Conditions: Helicobacter Pylori
Keywords: Drug Therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 44
Healthy volunteers: no

Brief summary:
Helicobacter Pylori (H Pylori) is a bug found in the digestive system. It can cause soreness and redness in the stomach (gastritis). It can also cause ulcers in the stomach and other parts of the digestive system. Vonoprazan is a medicine to treat people with H Pylori. It is taken together with other medicines to fight infections caused by H Pylori.

The main aim of this study is to learn if vonoprazan changes how the other medicines are processed by the body. It will be compared with another medicine called esomeprazole. Other aims are to check for side effects from the study medicines.

At the first visit, the study doctor will check who can take part. Participants who take part will be picked for 1 of 2 treatments by chance.

* Vonoprazan taken with bismuth, clarithromycin, and amoxicillin
* Esomeprazole taken with bismuth, clarithromycin, and amoxicillin

Both treatments will last for 14 days. Participants will stay in the clinic throughout their treatment.

After treatment, the clinic staff will telephone the participants 2 days later for a check-up. The participants will visit the clinic 4 weeks later for a final check-up.

Detailed description:
This is a study in healthy participants with Helicobacter pylori (HP positive) to evaluate the safety, tolerability and PK of a quadruple therapy with bismuth, clarithromycin, amoxicillin, and vonoprazan versus quadruple therapy with bismuth, clarithromycin, amoxicillin, and esomeprazole.

The treatment phase consists of quadruple therapy twice daily (BID) with bismuth potassium citrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and vonoprazan (20 mg) (Group B) or quadruple therapy BID with bismuth potassium citrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and esomeprazole (20 mg) (Group A) from Days 1 to 14. Participants will be discharged on Day 15 after all procedures have been performed.

This single-center will be conducted in China. Participants will remain confined to the study site from check-in (Day -1) through Day 15 and will followed up through call on Day 17 and return on Day 42 for a follow-up assessment.

Arms:
arm 1: Clarithromycin 500 milligram (mg), tablets, orally, BID, along with amoxicillin 1000 mg, capsules, orally, BID, bismuth potassium citrate 600 mg, capsules, orally, BID, and vonoprazan 20 mg, tablets, orally, BID on Days 1 to 14. arm 2: Clarithromycin 500 mg, tablets, orally, BID, along with amoxicillin 1000 mg, capsules, orally, BID, bismuth potassium citrate 600 mg, capsules, orally, BID, and esomeprazole 20 mg, tablets, orally, BID on Days 1 to 14.

Interventions: intervention 1: Clarithromycin intervention 2: Amoxicillin intervention 3: Bismuth potassium citrate intervention 4: Esomeprazole intervention 5: Vonoprazan
Intervention descriptions: intervention 1: Clarithromycin tablets. intervention 2: Amoxicillin capsules. intervention 3: Bismuth potassium citrate tablets. intervention 4: Esomeprazole tablets. intervention 5: Vonoprazan tablets.

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Study Number: 
A Phase 1, Double-Blind, Parallel Group Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Quadruple 
Therapy (Bismuth, Clarithromycin, and Amoxicillin) With 
Vonoprazan Versus Quadruple Therapy With Esomeprazole
NCT04753437
Vonoprazan-1001
Protocol Version and Date: 
Version 2: 23-June-2021 


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Double-Blind, Parallel Group Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Quadruple Therapy (Bismuth, Clarithromycin, and Amoxicillin) With 
Vonoprazan Versus Quadruple Therapy With Esomeprazole 
Study Identifier:
Vonoprazan-1001
Compound:
TAK-438 (vonoprazan)
Date:
23 June 2021
Version Number:
2
Date
Amendment Number
Amendment Type
Region
23 June 2021
Amendment 1
Substantial
China
28 October 2020
Initial protocol
Not applicable
China
PI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
With
With
us
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col
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me
keda: For non-co


