Hematocrit
Hemoglobin
Platelet count
RBC count
Reticulocyte count
WBC count (with differential) 
Erythrocyte indices (MCV, MCH, 
MCHC) 
Coagulation Tests
Prothrombin time
Partial thromboplastin time
International normalized ratio
ALT
Albumin
Alkaline phosphatase
Amylase
AST
Blood urea nitrogen
Calcium
Chloride
Cholesterol
CK 
C-reactive protein (CRP) (a)
Gastrin tests (b)
γ-Glutamyl transferase
Glucose
Lactate dehydrogenase
Magnesium
Pepsinogen I/II(c)
Potassium
Phosphate
Serum creatinine
Sodium
Standard iron panel (serum iron, TIBC, serum 
ferritin) (d)
Total bilirubin
Direct bilirubin (e)
Total protein
Triglycerides
Uric acid
Bilirubin
Glucose
Hemoglobin
Ketones
Leucocytes
Nitrites
pH
Protein
Specific gravity
Urobilinogen
Microscopy for 
abnormal urinalysis 
result (RBCs, WBCs, 
casts, crystals, 
organisms, and 
epithelial cells)


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Other:
Serum
Urine
Breath
Hepatitis panel, including HBsAg and 
anti-HCV
Thyroid-stimulating hormones (TSH)(f)
Female subjects only
hCCGI (for pregnancy, female subjects of 
childbearing potential)
All subjects
Drug screen including: amphetamines 
(including methamphetamine), barbiturates, 
benzodiazepines, cannabinoids, cocaine, 
opiates, methadone and phencyclidine (h)
Helicobacter pylori (i)
Female subjects only
Beta hCG (for pregnancy, female 
subjects of childbearing potential)
Follicle-stimulating hormone (FSH) if 
menopause is suspected (g)
MCH=mean corpuscular hemoglobin, MCHC=mean corpuscular hemoglobin concentration, MCV= mean 
corpuscular volume, RBC=red blood cell, TIBC= total iron binding capacity, WBC=white blood cell. 
(a) CRP will be collected at Visit 4 and Visit 6(or Early termination). 
(b) Gastrin and Gastrin-17 will be performed.
(c) This includes pepsinogen I, pepsinogen II and pepsinogen I/II ratio.
(d) Standard iron panel will be collected at Visit 1 and Visit 6(or Early termination). 
(e) Assess direct bilirubin only if total bilirubin >1.5×ULN. 
(f) TSH will be checked at Visit 4 and Visit 6(or Early termination).
(g) Follicle-stimulating hormone will be conducted at investigator’s discretion to determine the postmenopausal 
status of women whose duration of (consecutive) amenorrhea is borderline or open to doubt and where the 
investigator believes the subject to be menopausal by history. 
(h) The central laboratory will confirm any positive drug screen results.
(i) Helicobacter pylori breath test will be performed at Randomization via a urea breath test (C13 or C14 urea test) 
at a local laboratory. A stool test or a blood test may be performed at those centers which do not have the facilities to 
perform a H pylori breath test procedure.


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9.2 CRITERIA FOR MARKEDLY ABNORMAL VALUES
Hematology
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Red Blood Cells (×1012/L)
<0.8×LLN
>1.2×ULN
White Blood Cells (×109/L)
<0.5×LLN
>1.5×ULN
Hemoglobin (g/L)
<0.8×LLN
>1.2×ULN
Hematocrit (%)
<0.8×LLN
>1.2×ULN
Platelets (×109/L)
<75
>600
Neutrophils (%）
<0.5×LLN
>1.5×ULN
Eosinophils (%）
-
>2×ULN
Basophils (%）
-
>3×ULN
Monocytes (%）
-
>2×ULN
Lymphocytes (%）
<0.5×LLN
>1.5×ULN


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Serum Chemistry
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
ALT (U/L)
-
>3×ULN
ALP (U/L)
-
>3×ULN
AST (U/L)
-
>3×ULN
GGT (U/L)
-
>3×ULN
Total Bilirubin (μmol/L)
-
>34.2
Direct Bilirubin (μmol/L)
-
>2×ULN
CK (CPK) (U/L)
-
>5×ULN
Albumin (g/L)
<25
-
Total Protein (g/L)
<0.8×LLN
>1.2×ULN
Creatinine (μmol/L)
-
>177
BUN (mmol/L)
-
>10.7
Uric Acid (mmol/L)
-
>0.773
Total Cholesterol (mmol/L)
-
>7.72
Triglycerides (mmol/L)
-
>2.5×ULN
Glucose (mmol/L)
<2.8
>19.4
Potassium (mmol/L)
<3.0
>6.0
Sodium (mmol/L)
<130
>150
Magnesium (mmol/L)
<0.5
>1.2
Calcium (mmol/L)
<1.75
>2.88
Inorganic Phosphorus (mmol/L)
<0.52
>2.00
Chloride (mmol/L)
<75
>126
Vital Signs
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Body Temperature (C)
<35.6
>37.7
Systolic Blood Pressure (mmHg)
<85
>180
Diastolic Blood Pressure (mmHg)
<50
>110
Pulse (bpm)
<50
>120


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12-lead ECG
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Heart Rate (bpm)
<50
>120
QT Interval (msec)
<=50
>=460
QTcF Interval (msec)
<=50
>=500 OR (>=30 change 
from baseline and >=450)


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䣘䣱䣰䣱䣲䣴䣣䣼䣣䣰䢯䢴䢲䢲䢳䢢䣕䣶䣣䣶䣫䣵䣶䣫䣥䣣䣮䢢䣃䣰䣣䣮䣻䣵䣫䣵䢢䣒䣮䣣䣰䢢䢴䢲䢳䢻䢯䢲䢳䢯䢳䢷
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PPD