Vonoprazan (TAK-438)
Study ID Vonoprazan-1001 
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
1.1
Protocol Amendment 1 Summary of Changes..........................................................10
2.0
STUDY SCHEMATIC..................................................................................................13
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................14
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.2
Rationale for the Proposed Study.............................................................................18
4.3
Benefit-Risk Profile .................................................................................................19
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................19
5.1
Hypothesis...............................................................................................................19
5.2
Trial Objectives .......................................................................................................19
5.3
Endpoints.................................................................................................................20
5.3.1
Primary Endpoint.............................................................................................20
5.3.2
Secondary Endpoints .......................................................................................20
5.3.3
Safety Endpoints..............................................................................................20
5.3.4
Exploratory Endpoints .....................................................................................20
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................20
6.1
Trial Design.............................................................................................................20
6.2
Dose Escalation .......................................................................................................21
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................21
6.3.1
Rationale of Trial Design.................................................................................21
6.3.2
Rationale for Dose...........................................................................................22
6.3.3
Rationale for Endpoints ...................................................................................22
6.3.3.1
Efficacy Endpoints ..................................................................................22
6.3.3.2
Safety Endpoints......................................................................................22
6.3.3.3
PK Endpoints...........................................................................................22
6.3.3.4
Exploratory Biomarker Research .............................................................22
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures..............22
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................22
6.5
Trial Beginning and End/Completion.......................................................................22
6.5.1
Definition of Beginning of the Trial.................................................................22
6.5.2
Definition of End of the Trial...........................................................................23
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6.5.3
Criteria for Premature Termination or Suspension of the Study or 
Investigational Sites.........................................................................................23
6.5.3.1
Criteria for Premature Termination or Suspension of the Study................23
6.5.3.2
Criteria for Premature Termination or Suspension of a Site......................23
6.5.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site .........................................................23
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............23
7.1
Inclusion Criteria .....................................................................................................23
7.2
Exclusion Criteria ....................................................................................................24
7.3
Excluded Medications, Supplements, Dietary Products............................................26
7.4
Diet, Fluid, Activity.................................................................................................27
7.4.1
Diet and Fluid..................................................................................................27
7.4.2
Activity ...........................................................................................................28
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................28
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................29
7.7
Subject Replacement................................................................................................29
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................29
8.1
Clinical Study Drug .................................................................................................29
8.1.1
Clinical Study Drug Labeling ..........................................................................30
8.1.2
Clinical Study Drug Inventory and Storage......................................................30
8.1.3
Clinical Study Drug Blinding...........................................................................31
8.1.4
Randomization Code Creation and Storage......................................................31
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure..................................31
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs.............................31
9.0
STUDY PROCEDURES...............................................................................................33
9.1
Administrative Procedures.......................................................................................33
9.1.1
Informed Consent Procedure............................................................................33
9.1.1.1
Pharmacogenomic Informed Consent Procedure......................................33
9.1.2
Documentation of Screen Failure.....................................................................33
9.1.3
Inclusion and Exclusion...................................................................................34
9.1.4
Medical History/Demography..........................................................................34
9.1.5
Concomitant Medications ................................................................................34
9.2
Clinical Procedures and Assessments.......................................................................35
9.2.1
Full Physical Examination ...............................................................................35
9.2.2
Height and Weight...........................................................................................35
9.2.3
BMI.................................................................................................................35
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9.2.4
Vital Signs.......................................................................................................35
9.2.5
12-Lead ECG...................................................................................................36
9.2.6
Study Drug Administration..............................................................................36
9.2.7
AE Monitoring ................................................................................................36
9.2.7.1
PTE and AE Collection Period.................................................................36
9.2.7.2
PTE and AE Reporting ............................................................................36
9.2.7.3
Collection and Reporting of SAEs ...........................................................37
9.2.8
Laboratory Procedures and Assessments..........................................................38
9.2.8.1
Clinical Laboratory Tests.........................................................................38
9.3
Biomarker, PK, and Pharmacogenomics Samples ....................................................40
9.3.1
Collection of Urine for PK...............................................................................41
9.3.2
PK Measurements............................................................................................41
9.3.2.1
Plasma or Serum for PK Measurements...................................................42
9.3.2.2
Urine for PK Measurements.....................................................................42
9.3.3
Biomarker Measurements ................................................................................42
9.3.4
Pharmacogenomics Measurements...................................................................42
9.3.4.1
Blood Sample for DNA Pharmacogenomics Measurements.....................42
9.3.5
Confinement....................................................................................................43
10.0
ADVERSE EVENTS ....................................................................................................43
10.1
Definitions and Elements of AEs .............................................................................43
10.1.1
SAEs ...............................................................................................................45
10.1.2
Special Interest AEs.........................................................................................46
10.2
AE Procedures.........................................................................................................46
10.2.1
Assigning Severity/Intensity of AEs ................................................................46
10.2.2
Assigning Causality of AEs .............................................................................47
10.2.3
Start Date.........................................................................................................47
10.2.4
End Date..........................................................................................................47
10.2.5
Pattern of AE (Frequency) ...............................................................................47
10.2.6
Action Taken With Study Treatment................................................................47
10.2.7
Outcome..........................................................................................................48
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs................................................................................................................48
10.2.8.1
Collection Period.....................................................................................48
10.2.8.2
Reporting AEs.........................................................................................48
10.2.8.3
Reporting SAEs.......................................................................................49
10.2.8.4
Reporting Special Interest AEs ................................................................50
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10.2.8.5
Reporting of Abnormal LFTs...................................................................50
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...50
11.0
STATISTICAL METHODS..........................................................................................50
11.1
Statistical and Analytical Plans ................................................................................50
11.1.1
Analysis Sets ...................................................................................................50
11.1.1.1
Safety Set ................................................................................................51
11.1.1.2
PK Set .....................................................................................................51
11.1.2
Analysis of Demography and Other Baseline Characteristics ...........................51
11.1.3
PK Analysis.....................................................................................................51
11.1.4
Safety Analysis................................................................................................51
11.1.4.1
AEs .........................................................................................................51
11.1.4.2
Clinical Laboratory Evaluation, Vital Signs, and ECG.............................51
11.2
Interim Analysis and Criteria for Early Termination ................................................52
11.3
Determination of Sample Size..................................................................................52
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................52
12.1
Study-Site Monitoring Visits ...................................................................................52
12.2
Protocol Deviations..................................................................................................52
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................53
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................53
13.1
IRB and/or IEC Approval ........................................................................................53
13.2
Subject Information, Informed Consent, and Subject Authorization .........................54
13.3
Subject Confidentiality ............................................................................................55
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................56
13.4.1
Publication and Disclosure...............................................................................56
13.4.2
Clinical Trial Registration................................................................................56
13.4.3
Clinical Trial Results Disclosure......................................................................56
13.5
Insurance and Compensation for Injury....................................................................57
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................57
14.1
Administrative Information......................................................................................57
14.1.1
Study Contact Information...............................................................................57
14.1.2
Investigator Agreement....................................................................................58
14.1.3
Study-Related Responsibilities.........................................................................59
14.1.4
List of Abbreviations .......................................................................................60
15.0
DATA HANDLING AND RECORDKEEPING............................................................61
15.1
CRFs (Electronic and Paper)....................................................................................61
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15.2
Record Retention .....................................................................................................61
16.0
REFERENCES..............................................................................................................62
17.0
APPENDICES...............................................................................................................63
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................27
Table 8.a
Investigational Drugs .........................................................................................30
Table 9.a
Collection of Blood Samples for PK Analysis ....................................................41
Table 9.b
Time Windows for PK Blood Sample Collection ...............................................41
Table 9.c
Collection of Urine Samples for PK Analysis.....................................................41
Table 10.a
Takeda Medically Significant AE List................................................................46
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................63
Appendix B
Elements of the Subject Informed Consent.........................................................65
Appendix C
Investigator Consent to the Use of Personal Information ....................................68
Appendix D
Pregnancy and Contraception.............................................................................69
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples..............................71
Appendix F
Protocol History.................................................................................................75
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Vonoprazan (TAK-438)
Study ID Vonoprazan-1001 
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Asia Pte Ltd
8 Marina Boulevard #15-01
Marina Bay Financial Centre
Singapore 018981.
Compound:
Vonoprazan (TAK-438)
Study Identifier: Vonoprazan-1001
Phase: 1
Protocol Title: A Phase 1, Double-Blind, Parallel Group Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Quadruple Therapy (Bismuth, Clarithromycin, and Amoxicillin) With Vonoprazan Versus 
Quadruple Therapy With Esomeprazole.
Trial Design:
A phase 1, double-blind, parallel group study in healthy subjects with Helicobacter pylori (H pylori–positive) to 
evaluate the safety, tolerability, and pharmacokinetics (PK) of a quadruple therapy with bismuth, clarithromycin, 
amoxicillin, and vonoprazan versus quadruple therapy with bismuth, clarithromycin, amoxicillin, and esomeprazole. 
Approximately 42 (maximum 46 subjects) H pylori–positive healthy subjects aged 18 to 60 years, inclusive, who are 
considered eligible based on the inclusion and exclusion criteria, will participate in this study. All subjects will be 
enrolled and randomized to 1 of the 2 treatment groups as indicated in the schematic in Section 2.0.
The treatment phase will consist of quadruple therapy twice daily (BID) with bismuth potassium citrate (600 mg 
[equivalent to 220 mg bismuth]), BID clarithromycin (500 mg), amoxicillin (1000 mg), and vonoprazan (20 mg) 
(Group B) or quadruple therapy BID with bismuth potassium citrate (600 mg), clarithromycin (500 mg), amoxicillin 
(1000 mg), and esomeprazole (20 mg) (Group A) administered from Days 1 to 14. Subjects will be discharged on Day 
15 after all procedures have been performed. The subjects who complete study treatment are to be followed-up at 
Week 4 post-treatment to provide a 13C urea breath test (13C UBT) for H pylori.
Trial Primary Objective:
To evaluate the safety, tolerability, and PK of quadruple therapy with bismuth, clarithromycin, amoxicillin, and 
vonoprazan versus quadruple therapy with bismuth, clarithromycin, amoxicillin, and esomeprazole. 
Trial Subject Population: H pylori positive, healthy male and female subjects in China, aged 18 to 60 years, 
inclusive
Planned Number of Subjects:
Approximately 42 (maximum 46, if drop-out rate from 
PK Analysis Set increases to more than 25%)
Planned Number of Sites:
1 site in China
Dose Levels:
Vonoprazan (20 mg)
Bismuth potassium citrate (600 mg equivalent to 
bismuth 220 mg)
Clarithromycin (500 mg)
Amoxicillin (1000 mg)
Esomeprazole (20 mg)
Route of Administration:
Oral
Duration of Treatment:
Quadruple therapy BID for 14 days (Days 1 to 14)
Planned Trial Duration:
Approximately 70 days (including screening, Day -1 
through study exit, follow-up call, and follow-up visit)
Main Criteria for Inclusion:
To be eligible for study participation, subjects must: 
1.
Be H pylori–positive healthy male or female subjects aged 18 to 60 years.
2.
Have a body mass index between >18.0 and ≤30.0 kg/m2 and weigh ≥50 kg
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Vonoprazan (TAK-438)
Study ID Vonoprazan-1001 
Page 8 of 75
Protocol Amendment 1
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Main Criteria for Exclusion:
The subject must be excluded from participating in the study if the subject has: 
1.
A history of hypersensitivity to clarithromycin, amoxicillin, or any excipients of vonoprazan and esomeprazole.
2.
A history of gastroesophageal reflux disease (GERD), symptomatic GERD, erosive esophagitis, duodenal ulcer, 
gastric ulcer, Barrett’s esophagus, or Zollinger-Ellison syndrome.
3.
Levels of aspartate aminotransferase, alanine aminotransferase, or total bilirubin levels above the upper limit of 
normal.
4.
A history of neurological diseases.
5.
Any clinically significant disease or is currently using prescription medications or herbal therapies.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the study is:
!
Evaluation of bismuth plasma PK parameters when bismuth potassium citrate (600 mg [equivalent to 220 mg 
bismuth]) BID is coadministered with clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and vonoprazan 
(20 mg BID), and when coadministered with clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and 
esomeprazole (20 mg BID):
–
Maximum observed plasma concentration (Cmax) at Day 14.
–
The area under the plasma concentration-time curve during a dosing interval (AUCτ) at Day 14.
–
The amount of drug excreted in urine during a dosing interval (Aeτ) at Day 14.
The secondary endpoints will be assessed through evaluation of the following parameters: 
!
Percentage of subjects who experience at least 1 treatment-emergent adverse event (TEAE).
!
Percentage of subjects who discontinue due to an adverse event (AE).
Safety endpoints are as follows:
!
Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at least once post dose.
!
Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at least once post 
dose.
!
Percentage of subjects who meet the markedly abnormal criteria for safety electrocardiogram (ECG) parameters 
at least once post dose.
Statistical Considerations:
AEs
All TEAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Data will be 
summarized using Preferred Term and primary System Organ Class. All TEAEs, drug-related TEAEs, serious TEAEs, 
and TEAEs leading to study drug discontinuation will be summarized by treatment group (vonoprazan quadruple 
therapy and esomeprazole quadruple therapy)
Clinical Laboratory Evaluations, Vital Signs, and 12-Lead Electrocardiograms
Observed values and changes from baseline for continuous variables will be summarized over time by treatment group 
using descriptive statistics.
For categorical variables, shift tables will be presented by treatment group.
The number and percentage of subjects who meet the markedly abnormal criteria at least once post dose for safety 
laboratory tests, vital sign measurements, and safety ECG parameters will be summarized by treatment group.
PK
Plasma concentrations of bismuth, freebase of vonoprazan (TAK-438F), and esomeprazole will be summarized at 
each scheduled sampling point by treatment group using descriptive statistics. The plasma and urine PK parameters of 
bismuth at Day 14 will be summarized by treatment group using descriptive statistics.
Point estimate and the 2-sided 90% and 95% CIs of the geometric mean ratios between treatment group will be 
calculated using an analysis of variance with natural log-transformed AUCτ and Cmax of bismuth. It will be concluded 
that vonoprazan has no significant effect on bismuth PK compared with esomeprazole if the 90% CIs for AUCτ and 
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Vonoprazan (TAK-438)
Study ID Vonoprazan-1001 
Page 9 of 75
Protocol Amendment 1
23 June 2021
Cmax completely fall within 0.5 to 2.0.
Statistical analyses of other plasma and urine PK parameters will be performed if appropriate.
Sample Size Justification: 
The study will randomize approximately 42 subjects (maximum 46 subjects, if drop-out rate from PK Analysis Set 
increases to more than 25%) to provide at least 80% power of showing no significant difference in Cmax and AUCτ of 
bismuth potassium citrate between vonoprazan and esomeprazole quadruple therapy. 
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Vonoprazan (TAK-438)
Study ID Vonoprazan-1001 
Page 10 of 75
Protocol Amendment 1
23 June 2021
1.1
Protocol Amendment 1 Summary of Changes
Rationale for Amendment 1
This section describes the changes in reference to the protocol incorporating Amendment 1. The 
primary reasons for this amendment are to:
!
Increase the planned sample size from 34 to 42 subjects (maximum 46 subjects).
!
Amend inconsistencies between different sections of the protocol concerning the neurological 
examination.
!
Standardize the interval for continued contraception use (inclusion criteria), anticipated 
pregnancy (exclusion criteria) and reporting of pregnancy (Appendix D) to 4 weeks.
!
Clarify procedures for protocol deviations and add time windows for pharmacokinetic (PK) 
sample collection.
!
Update PK sample storage conditions.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1
Section 1.0 STUDY SUMMARY
Sponsor’s address updated
Administrative
2
Section 1.0 STUDY SUMMARY
Section 11.3 Determination of Sample Size
The planned sample size 
was increased from 
approximately 34 to 42 
subjects (maximum of 46 
subjects).
This change is being 
implemented to account for 
an observed
discontinuation rate of 
approximately 25% 
compared to the predicted 
drop out rate of 10%. 
Increasing the sample size 
to 42 subjects (maximum 
46 if dropout rate increases 
above 25%) will provide 30 
completers and retain the 
power of the study.
3
Section 1.0 STUDY SUMMARY
Section 3.0 Schedule of Study Procedures
Section 9.2.8 Laboratory Procedures and 
Assessments
Clarification that follow up 
13C urea breath test was 
only performed for subjects 
who completed the study 
treatment
To clarify end of study 
procedures
4
Section 3.0 Schedule of Study Procedures
Section 9.2 Clinical Procedures and 
Assessments
Description and timing of 
neurological exam has been 
amended.
To correct inconsistencies 
between Section 3.0 and 
Section 9.2.1.
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Vonoprazan (TAK-438)
Study ID Vonoprazan-1001 
Page 11 of 75
Protocol Amendment 1
23 June 2021
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
5
Section 3.0 Schedule of Study Procedures
Section 9.2.5 12-Lead ECG
Time window for 
electrocardiogram (ECG) 
assessments added 
(±15 mins).
Administrative change to 
standardize the procedure.
6
Section 6.1 Trial Design
Section 7.4.1 Diet and Fluid
Text updated to state that 
subjects only need to fast 
for a minimum of 8 hours 
overnight before morning
dosing.
To correct a previous 
inconsistency.
7
Section 7.1 Inclusion Criteria
Section 7.2 Exclusion Criteria
Appendix D Pregnancy and Contraception
Clarified that contraception 
use by female subjects of 
childbearing potential must 
continue for 4 weeks (not 1 
month) after last dose of 
study medication, that 
subjects intending or 
expecting to become 
pregnant during or within 4 
weeks (not 1 month) after 
participating in the study 
were excluded and that any 
pregnancy occurring within
4 weeks (not 30 days) of the 
last dose should be reported 
immediately.
To comply with Informed 
Consent Form
8
Section 9.2.8.1 Clinical Laboratory Tests
Creatinine kinase and 
creatinine kinase MB, 
corrected to creatine kinase 
and creatine kinase MB.
To correct typographical 
error.
9
Section 9.3 Biomarker, PK, and 
Pharmacogenomics Samples
Time windows for PK 
blood samples were added.
To add changes in PK time 
windows implemented in 
administrative letter dated 6 
January 2021.
10
Section 10.2.8.2 Reporting AEs
Clarified that only start and 
end date was required for 
adverse event (AE)
recording. Time of day was 
deleted from the text.
It was not necessary to 
report the time of day that 
an AE occurred.
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Vonoprazan (TAK-438)
Study ID Vonoprazan-1001 
Page 12 of 75
Protocol Amendment 1
23 June 2021
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
11
Section 12.2 Protocol Deviations
PK sampling outside of 
specified time windows 
were to be regarded as 
protocol deviations. 
Procedures for 
documentation of protocol 
deviations were clarified.
To add clarity to definitions 
and procedures for 
documenting protocol 
deviations.
12
Section 14.1.1 Study Contact Information
Procedures for reporting 
serious adverse events and 
pregnancy have been 
updated.
To reflect current processes 
/ procedures.
13
Appendix E Collection, Storage, and 
Shipment of Bioanalytical Samples
Storage conditions for PK 
samples were updated.
To add changes 
implemented in 
administrative letter dated 6 
Jan 2021.
PI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
s
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Vonoprazan (TAK-438)
Study ID Vonoprazan-1001 
Page 13 of 75
Protocol Amendment 1
23 June 2021
2.0
STUDY SCHEMATIC
Pretreatment
Treatment Period
Follow-Up
Screening
Check-in 
Baseline
<--------------------Confinement----------------->
Check-
out
Follow-up 
call
Follow-up 
visit
Days -28 to -2
Day -1
Days 1-11
Days 12-13
Day 14
Day 15
Day 17 
(+2 days)
Day 42
(+ 6 days)
Group A: clarithromycin a + amoxycillin b + 
bismuth c + esomeprazole d
13C UBT 
for H pylori
13C UBT for 
H pylori
Group B: clarithromycin a + amoxycillin b + 
bismuth c + vonoprazan e
Vonoprazan PK or 
esomeprazole PK in plasma 
f
Bismuth PK in 
plasma and 
urine g
13C: carbon 13 isotope; BID: twice daily; PK: pharmacokinetics; UBT: urea breath test.
a Clarithromycin 500 mg BID.
b Amoxycillin 1000 mg BID.
c Bismuth potassium citrate 600 mg BID.
d Esomeprazole 20 mg BID.
e Vonoprazan: 20 mg BID.
f Blood samples for vonoprazan and esomeprazole PK on Days 12-14 are to be taken predose (morning and evening).
g Blood samples for bismuth PK are to be taken on Day 14 predose (0 hours), 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 
5.0, 6.0, 8.0, 10.0, and 12.0 hours after the morning dose. Urine samples for bismuth PK are to be taken on Day 14 at 
0 to 12 hours after the morning dose.
PI
Property of Takeda: For non-commercial use only and 
; UBT: u
UBT: 
prazole PK
razole
d subject to the applicable Terms of Use
ms
w-up 
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visit
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 14 of 75
Protocol Amendment 1
23 June 2021
3.0
SCHEDULE OF STUDY PROCEDURES 
Study Phase
Screening
Check-in 
Baseline
Quadruple Therapy 
Dosing 
(Group A or B)
Quadruple 
Therapy Dosing/ 
Vonoprazan or 
Esomeprazole PK
Quadruple 
Therapy Dosing / 
Bismuth PK and 
Vonoprazan or 
Esomeprazole PK
Check-out/ 
Early 
Termination a
Follow-up
Days -28 to
-2
Day -1
Day 1
Day 2 to 11
Day 12 to 13
Day14
Day 15
Day 17 
(+2 Days) b
Day 42
(+6 Days) c
Confinement
X
X
X
X
X
X
Informed consent
X
Inclusion/exclusion criteria 
assessment
X
X
Medical history and 
demographics d
X
Medication history and 
concurrent medical conditions
X
X
Physical examination
X
X
X
Neurological examination e 
X
X
X
X
X
X
X
Vital signs f
X
X
X
X
X
X
X
Body weight and height g
X
X
X
BMI calculation
X
X
Clinical laboratory tests h
X
X
X
X
X
X
Liver function tests i
X
X
X
X
X
X
Urine drug screen j
X
X
Urine pregnancy test (hCG) k
X
X
X
13C UBT for H pylori
X
X
Alcohol breath test
X
Hepatitis panel and HIV panel
X
Randomization
X
Property of Takeda: 
X
a: For non-commercial use only and subject to the applicable Terms of Use
e
osing / 
ng / 
PK and
K an
oprazan o
raza
omeprazo
mepraz
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 15 of 75
Protocol Amendment 1
23 June 2021
Study Phase
Screening
Check-in 
Baseline
Quadruple Therapy 
Dosing 
(Group A or B)
Quadruple 
Therapy Dosing/ 
Vonoprazan or 
Esomeprazole PK
Quadruple 
Therapy Dosing / 
Bismuth PK and 
Vonoprazan or 
Esomeprazole PK
Check-out/ 
Early 
Termination a
Follow-up
Days -28 to
-2
Day -1
Day 1
Day 2 to 11
Day 12 to 13
Day14
Day 15
Day 17 
(+2 Days) b
Day 42
(+6 Days) c
12-lead ECG l
X
X
X
X
X
X
PTE monitoring
X
X
X
AE monitoring
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
PK sampling m
X
X
CYP2C19 sample collection n
X
Dispense study medication
X
X
X
X
13C: carbon 13 isotope; AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; CYP: cytochrome P; ECG: 
electrocardiogram; hCG: human chorionic gonadotrophin; PK: pharmacokinetic(s); PTE: pretreatment event; UBT: urea breath test.
a In the event of early termination, all check-out procedures should be done at the time of withdrawal.
b A follow-up phone call will be made approximately 2 days after check-out to update safety information including AEs and concomitant medications. Subjects may 
be brought back to the unit at the principal investigator’s discretion if any laboratory test abnormalities or other abnormalities are deemed clinically significant at the 
check-out visit.
c A follow-up visit will be arranged after 4 weeks for a 13C UBT for H pylori for subjects who complete the study treatment.
d Demographics are collected at screening only. All medical history updates should include tobacco, alcohol, and caffeine use.
e Neurological examination will be performed daily on screening, Day -1, 1, 2, 5, 8, 11, 12, 13, 14, and 15/early termination visit. If the subject has symptoms or 
signs of neurological deficits, then a full neurological exam is required daily and until symptoms or signs are resolved. 
f Vital signs will include body temperature (oral or tympanic measurement), sitting blood pressure (after 5 minutes resting), respiration rate, and pulse (bpm) at 
screening, Day -1, and predose from Days 1 to 15.
g Height is only collected at the screening visit and used for BMI calculation.
h Fasting clinical laboratory tests (hematology, clinical chemistry, and urinalysis) will be collected at screening, check-in, and Days 5, 8, 12, 13, 14, and 15. If any 
results are clinically significant at Day 15, subjects may be requested to return for repeat tests.
i Liver function tests comprise AST, ALT, and total and direct bilirubin, and measurements are to be taken at screening, check-in, and Days 5, 8, 12, 13, 14, and 15. 
If any results are clinically significant at Day 15, subjects may be requested to return for repeat tests.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
e
nd
an or 
or
azole PK
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Ch
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 16 of 75
Protocol Amendment 1
23 June 2021
Study Phase
Screening
Check-in 
Baseline
Quadruple Therapy 
Dosing 
(Group A or B)
Quadruple 
Therapy Dosing/ 
Vonoprazan or 
Esomeprazole PK
Quadruple 
Therapy Dosing / 
Bismuth PK and 
Vonoprazan or 
Esomeprazole PK
Check-out/ 
Early 
Termination a
Follow-up
Days -28 to
-2
Day -1
Day 1
Day 2 to 11
Day 12 to 13
Day14
Day 15
Day 17 
(+2 Days) b
Day 42
(+6 Days) c
j Drug screen includes amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, cotinine, methadone, and opiates. 
k Urine hCG test to be performed only in female subjects of childbearing potential. Guidance on pregnancy avoidance is provided in Appendix D.
l ECGs will be collected at screening and check-in; on dosing Days 1, 3, and 7 before the morning dose; on Day 14 before the morning dose and at 1, 2 and, 4 hours 
after the morning dose (time window for ECGs: ± 15 minutes) and at check-out or at early termination.
m Blood PK samples for vonoprazan or esomeprazole analysis will be collected on Days 12 to 14 at predose (morning and evening). Blood PK samples for bismuth 
analysis will be collected on Day 14 before the morning dose (0 hours) and at 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after the 
morning dose. Urine PK samples for bismuth analysis will be collected on Day 14 at 0 to 12 hours after the morning dose.
n Mandatory collection of 1 whole blood sample (3 mL) for DNA CYP2C19 genotyping will be taken at Day -1.
Property of Takeda: For non-commercial use only and subject to
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metha
pregnancy
regnan
ning dose;
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terminati
termina
 12 to 14 
12 to 
0.50, 0.75
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 17 of 75
Protocol Amendment 1
23 June 2021
4.0
INTRODUCTION
4.1
Background
Helicobacter pylori (H pylori) is a gram-negative, microaerophilic bacteria mainly found in the 
gastric mucus and mucosa and whose causal relationships to gastrointestinal diseases have been 
extensively studied [1,2] since it was first isolated from the gastric mucosa of a patient with 
chronic gastritis in 1983 [3]. Since then, H pylori eradication therapy has been shown to be 
effective in reducing the recurrence of gastric and duodenal ulcer [4,5], and H pylori eradication 
therapy using proton pump inhibitors (PPIs) and antibiotics has been approved in various countries 
around the world.
In Japan, in September 2000, a triple therapy with lansoprazole/amoxicillin/clarithromycin was 
the first treatment regimen to gain approval for H pylori eradication in patients with gastric or DU, 
and, in August 2007, a triple therapy with PPI/amoxicillin/metronidazole was approved as 
second-line eradication therapy for patients who failed first-line eradication therapy. These triple 
therapies for H pylori eradication were approved in June 2010 for gastric mucosa–associated 
lymphoid tissue lymphoma, idiopathic thrombocytopenic purpura, and endoscopically treated 
early gastric cancers. 
Developed at Takeda Pharmaceutical Company Ltd, vonoprazan (TAK-438) belongs to a new 
class of acid-inhibitory agents called potassium-competitive acid blockers. Vonoprazan inhibits 
the hydrogen, potassium adenosine triphosphatase (H+,K+-ATPase) enzyme in the final step of 
acid secretion, as the PPIs do, but it does not require the presence of acid for its activation and it 
inhibits the H+,K+-ATPase enzyme in a potassium-competitive fashion. Vonoprazan is stable in 
the presence of acid and is water-soluble, requiring no particular pharmacological preparations, 
such as an enteric coating. Vonoprazan is predominantly metabolized by the cytochrome P-450 
(CYP) enzyme CYP3A4, and contribution of polymorphic CYP2C19 is considered to be limited. 
The PPIs take 3 to 5 days to produce their maximum acid-inhibitory effects, whereas vonoprazan 
accumulates rapidly in the gastric parietal cells and has a longer half-life than the PPIs. It is, 
therefore, expected to produce its maximum acid-inhibitory effects in a much shorter time and 
have better potential clinical outcomes than the PPIs due to its potent and sustained acid-inhibitory 
effects. 
A 4 × 4 crossover study of pharmacokinetic (PK) drug-drug interactions of triple therapy twice 
daily (twice daily [BID]) with vonoprazan/amoxicillin/clarithromycin or 
vonoprazan/amoxicillin/metronidazole was conducted in healthy Japanese male subjects 
(TAK-438_CPH-401). In Cohort 1 (triple therapy BID with vonoprazan, amoxicillin, and 
clarithromycin), compared with single-agent use of vonoprazan, the mean area under the plasma 
concentration-time curve from time 0 to 12 hours (AUC0-12) and mean maximum observed plasma 
concentration (Cmax) for freebase of TAK-438 (TAK-438F) increased approximately 1.8- and 
1.9-fold, respectively, when vonoprazan was administered as triple therapy. No difference was 
observed in the PK of plasma amoxicillin when amoxicillin was administered alone or as triple 
therapy. Compared with single-agent use of clarithromycin, the mean AUC0-12 and mean Cmax for 
clarithromycin increased approximately 1.5-fold and 1.6-fold, respectively, when clarithromycin 
PI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
n the
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 18 of 75
Protocol Amendment 1
23 June 2021
was administered as triple therapy. In Cohort 2 (triple therapy BID with vonoprazan, amoxicillin, 
and metronidazole), no difference was observed in the PK of plasma metronidazole when 
metronidazole was administered alone or as triple therapy. Compared with the single-agent 
therapies, the AUC0-12 and Cmax for TAK-438F and clarithromycin increased during triple therapy 
with vonoprazan/amoxicillin/clarithromycin. However, no safety concern was identified with the 
triple therapy. Although further investigation in more subjects is required, the changes during 
triple therapy with vonoprazan/amoxicillin/clarithromycin or 
vonoprazan/amoxicillin/metronidazole are not considered to be clinically significant.
In a phase 3 H pylori eradication study (TAK-438/CCT-401), 7-day treatment with vonoprazan 20 
mg (n = 329) or lansoprazole 30 mg (n = 321) in combination with amoxicillin 750 mg plus 
clarithromycin 200 or 400 mg, eradication rates were 92.6% and 75.9%, respectively. In this study, 
the first 50 treatment failures with good compliance received second-line triple-therapy with
vonoprazan 20 mg (in combination with amoxicillin 750 mg and metronidazole 250 mg) in an 
open-label manner, and an eradication rate of 98% was observed. All treatments were 
well-tolerated.
4.2
Rationale for the Proposed Study
In China, eradication guidelines recommend quadruple therapy for H pylori eradication consisting 
of 2 antibiotics, a PPI and bismuth [6]. As a replacement for PPIs in China, vonoprazan would be 
expected to be used as part of a quadruple treatment regimen.
As bismuth is minimally absorbed and renally excreted, it is not expected to have an effect on the 
PK of vonoprazan, esomeprazole, clarithromycin, or amoxicillin, and the combination of 
clarithromycin and amoxicillin is not expected to have an effect on bismuth concentrations [7]. 
However, it has been reported that with increasing gastric pH, an increase in bismuth absorption is 
observed with the exposure to bismuth increasing by 3- to 7-fold when administered with 
histamine-2 receptor antagonists and PPIs [8]. Increased levels of bismuth may be associated with 
increased potential for neurotoxicity [9]. As vonoprazan achieves high stomach pH over a full 
24-hour period, Study TAK-438_115 in Korea evaluated the drug interaction potential and 
tolerability when vonoprazan and bismuth are coadministered with lansoprazole as comparator. 
Mean cumulative fractions of bismuth excreted unchanged in the urine were found to be almost 
unaffected between the 2 treatment groups, suggesting a lack of a clinically meaningful effect of 
vonoprazan on the PK of bismuth compared with lansoprazole. Daily neurological examination 
showed the absence of bismuth-related neurological adverse events (AEs) in the 2 treatment 
groups, and review of treatment-emergent adverse events (TEAEs) in the vonoprazan and 
lansoprazole groups did not raise any safety concern that could be related to potential drug-drug 
interaction between bismuth and vonoprazan.
An ongoing phase 3 study in H pylori eradication conducted by the sponsor in China 
(Vonoprazan-3002) utilizes esomeprazole as the comparator. The China Center for Drug 
Evaluation (CDE) has indicated that the applicant’s combination drug therapy was not approved in 
China or abroad and that studies on drug interactions should be conducted. They also commented 
on the potential risk related to the combined use of bismuth and gastric acid inhibitors. The present
PI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 19 of 75
Protocol Amendment 1
23 June 2021
phase 1, double-blind, parallel group study was therefore undertaken to evaluate the safety,
tolerability, and PK of quadruple therapy with bismuth, clarithromycin, amoxicillin, and 
vonoprazan versus quadruple therapy with bismuth, clarithromycin, amoxicillin, and 
esomeprazole in subjects who were H pylori positive. CDE agreement was obtained on the 
proposed study design.
4.3
Benefit-Risk Profile
In the most recent treatment recommendations, bismuth-based quadruple therapy is now the 
recommended first-line treatment to eradicate H pylori in regions of high dual resistance to 
clarithromycin and metronidazole. The short-term use of low-dose bismuth for eradication of 
H pylori is not thought to be associated with the high risk of encephalopathy that was reported in 
the 1970s with chronic intake of large doses of bismuth. 
As bismuth is minimally absorbed and renally excreted, it is not expected to have an effect on the 
PK of vonoprazan, clarithromycin, or amoxicillin, and the combination of clarithromycin and 
amoxicillin is not expected to have an effect on bismuth concentrations. However, increased 
bismuth concentration has been observed when administered with PPIs due to increased gastric pH, 
therefore the coadministration of bismuth and vonoprazan may result in an increase in bismuth 
exposure. Increased bismuth exposure may be associated with increased potential for 
neurotoxicity.
The plasma PK parameters of bismuth were evaluated when coadministered with vonoprazan 
clarithromycin, and amoxicillin, or with lansoprazole, clarithromycin, and amoxicillin for 14 days 
in Study TAK-438_115 in Korea. There were no obvious differences in plasma PK parameters of 
bismuth between the 2 treatment groups, with a mean Cmax of 28 ng/mL in the vonoprazan group 
and 30 ng/mL in the lansoprazole group.
5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study is being undertaken to evaluate bismuth exposure when vonoprazan or esomeprazole 
(the comparator in the ongoing phase 3 study Vonoprazan-3002) are administered in quadruple 
therapy.
5.2
Trial Objectives
To evaluate the safety, tolerability, and PK of quadruple therapy BID with bismuth, clarithromycin, 
amoxicillin, and vonoprazan versus quadruple therapy with bismuth, clarithromycin, amoxicillin, 
and esomeprazole.
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 20 of 75
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5.3
Endpoints
5.3.1
Primary Endpoint
The primary endpoint of the study is:
!
To evaluate plasma PK parameters of bismuth potassium citrate (600 mg) when 
coadministered with clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and 
vonoprazan (20 mg BID), and when coadministered with clarithromycin (500 mg BID), 
amoxicillin (1000 mg BID), and esomeprazole (20 mg BID):
–
Cmax at Day 14.
–
The area under the plasma concentration-time curve during a dosing interval (area under 
the plasma concentration-time curve during a dosing interval, where tau (τ) is the length of 
the dosing interval [AUCτ]) at Day 14.
–
The amount of drug excreted in urine during a dosing interval (Aeτ) at Day 14.
5.3.2
Secondary Endpoints 
Secondary endpoints include: 
1. Percentage of subjects who experience at least 1 TEAE.
2. Percentage of subjects who discontinue due to an AE.
5.3.3
Safety Endpoints
Safety endpoints include:
1. Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at 
least once post dose.
2. Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at 
least once post dose.
3. Percentage of subjects who meet the markedly abnormal criteria for safety electrocardiogram
(ECG) parameters at least once post dose.
5.3.4
Exploratory Endpoints
Evaluation of plasma drug concentrations at the end of dosing intervals (Ctrough) of vonoprazan and 
esomeprazole.
6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
This phase 1, double-blind, parallel group study in H pylori–positive subjects is being undertaken 
to evaluate the safety, tolerability, and PK of quadruple therapy with bismuth, clarithromycin, 
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6.0


Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 21 of 75
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amoxicillin, and vonoprazan versus quadruple therapy with bismuth, clarithromycin, amoxicillin, 
and esomeprazole.
H pylori–positive male or female subjects aged 18 to 60 years, inclusive, considered eligible based 
on the inclusion and exclusion criteria, will participate in this study. All subjects will be enrolled 
and will be randomized to 1 of 2 treatment groups. The study will be conducted at a single center in 
China.
The treatment phase consists of quadruple therapy BID with bismuth potassium citrate, 
clarithromycin, amoxicillin, and vonoprazan, or quadruple therapy BID with bismuth potassium 
citrate, clarithromycin, amoxicillin, and esomeprazole for 14 days (Days 1 to 14). Subjects will be 
discharged on Day 15 after all procedures have been performed. 
Screening for potential subjects will occur between Day -28 and Day -2. Eligibility will be 
reconfirmed on Day -1, and eligible subjects will be confined at the phase 1 unit. Having fasted 
overnight for a minimum of 8 hours, subjects will receive treatment with oral doses of bismuth 
potassium citrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and vonoprazan 
(20 mg) BID (Group B) or bismuth potassium citrate (600 mg), clarithromycin (500 mg), 
amoxicillin (1000 mg), and esomeprazole (20 mg) BID (Group A) on Days 1 to 14. In both groups, 
the last dose will be on the evening of Day 14. Blood sampling for vonoprazan and esomeprazole 
PK measurements will be taken on Days 12 to 14 (predose evening and morning) and for bismuth 
PK measurements on Day 14 (before the morning dose to 12 hours after the morning dose). Urine 
sampling for bismuth PK measurements will be taken on Day 14 (before the morning dose to 12 
hours after the morning dose). 
The subjects will be confined to the phase 1 unit from Day -1 (check-in) through to Day 15 
(check-out) and will be contacted by the study site for a follow-up call on Day 17 and a clinic visit
on Day 42 for a carbon 13 isotope (13C) urea breath test (UBT) for H pylori.
A schematic of the study design is included in Section 2.0, and the Schedule of Study Procedures is 
provided in Section 3.0.
6.2
Dose Escalation
Not applicable.
6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale of Trial Design 
A parallel group design will be utilized because of the long washout that would be required in a 
crossover design due to the long half-life of bismuth. The first, second, and third elimination 
phases for bismuth are: 1 to 4 hours, 5 to 11 days, and 21 to 72 days [8]. The population will 
comprise healthy subjects who are H pylori positive since the target population for bismuth 
containing quadruple therapy in whom intragastric pH is affected by their H pylori–positive status.
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
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6.3.2
Rationale for Dose 
The doses selected reflect those used in the ongoing phase 3 study in China (Vonoprazan-3002).
6.3.3
Rationale for Endpoints
6.3.3.1
Efficacy Endpoints
There is no formal efficacy endpoint. However, a 13C UBT for H pylori will be conducted at 
screening and at Day 42 (+6 days) for the assessment of H pylori eradication through the detection 
of urase activity.
6.3.3.2
Safety Endpoints
An increase in bismuth concentration is observed when administered with PPIs, which is 
associated with increased stomach pH. It is expected that when bismuth is coadministered with 
either vonoprazan or esomeprazole, there may be an increase in bismuth exposure due to increase 
solubility of bismuth at higher gastric pH. Increased exposure to bismuth may be associated with
increased potential for neurotoxicity.
6.3.3.3
PK Endpoints
Assessing bismuth PK parameters will allow the determination of bismuth exposure on Day 14 
following 2 weeks of quadruple therapy and facilitate comparisons of bismuth exposure between
the 2 quadruple therapy regimens. Assessing the Ctrough levels of esomeprazole and vonoprazan 
will be an exploratory endpoint and will provide an additional measure of exposure.
6.3.3.4
Exploratory Biomarker Research 
Esomeprazole is metabolized primarily by CYP2C19. Therefore, CYP2C19 genotyping for 
metabolized status will be determined.
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures 
For this trial, blood sampling and 13C UBT for H pylori are critical procedures. 
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
None.
6.5
Trial Beginning and End/Completion
6.5.1
Definition of Beginning of the Trial
The trial will begin when the first subject enters the screening phase.
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6.5.2
Definition of End of the Trial
The end of the trial will occur when the last subject completes the follow-up visit on Day 42 (+ 6 
days).
6.5.3
Criteria for Premature Termination or Suspension of the Study or Investigational 
Sites
6.5.3.1
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study.
!
New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known benefit-risk profile for the compound, such that the 
benefit-risk 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.
6.5.3.2
Criteria for Premature Termination or Suspension of a Site
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, or is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.5.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site
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.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed before randomization or first dose.
7.1
Inclusion Criteria 
Subject eligibility is determined according to the following criteria before 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 before the initiation 
of any study procedures, including requesting that a subject fast for any laboratory evaluations.
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 24 of 75
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3. The subject is H pylori positive at screening.
4. The subject is male or female and aged 18 to 60 years, inclusive, at the time of informed 
consent and first study medication dose. 
5. The subject weighs at least 50 kg and has a body mass index (BMI) >18.0 and ≤30.0 kg/m2, 
inclusive, at screening and Day -1 (check-in).
6. 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 and 
throughout the duration of the study and for 4 weeks after last dose of the study medication.
*Definitions and acceptable methods of contraception together with contraception 
and pregnancy avoidance procedure and reporting responsibilities are defined in 
Appendix D.
7. The subject is willing to abstain from strenuous exercise from 72 hours before first dose (Day 1) 
until the follow-up call on Day 17.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received any investigational compound within 90 days before providing their 
informed consent.
2. The subject has received vonoprazan in a previous clinical study or as a therapeutic agent.
3. The subject is an immediate family member or study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress.
4. The subject has an uncontrolled, clinically significant cardiovascular condition or other 
abnormality (other than the disease being studied) that may impact the ability of the subject to 
participate or potentially confound the study results. 
5. The subject has a known hypersensitivity to any component of the formulation of vonoprazan, 
penicillins, macrolides, bismuths, and esomeprazole (eg, D-mannitol, crystalline cellulose, 
hydroxypropyl cellulose, fumaric acid, croscarmellose sodium, magnesium stearate, 
hypromellose, macrogol 6000, titanium oxide, yellow iron sesquioxide, and iron sesquioxide).
6. The subject has a positive urine drug result for drugs of abuse at screening or check-in 
(Day -1).
7. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol
abuse (defined as regular consumption of 21 units or more units per week) at any time before 
the screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the 
study (up to Day 17).
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
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8. The subject has taken any prescription medications or herbal remedies or excluded 
medications, supplements, or food products listed in the table of excluded medications, 
supplements, and dietary products in Section 7.3 of the protocol.
9. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 4 weeks after participating in this study; or intending to donate ova during such time 
period.
10. The subject has a history of neurological disease.
11. The subject has evidence of current cardiovascular, central nervous system, hepatic, or 
hematopoietic disease; renal dysfunction; metabolic or endocrine dysfunction; serious allergy; 
asthma hypoxemia; hypertension; seizures; or allergic skin rash. Subjects may also be 
excluded if there is any finding in their medical history, physical examination, or safety 
laboratory tests giving reasonable suspicion of a disease that would contraindicate taking 
vonoprazan, or contraindicate any drug used to reduce acid secretion by the stomach or that 
might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer 
disease, seizure disorders, and cardiac arrhythmias.
12. The subject has a history of gastroesophageal reflux disease (GERD), symptomatic GERD, 
erosive esophagitis, duodenal or gastric ulcer, Barrett’s esophagus, or Zollinger-Ellison 
syndrome, or has current or recent (within 6 months) gastrointestinal disease that would be 
expected to influence the absorption of drugs.
13. Subjects who have undergone therapeutic upper gastrointestinal endoscopic therapy
(eg, endoscopic hemostasis or excision including biopsy) within 30 days before screening.
14. Subjects who have undergone major surgical procedures within the past 1 month or are 
scheduled to undergo surgical procedures that may affect gastric acid secretion (eg, abdominal 
surgery, vagotomy, or craniotomy).
15. The subject has any known disease or is taking any medication that is contraindicated with 
bismuth, clarithromycin, or amoxicillin.
16. The subject has a history of cancer, except basal cell carcinoma or Stage 1 squamous cell 
carcinoma of the skin that has been in remission for at least 5 years before Day 1.
17. The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, 
or HIV antibody/antigen at screening. 
18. The subject has used nicotine-containing products (including but not limited to cigarettes, 
pipes, cigars, chewing tobacco, nicotine patch, or nicotine gum) within 6 weeks before 
check-in. Cotinine test is positive at screening or check-in.
19. The subject has poor peripheral venous access.
20. The subject has donated or lost ≥450 mL of blood volume (including plasmapheresis), or had a 
transfusion of any blood product within 90 days before Day 1.
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Vonoprazan (TAK-438)
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Protocol Amendment 1
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21. The subject has a clinically significant abnormality on screening or check-in ECG. Entry of
any subject with an abnormality on ECG that is not clinically significant must be approved and 
documented by signature of both the investigator and the contract research organization (CRO) 
medical monitor.
22. The subject has abnormal screening or check-in laboratory values that suggest a clinically
significant underlying disease or subject with the following laboratory abnormalities: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin greater than the 
upper limit of normal (ULN).
23. The subject has reduced renal function assessed by having an estimated glomerular filtration 
rate <90 mL/min/1.73 m2 (as estimated by Chronic Kidney Disease-Epidemiology
Collaboration) at screening or check-in.
7.3
Excluded Medications, Supplements, Dietary Products
Use of excluded prescription or nonprescription agents or dietary products, outlined in Table 7.a is 
prohibited from the time points specified until completion of all study activities (Day 17).
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 27 of 75
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Table 7.a
Excluded Medications, Supplements, and Dietary Products
6 Weeks Before 
Check-in 
(Day -1)
28 Days Before Check-in 
(Day -1)
7 Days Before Check-in 
(Day -1)
72 Hours Before 
Check-in 
(Day -1)
Nicotine-contain
ing products
Prescription medications
OTC medications including 
salicylates a
Products 
containing 
caffeine or 
xanthine
Immunization/
vaccines
St. John’s wort, ginseng, kava, 
ginkgo biloba, Chinese herbs, 
melatonin, other herbal or 
homeopathic preparations or other 
nutraceuticals
Vitamin supplements
CYP3A4 inhibitors/inducers
Foods or beverages containing 
grapefruit or Seville-type (sour) 
oranges and marmalade, apple, 
orange, or pineapple juices, 
vegetables from the mustard green 
family (eg, kale, broccoli, watercress, 
collard greens, kohlrabi, Brussels 
sprouts, mustard), and charbroiled 
meats
Alcohol-containing products
OTC: over-the-counter.
a Occasional use of acetaminophen/paracetamol (∀1 g/day) or other medication is allowed. OTC = over-the-counter
Subjects must be instructed not to take any medications including over-the-counter (OTC) 
products, without first consulting with the investigator. Use of concomitant medications will not 
be allowed during the study (up to Day 17) except for those approved by CRO/Takeda medical 
monitor on a case-by-case basis, unless deemed necessary in a medical emergency. 
Concomitant medications will include all medications the subject has taken from signing of 
informed consent to the follow-up call (Day 17). If the subject reports taking any medication or if 
administration of any medication becomes necessary during the course of this study (up to Day 17), 
the CRO/Takeda medical monitor must be notified. All medications must be recorded in the source 
documents as well as on the appropriate electronic case report form (eCRF) along with dosage 
information, dates of administration, and reasons for use.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
Subjects will be confined to the clinic for the duration of the treatment period (Day -1 until 
check-out on Day 15).
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Vonoprazan (TAK-438)
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During the confinement period, subjects will be given a menu for the dosing period that includes 
3 meals, each containing approximately 30% fat (relative to the total calories). The meals served 
on the day of dosing should be identical for each treatment group in the study. The study menu 
should be recorded and submitted to the study file with a copy provided to the sponsor. Subjects 
should be fasted overnight for a minimum of 8 hours before morning dosing. Breakfast and dinner 
should be given at approximately the same time each day on Days 1 to 14. Subjects should refrain 
from drinking for at least 1 hour after the clarithromycin and amoxicillin dose, after which water 
can be given freely.
7.4.2
Activity
Subjects should refrain from strenuous exercise from 72 hours before the first dose through Day 17 
follow-up call.
Blood donation is not allowed for at least 12 weeks after the final examination of this study 
(Day 17).
If a subject visits another medical institution during the study period, the investigator should be 
informed of the circumstances and any prescribed therapy and should communicate with the 
medical institution about the subject’s participation in the study.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the eCRF using the following categories.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.
2. Liver function test abnormalities.
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests until a subject’s laboratory profile has returned to 
normal/baseline status), if the following circumstances occur at any time during study 
medication treatment:
!
ALT or AST or total bilirubin >2 times the ULN.
3. 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.
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
PI


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5. 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 should not be recorded in the “voluntary withdrawal” category).
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
7. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Appendix D.
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. 
7.7
Subject Replacement
Discontinued or withdrawn subjects will not be replaced.
8.0
CLINICAL STUDY 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
Clinical Study Drug 
In this protocol, the term study medication refers to vonoprazan, esomeprazole, bismuth potassium 
citrate, clarithromycin, and amoxicillin. A description of the investigational drugs is provided in 
Table 8.a.
PI


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Table 8.a
Investigational Drugs
Name, Strength, and Dose Form
Description
Manufacturer
Vonoprazan (TAK-438) 20 mg 
tablets
Overencapsulated TAK-438 20 mg 
tablets
Takeda Pharmaceutical Company 
Limited, Hikari Plant, Japan
Esomeprazole 20 mg tablets
Over-encapsulated esomeprazole 
20 mg tablets
AstraZeneca
Bismuth potassium citrate 300 mg
capsules
Locally sourced
Clarithromycin 250 mg tablets
Locally sourced
Amoxicillin 500 mg capsules
Locally sourced
8.1.1
Clinical Study Drug Labeling
Vonoprazan (TAK-438) and esomeprazole will be foil/foil blister packaged into child-resistant 
blister cards. Each blister card will contain 32 overencapsulated vonoprazan (TAK-438) 20 mg 
tablets or 32 over-encapsulated esomeprazole 20 mg tablets. The carton box and each blister card 
will be labeled in a blinded fashion with a single panel. The labels will include pertinent study 
information and a country-specific regulatory caution statement.
Amoxicillin (500 mg capsules), clarithromycin (250 mg tablets), and bismuth potassium citrate 
(300 mg capsules [equivalent to 110 mg bismuth]) will be provided by the sponsor and will be 
packaged in an open fashion.
8.1.2
Clinical Study Drug Inventory and Storage
Vonoprazan (TAK-438) and esomeprazole overencapsulated tablets will be kept in an appropriate, 
limited-access, secure place until the supply is used or returned to the sponsor or designee for 
destruction. Vonoprazan and esomeprazole overencapsulated tablets should be stored at 20°C to 
25°C with excursions permitted 15°C to 30°C. Protect from moisture and humidity. 
Sponsor-supplied drugs are to remain in the white carton box and the blister sheet until time of 
dosing.
Companion medication will be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. Amoxicillin capsules will be stored at 10°C 
to 30°C. Clarithromycin tablets will be stored at 2°C to 20°C, and bismuth capsules will be stored 
at 10°C to 30°C. All of these medications will remain in their original containers until dispensed.
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. All clinical study material 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. 
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8.1.3
Clinical Study Drug Blinding
The investigator will receive the subject’s investigational drug blind information in the form of a 
sealed envelope that will reveal the subject’s study treatments if opened. The site-designated study 
personnel will maintain the investigational drug blind information. During regularly scheduled 
monitoring visits, a study monitor from the sponsor or a designee will perform an inventory of 
blinded investigational drug unassigned and assigned treatment packages, sealed envelopes. All 
treatment packages will be reconciled and returned to the sponsor or a designee before study 
closure.
8.1.4
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.
A blinded randomization schedule will be provided to the site pharmacist or authorized study 
designee before the start of this study. The medical identification to be dispensed to each subject 
will be provided in this schedule.
8.1.5
Clinical Trial Blind Maintenance/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. All study 
assessments and causality should be performed, if possible, before unblinding. In the event of a 
medical emergency, if possible, the medical monitor should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding.
For unblinding a subject, the investigational drug blind can be obtained by opening sealed 
envelope.
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.
No change should be made to any assessment of the subject after unblinding.
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug (TAK-438 20 mg overencapsulated tablets, esomeprazole 20 mg 
overencapsulated tablets, bismuth 300 mg, clarithromycin 250 mg, and amoxicillin 500 mg), the 
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investigator or designee must maintain records of all study 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 signing the bottom half of the packing list and 
faxing per instructions provided on the form. 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 
dispensed during his or her entire participation in the study. Proper drug accountability includes 
but is not limited to:
!
Continuously monitoring expiration dates if expiry date is provided to the investigator or 
designee (drug label).
!
Frequently verifying that actual inventory matches documented inventory.
!
Verifying that the log is completed for the drug lot 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.
!
A site representative or unblinded pharmacy monitor, otherwise uninvolved with study 
conduct, will review the randomization schedule and subject dosing log before Day 1 dosing 
and following dosing to ensure all subjects received the correct dose of study medication. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator or designee must record the current inventory of all study drugs (TAK-438 20 mg 
overencapsulated tablets, esomeprazole 20 mg overencapsulated tablets, bismuth 300 mg, 
clarithromycin 250 mg, and amoxicillin 500 mg) 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 date and 
amount dispensed, initials of the person dispensing the drug, and the date and amount returned to 
the site by the subject, including the initials of the person receiving the sponsor-supplied drug. The 
log should include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
Before 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.
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The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction.
In the event of expiry date extension of supplies already at the study site, sponsor-supplied drugs 
may be relabeled 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.
9.0
STUDY PROCEDURES
The following sections describe the study procedures and data to be collected. The Schedule of 
Study Procedures is located in Section 3.0.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Appendix B.
Informed consent must be obtained before the subject enters into the study and before any 
protocol-directed procedures are performed, including requesting that a subject fast for laboratory 
evaluations.
If the subject is to undergo the 13C UBT for H pylori (one of the screening procedures) at a satellite 
site, the subject must sign the informed consent form before performing this test.
A unique subject identification number (subject number) will be assigned to each subject at the 
time 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 to participate in this study. The informed consent for the CYP2C19 
genotyping analysis is a component of the overall study informed consent.
9.1.2
Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If the subject is found to be 
not eligible at this visit, the investigator should complete the eCRF screen failure form.
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 (specify reason). 
!
Significant protocol deviation.
!
Lost to follow-up.
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!
Voluntary withdrawal (specify reason).
!
Study termination.
!
Other (specify reason).
Subject numbers assigned to subjects who fail screening should not be reused. If a subject fails 
screening but is later successfully rescreened, the data for the subject will be entered as if these 
were 2 separate subjects. Therefore, the data should be entered as follows: 
1. The screen failure data should be entered as a screen failure subject.
2. Rescreened subjects should be assigned a new subject number and treated as a standalone 
subject.
9.1.3
Inclusion and Exclusion 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.1.4
Medical History/Demography
Demographic information to be obtained will include age, sex, alcohol and caffeine consumption,
and smoking status of the subject at screening.
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the condition/disease under study that stopped at or before 
signing of informed consent. 
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at screening examination. The condition (ie, diagnosis) should be 
described.
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 28 days before signing of informed consent.
9.1.5
Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or OTC medications obtained by the subject. 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 [Day 17]), and all medication, including vitamin supplements, OTC medications, 
and oral herbal preparations, must be recorded in the eCRF. 
Documentation will include generic medication name, dose, unit, frequency, route of 
administration, start and end dates, and reason for use.
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9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Examination
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; 
(11) genitourinary system; and (12) other.
A neurological examination will be performed per Section 3.0 Schedule of Study Procedures.
Any abnormal finding on a pretreatment physical examination assessment must be assessed as not 
clinically significant or clinically significant by the investigator and recorded in the source 
document and eCRF. All clinically significant findings/changes will be recorded as a PTE or 
concurrent medical condition in the source document and on the appropriate eCRF described in 
Section 10.0 or Section 9.1.4. 
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately before the start of the investigational drug (Day 1) must be 
assessed as not clinically significant or clinically significant by the investigator and recorded in the 
source document and eCRF. Any clinically significant change or new diagnosis as a result of a 
clinically significant change, as determined by the investigator, will be recorded as an AE in 
source documentation and on the PTE/AE eCRF described in Section 10.0. 
9.2.2
Height and Weight
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below.
9.2.3
BMI
Per Takeda standard, height measurements should be collected in centimeters without decimal 
places and weight should be reported in kilograms with 1 decimal place. BMI should be derived 
as:
Metric:
BMI = weight (kg)/height (m)2
Note that although height is reported in centimeters, the formula uses meters for height; meters can 
be determined from centimeters by dividing by 100. Thus, for example, a subject whose height is 
176 cm (1.76 meters) and weight is 79.2 kg would have a BMI of 25.6 kg/m2 (79.2/1.762).
9.2.4
Vital Signs
Vital signs will include body temperature (oral or tympanic measurement), sitting blood pressure 
(systolic and diastolic, resting more than 5 minutes), respiration rate, and pulse (bpm).
Vital signs may be repeated. All measurements will be recorded on the source documents and in 
the eCRF. 
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When vital signs are scheduled at the same time as blood draws, vital signs will be obtained before 
the scheduled blood draw.
9.2.5
12-Lead ECG
12-lead ECGs printed in standard format will be collected at screening; at check-in; on Days 1, 3, 
and 7 before the morning dose; on Day 14 before the morning dose, and 1, 2 and 4 hours after the 
morning dose (time window for ECGs: ± 15 minutes), and at check-out day or the early 
termination of the study for safety assessment.
The investigator will be responsible for providing the interpretation of all safety ECGs 
(normal/abnormal). These results will be reviewed by the investigator for subject safety and will 
be provided in an appropriate format with the clinical study report.
9.2.6
Study Drug Administration
Subjects should be fasted overnight for a minimum of 8 hours before dosing. Breakfast and dinner 
should be given at approximately the same time each day on Days 1 to 14. Vonoprazan /
esomeprazole and bismuth should be administered 0.5 hour before breakfast and dinner. Breakfast 
and dinner should be completed within 0.5 hour, and then clarithromycin and amoxicillin should 
be administered 0.5 hour after the start of breakfast and dinner on Days 1 to 14. Subjects should 
take all doses with 240 mL water (120 mL with bismuth and vonoprazan or esomeprazole dosing 
and 120 mL with clarithromycin and amoxicillin doses) and refrain from drinking for at least 1 
hour post clarithromycin and amoxicillin dose, after which water can be given freely.
For each dose, the subject’s actual dose date and time of administration will be recorded, to the 
nearest minute, in the subject’s source documents and transcribed on the eCRF. 
9.2.7
AE Monitoring
9.2.7.1
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 (Day 1) 
or until screen failure. For subjects who discontinue before 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 (Day 1). Routine collection of AEs will continue until the follow-up telephone call.
9.2.7.2
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. 
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Nonserious PTEs, related or unrelated to the study procedure, do not require follow-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. Frequency.
4. Severity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study medication (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
9.2.7.3
Collection and Reporting of SAEs
When a serious adverse event (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 14.1.1. 
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
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Reporting of serious PTEs will follow the procedure described for SAEs.
9.2.8
Laboratory Procedures and Assessments
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit ranges from 20 to 68 mL, and the approximate total volume of 
blood for the study is 223 mL (may be up to 243 mL if repeat tests are required for laboratory and 
PK samples. Laboratory samples will be taken following a minimum 8-hour overnight fast on the 
days stipulated in the Schedule of Study Procedures (Section 3.0).
9.2.8.1
Clinical Laboratory Tests
The site’s local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis as well as the laboratory screening tests (HIV, hepatitis panel, drug screen, and urine 
hCG pregnancy tests). The results of laboratory tests will be returned to the investigator, who is 
responsible for reviewing and filing these results.
Hematology
Hematology will consist of the following tests:
RBCs
Platelets
WBCs (with differential: neutrophils, eosinophils, 
basophils, monocytes, lymphocytes)
PT/INR
Hemoglobin
aPPT
Hematocrit
Reticulocyte count
aPPT: activated partial thromboplastin time; PT/INR: prothrombin time/international normalized ratio; RBC: red cell 
count; WBC: white cell count.
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Chemistry 
Chemistry evaluations will consist of the following standard chemistry panel:
ALT a b
Blood urea nitrogen
Albumin
Creatine kinase
Alkaline phosphatase a
Creatine kinase MB
Amylase
Potassium 
AST a b
Sodium
GGT
Glucose
Total bilirubin a b c
Chloride
Direct bilirubin a b
Magnesium
Uric acid
Calcium
Total protein
Cholesterol (HDL and LDL) a
Triglycerides a
LDH d
Serum creatinine
ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma glutamyl transferase; HDL: high 
density lipoprotein; LDH: lactate dehydrogenase; LDL: low density lipoprotein; MB: myocardial band.
a To be measured under fasting conditions.
b Included in liver function tests.
c Direct bilirubin will be measured if total bilirubin is >1.5 times the ULN.
d LDH1/LDH5 (in % and total) will be measured if clinically significant increase in LDH is reported.
If subjects experience an increase in any one of ALT, AST, or total bilirubin >2 times the ULN, 
then trial medication should be stopped because 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, gamma-glutamyl transferase, and 
international normalized ratio) to monitor recovery should be performed within a maximum of 7 
days and preferably within 48 to 72 hours after the abnormality was noted.
Please refer to Section 10.2.8.5 for the appropriate guidance on reporting abnormal liver function 
test (LFT) as an SAE.
All laboratory safety data will be transferred electronically to Takeda or designee in the format 
requested by Takeda. If the laboratory is unable to electronically transfer data, the study site 
coordinator or designee is responsible for transcribing laboratory results to the eCRF. The 
investigator will maintain a copy of the laboratory accreditation and the reference ranges for the 
laboratory used.
Laboratory reports must be signed and dated by the principal investigator or subinvestigator 
indicating that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified before the first dose will require clear and complete 
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with enrollment/randomization.
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All clinically significant laboratory abnormalities must be recorded as a PTE/AE in the subject’s 
source documents and on the appropriate eCRF. A clinically significant laboratory abnormality 
that has been verified by retesting will be followed until the abnormality returns to an acceptable 
level or a satisfactory explanation has been obtained.
Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Hemoglobin
Protein
Ketones
Glucose
Leucocytes
Nitrites
Urobilinogen
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of red blood 
cell/high-power field, white blood cell/high-power field, casts, epithelial cells, crystals, and 
organisms.
Other 
HIV
Drug screen, including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, cotinine, 
methadone, and opiates.
Hepatitis panel: HBsAg and anti-HCV
Female subjects of childbearing potential only:
hCG (for pregnancy)
13C UBT for H pylori a and alcohol breath test
13C: carbon 13 isotope; HBsAg: hepatitis B surface antigen; hCG: human chorionic gonadotropin; HCV: hepatitis C 
virus; UBT: urea breath test.
a 13C UBT will be performed at screening and must be positive at screening. A follow-up breath test will be performed 
on Day 42 for subjects who complete the study treatment.
9.3
Biomarker, PK, and Pharmacogenomics Samples
Blood samples for PK analysis of TAK-438F, esomeprazole, and bismuth will be collected into 
Vacutainers containing anticoagulant sodium heparin according to the schedule in Section 3.0. 
Instructions for sample processing and shipment are provided in Appendix E.
Serial blood samples for determination of TAK-438F, esomeprazole, and bismuth will be 
collected according to Table 9.a.
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Table 9.a
Collection of Blood Samples for PK Analysis
Analyte
Matrix
Dosing Day
Scheduled Time (Hours)
TAK-438F
Plasma
12-14
Predose (morning and evening)
Esomeprazole 
Plasma
12-14
Predose (morning and evening)
Bismuth
Plasma
14
Pre–morning dose (0 hours) and 0.25, 0.50, 0.75, 1.0, 
1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0 hours post 
morning dose
PK: pharmacokinetic(s); TAK-438F: freebase of TAK-438.
Every attempt will be made to collect each drug concentration (PK) blood sample at the 
designated timepoint (Table 9.E) and the actual time of each PK blood sample will be recorded 
accurately on the source document and eCRF (with minute clock time precision). 
Table 9.b
Time Windows for PK Blood Sample Collection
Nominal PK Blood Sample Time
Actual PK Blood Sample Time Window
0 hours (predose)
No more than 10 minutes predose a
Immediately postdose to ≤6 hours postdose
±5 minutes b
>6 hours to ≤12 hours postdose
±10 minutes b
PK: pharmacokinetic.
a For vonoprazan (TAK-438), esomeprazole, and bismuth PK blood samples.
b For bismuth PK blood samples only.
The actual time of sample collection will be recorded on the source document and eCRF.
9.3.1
Collection of Urine for PK
Urine samples for PK analysis of bismuth will be collected according to Table 9.c.
Table 9.c
Collection of Urine Samples for PK Analysis
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
Bismuth
Urine
14
0 to 12 hours post morning dose.
PK: pharmacokinetic(s).
Instructions for sample processing and shipment are provided in Appendix E.
9.3.2
PK Measurements 
Bismuth PK parameters will be determined from the concentration-time profiles for all evaluable 
subjects. Actual sampling times, rather than scheduled (nominal) sampling times, will be used in 
all computations involving sampling times. The following PK parameters will be calculated using 
plasma bismuth concentrations:
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Symbol/Term
Definition
Plasma
AUCτ
Area under the plasma drug concentration-time curve during a dosing interval, where tau (τ) is 
the length of the doing interval, calculated using the linear trapezoidal rule.
Cmax
Maximum observed plasma drug concentration.
CL/F
Apparent clearance after extravascular administration, calculated as dose/AUCτ after multiple 
dosing.
λz
Terminal elimination rate constant, calculated as the negative of the slope of the log-linear 
regression of the natural logarithm concentration-time curve during the terminal phase.
t1/2z
Terminal elimination half-life, calculated as ln(2)/λz.
tmax
Time to reach Cmax.
Vz/F
Apparent volume of distribution during the terminal phase after extravascular administration, 
calculated as (CL/F)/λz.
The following PK parameters will be derived from urine bismuth concentrations:
Urine
Aeτ
Amount of drug excreted in urine during a dosing interval (τ).
fe
Fraction of drug excreted in urine, calculated as fe = (Aeτ/dose) × 100. 
CLR
Renal clearance, calculated as CLR = Aeτ/AUCτ.
9.3.2.1
Plasma or Serum for PK Measurements
Blood samples for vonoprazan or esomeprazole PK analysis will be collected on Day 12 to Day 14 
predose (morning and evening). Blood PK samples for bismuth analysis will be collected on Day 
14 before the morning dose (0 hours) and 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 
and 12.0 hours after the morning dose.
9.3.2.2
Urine for PK Measurements
Urine samples for bismuth PK analysis will be collected quantitatively on Day 14 at 0 to 12 hours 
after the morning dose.
9.3.3
Biomarker Measurements 
Esomeprazole is metabolized primarily by CYP2C19. Therefore, CYP2C19 genotyping for 
metabolized status will be determined.
9.3.4
Pharmacogenomics Measurements 
9.3.4.1
Blood Sample for DNA Pharmacogenomics Measurements
During the screening period, each subject will provide one 3 mL whole blood sample for DNA 
isolation and CYP2C19 genotyping that will be collected in a plastic tube that has been 
spray-coated with potassium ethylenediamine tetraacetic acid.
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The genetic material will be sent to a testing laboratory to determine the CYP2C19 metabolic 
status of each subject. Any remaining sample after pharmacogenomics (PGx) testing will be 
destroyed.
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.
9.3.5
Confinement
Confinement will begin once subjects’ eligibility is confirmed after study assessments. 
Randomization will take place on Day -1 after all procedures are completed and the subject will 
remain confined to the phase 1 unit until Day 15.
10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the 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.
An untoward finding generally may:
!
Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)
!
Necessitate therapeutic intervention.
!
Require an invasive diagnostic procedure.
!
Require discontinuation or a change in dose of study medication or a concomitant medication.
!
Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:
!
Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:
!
Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
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judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.
!
If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:
!
A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. An abnormal 
finding during baseline evaluation (eg, laboratory test, ECG, X-ray) should NOT be recorded 
as an AE unless related to a study procedure. However, if the subject experiences a worsening 
or complication of such a concurrent medical history condition, the worsening or complication 
should be recorded appropriately as an AE (worsening or complication occurs after informed 
consent is signed). 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), any occurrence of an episode 
should only be captured as an AE if the episodes become more frequent, serious, or severe in 
nature. Investigators should ensure that the AE term recorded captures the change from 
baseline in the condition (eg “worsening of…”).
!
If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:
!
If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or 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:
!
If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:
!
Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) due to a worsening of the pre-existing condition, the worsening of the condition 
should be captured appropriately as an AE. Complications resulting from any planned surgery 
should be reported as AEs.
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Elective surgeries or procedures:
!
Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
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. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the sponsor.
!
All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the (e)CRF to capture this important safety information consistently in the database. 
AEs associated with an overdose will be documented on an AE CRF(s) according to 
Section 10.0.
!
The SAE of overdose should be reported according to the procedure outlined in Section 10.2.8.
!
In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.
!
The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
!
May require intervention to prevent items 1 through 5 above.
!
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
!
Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by a 
medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
COVID-19 pneumonia
COVID-19–related disease
Spontaneous abortion / stillbirth and fetal death
AE: adverse event; COVID-19: coronavirus disease 2019.
Any AE that fulfills 1 or more of the serious criteria above is to be considered an SAE and should 
be reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2
Special Interest AEs
Not applicable.
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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10.2.2
Assigning 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 a causal 
relationship is at least a reasonable possibility, ie, the relationship 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 medications, and concurrent 
treatments.
10.2.3
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.4
End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.2.5
Pattern of AE (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6
Action Taken With Study Treatment
!
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 had not yet 
started or dosing with study medication was already stopped before the onset of the AE.
!
Dose reduced – the dose was reduced due to the particular AE.
!
Dose increased – the dose was increased due to the particular AE.
!
Drug interrupted – the dose was interrupted due to the particular AE.
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10.2.7
Outcome 
!
Recovered/resolved – subject returned to first assessment status with respect to the AE.
!
Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”
!
Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”
!
Recovered/ resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).
!
Fatal – an AE that is considered as the cause of death.
!
Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs
10.2.8.1
Collection Period
Collection of AEs (ie, AEs, SAEs, special interest AEs, and abnormal LFTs) will commence at the 
time the subject signs the informed consent. Routine collection of AEs will continue until the 
follow-up phone call. For subjects who discontinue before the administration of study medication. 
AEs will be followed until the subject discontinues study participation. 
10.2.8.2
Reporting AEs
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 an 
SAE before the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin before the first exposure to 
investigational product, related or unrelated to the study procedure, do not require follow-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 
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changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:
!
Event term.
!
Start and end date.
!
Pattern of AE (frequency).
!
Severity/intensity.
!
Causality (investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).
!
Action taken with study drug.
!
Outcome of event.
!
Seriousness.
10.2.8.3
Reporting SAEs
When an SAE occurs through the AE collection period, it should be reported according to the 
procedure outlined below:
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 14.1.1.
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 SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
10.2.8.3.1
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
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fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4
Reporting Special Interest AEs 
Not applicable.
10.2.8.5
Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 times the ULN on 2 consecutive occasions, 
the abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be 
completed, providing additional information on relevant recent history, risk factors, clinical signs 
and symptoms, and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 times the ULN and total bilirubin >2 times the ULN 
for which an alternative etiology has not been identified, the event should be recorded as an SAE 
and reported as per Section 10.2.8.3. The investigator must contact the medical monitor for 
discussion of the relevant subject details and possible alternative etiologies, such as acute viral 
hepatitis A or B or other acute liver disease. Follow-up laboratory tests as described in 
Section 9.2.8 must also be performed. In addition, an LFT Increases eCRF must be completed and 
transmitted with the Takeda SAE form (as per Section 10.2.9). 
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
11.1.1
Analysis Sets
The definition of each analysis set will be described in the statistical analysis plan (SAP).
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11.1.1.1
Safety Set
The safety analysis set will consist of subjects who received at least 1 dose of the study drug.
11.1.1.2
PK Set
The PK analysis set will consist of subjects who received the study drug, completed the minimum 
protocol specified procedures with no significant protocol deviations, and were evaluable for the 
PK.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized using the safety analysis set 
and PK analysis set.
11.1.3
PK Analysis
The following analyses will be performed in the PK analysis set.
Plasma concentrations of bismuth, freebase of vonoprazan (TAK-438F) and esomeprazole will be 
summarized at each scheduled sampling point by treatment group using descriptive statistics. The 
plasma and urine PK parameters of bismuth at Day 14 will be summarized by treatment group 
using descriptive statistics.
Point estimates and the 2-sided 90% and 95% CI of the geometric mean ratios between treatment 
group will be calculated using an analysis of variance with natural log-transformed AUCτ and Cmax
of bismuth. It will be concluded that vonoprazan has no significant effect on bismuth PK compared 
with esomeprazole if the 90% CIs for AUCτ and Cmax completely fall within the range 0.5 and 2.0.
Statistical analyses of other plasma and urine PK parameters will be performed if appropriate.
11.1.4
Safety Analysis
All summaries of safety data will be presented based on the safety analysis set. No statistical 
testing or inferential statistics will be generated.
11.1.4.1
AEs
A TEAE is defined as an AE whose date of onset occurs on or after the start of the study drug. All 
TEAEs will be coded using the MedDRA dictionary. Data will be summarized using Preferred 
Term (PT) and primary System Organ Class. All TEAEs, drug-related TEAEs, serious TEAEs, 
and TEAEs leading to study drug discontinuation will be summarized by treatment group 
(vonoprazan quadruple therapy and esomeprazole quadruple therapy).
11.1.4.2
Clinical Laboratory Evaluation, Vital Signs, and ECG
Observed values and changes from baseline for continuous variables will be summarized over time 
by treatment group using descriptive statistics.
For categorical variables, shift tables will be presented by treatment group.
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The number and percentage of subjects who meet the markedly abnormal criteria at least once post 
dose for safety laboratory tests, vital sign measurements, and safety ECG parameters will be 
summarized by treatment group.
11.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
11.3
Determination of Sample Size
This study will randomize approximately 42 subjects (maximum 46 subjects) to provide at least 80% 
power of showing no significant difference in Cmax and AUCτ of bismuth potassium citrate 
between vonoprazan and esomeprazole quadruple therapy. Assuming the ratio of PK parameter is 
0.9 to 1.1, and the SD of the natural log-transformed value in each group is 0.6, based on the results 
from Study TAK-438_115, a total of 30 subjects (15 subjects per group) is required for the 90% CI 
of the geometric mean ratio to fall completely within the range of 0.5 to 2.0 with 80% probability. 
Given the observed discontinuation rate of approximately 25%, and consideration for potential 
drop-out from the PK analysis set, the plan is to enroll approximately 42 randomized subjects. If 
the drop-out rate from the PK Analysis Set increases to more than 25%, a maximum of 46 subjects 
will be enrolled.
12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
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 study site 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 the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
investigator’s binder, study drug, subject medical records, informed consent documentation, 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.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial 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.
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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.
12.3
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 Food and Drug Administration [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 guarantees access for quality assurance auditors 
to all study documents as described in Section 12.1.
13.0
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 International Conference on Harmonisation (International Conference on Harmonisation 
[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 A. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
13.1
IRB and/or IEC Approval
Institutional review board 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 
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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.
13.2
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 before 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 
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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 before 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 before the subject enters 
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 and time of day the subject signs the informed consent in the 
subject’s medical record. Copies of the signed informed consent form, the signed subject 
authorization form (if applicable), and subject information sheet (if applicable) shall be given to 
the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time before analysis. The sponsor 
should be notified of consent withdrawal.
13.3
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, 
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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 13.2).
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).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1
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.
13.4.2
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 all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/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 Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study 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 the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3
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.
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13.5
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 study subjects. Refer to 
the 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.
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information 
Contact Type/Role
Contact
SAE reporting
EDC (RAVE) – Primary method of reporting Serious
Adverse Events
If transmission of an EDC SAE report is not feasible, a 
completed Takeda paper-based Safety Report Form 
should be transmitted. The fax number and email address 
are provided in the Form Completion Guidelines.
Pregnancy reporting
Complete and submit the Takeda paper-based Pregnancy 
Report Form via fax or email. The fax number and email 
address are provided in the Form Completion Guidelines.
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14.1.2
Investigator Agreement 
I confirm that I have read and that I understand this protocol, the investigator’s brochure, package 
insert, 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.
!
ICH, E6 GCP: Consolidated Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.
!
Regulatory requirements for reporting SAEs defined in Section 10.2.9 of this protocol.
!
Terms outlined in the study site agreement.
!
Responsibilities of the investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C 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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14.1.3
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
study-related responsibilities template. The vendors identified for specific study-related activities 
will perform these activities in full or in partnership with the sponsor.
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14.1.4
List of Abbreviations
AE
adverse event
Aeτ
amount of drug excreted in urine during a dosing interval
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUCτ
area under the plasma concentration-time curve during a dosing interval, where tau (τ) is 
the length of the dosing interval
AUC0-12
area under the plasma concentration-time curve from time 0 to 12 hours
BID
twice daily
BMI
body mass index
CDE
Center for Drug Evaluation
Cmax
maximum observed plasma concentration
CRO
contract research organization
Ctrough
observed plasma concentration at the end of a dosing interval
ECG
electrocardiogram
eCRF
electronic case report form 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
H+,K+-ATPase
hydrogen, potassium adenosine triphosphatase
hCG
human chorionic gonadotropin
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
OTC
over-the-counter
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PPI
proton pump inhibitors
PT
Preferred Term
PTE
pretreatment event
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reactions
TAK-438F
freebase of TAK-438
TEAE
treatment-emergent adverse event
UBT
urea breath test
ULN
upper limit of normal
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
Adverse event, medical history, and concurrent conditions will be coded using the MedDRA. 
Drugs will be coded using the World Health Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Relevant medical records should be included in the outpatient or inpatient medical record system. 
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. eCRF 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.
Electronic case report form 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.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 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, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
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(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 and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
16.0
REFERENCES
1. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis 
and peptic ulceration. Lancet 1984;323(8390):1311-5.
2. Axon ATR, Quina M. Ten-year milestones. Curr Opin Gastroenterol 1994;10(Suppl 1):1-5.
3. O'Connor HJ. The role of Helicobacter pylori in peptic ulcer disease. Scand J Gastroenterol 
Suppl 1994;201:11-5.
4. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and 
reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 
1996;110(4):1244-52.
5. Soll AH. Consensus conference. Medical treatment of peptic ulcer disease. Practice guidelines. 
Practice Parameters Committee of the American College of Gastroenterology. JAMA 
1996;275(8):622-9.
6. Chinese Society of Gastroenterology, Chinese Study Group on Helicobacter pylori, Liu WZ, 
Xie Y, Cheng H, Lu NH, et al. Fourth Chinese National Consensus Report on the management 
of Helicobacter pylori infection. J Dig Dis 2013;14(5):211-21.
7. Koch KM, Davis IM, Gooding AE, Yin Y. Pharmacokinetics of bismuth and ranitidine 
following single doses of ranitidine bismuth citrate. Br J Clin Pharmacol 1996;42(2):201-5.
8. Klotz U. Pharmacokinetic considerations in the eradication of Helicobacter pylori. Clin 
Pharmacokinet 2000;38(3):243-70.
9. Hillemand P, Palliere M, Laquais B, Bouvet P. [Bismuth treatment and blood bismuth levels]. 
Sem Hop 1977;53(31-32):1663-9.
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17.0
APPENDICES
Appendix A
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 responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. 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.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. 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.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
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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.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if so, 
what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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legally acceptable representative 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 PGx 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
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study, and for 4 
weeks after the last dose of study drug. 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 drug will be discontinued and the investigator will offer the subject the 
choice to receive unblinded treatment information. 
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 4 weeks after 
the last dose of study drug. If the partner or wife of the subject is found to be pregnant during 
the study, the investigator will offer the subject the choice to receive unblinded treatment 
information. 
27. 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 C
Investigator Consent to the 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 D
Pregnancy and Contraception
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 follicle-stimulating hormone (FSH) > 40 IU/L 
or at least 5 years since last regular menses, confirmed before any study medication is 
implemented).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are excluded, the only 
acceptable methods of contraception are:
Barrier Methods (Each Time the Subject Has Intercourse) 
Where Applicable a
Intrauterine Devices
Cap (plus spermicidal cream or jelly) PLUS male condom 
Diaphragm (plus spermicidal cream or jelly) PLUS male condom 
Copper T 
a Barrier methods are only applicable in countries where spermicide is available.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study.
During the course of the study, regular urine 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 (Section 3.0). Female subjects must have a 
negative urine hCG pregnancy test on Day 1 before receiving any dose of study medication.
Pregnancy
If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied drug (vonoprazan 20 mg tablets or esomeprazole 20 mg tablets) should be 
immediately discontinued. 
If the pregnancy occurs during administration of active study medication, eg, after Day 1 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 14.1.1.
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If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time 
she became pregnant and provide details of treatment the subject received (blinded or unblinded, 
as applicable).
All reported pregnancies will be followed up to outcome using the pregnancy form. The outcome, 
including any premature termination, must be reported to the sponsor. An evaluation after the birth 
of the child will also be conducted.
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Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples
Instructions for Processing of Plasma Samples for PK Analysis of Vonoprazan or 
Esomeprazole
1. Collect 3 mL of venous blood for the plasma into a Becton-Dickinson Vacutainer at room 
temperature. All vonoprazan or esomeprazole blood samples should be collected into 
Vacutainers containing sodium heparin.
2. Gently invert the vacutainer several times to mix the additive with the collected blood before 
centrifugation and place immediately on ice.
3. Centrifuge the vacutainers for 10 minutes at approximately 1100 to 1300 (relative centrifugal 
force [RCF]) at approximately 4°C. Note: 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 may include protocol number (Vonoprazan-1001), sample matrix (ie, 
plasma), analyte (TAK-438F or esomeprazole), randomization sequence number, nominal day 
and time, and either “SET 1” (for original sample) or “SET 2” (for duplicate sample).
5. Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately -20°C to -70°C or lower until shipment to the selected laboratory in China. No 
more than 45 to 60 minutes should elapse between blood collection and freezing the plasma 
sample.
Instructions for Processing of Plasma Samples for PK Analysis of Bismuth
1. Collect 3 mL of venous blood for the plasma into a Becton-Dickinson Vacutainer. All Bismuth 
blood samples should be collected into vacutainers containing sodium heparin.
2. Gently invert the vacutainer several times to mix the additive with the collected blood before 
centrifugation and place immediately on ice.
3. Centrifuge the vacutainers for 10 minutes at approximately 1100 to 1300 (RCF) at 
approximately 4°C. Note: 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 may include protocol number (Vonoprazan-1001), sample matrix (ie, 
plasma), analyte (Bismuth), randomization sequence number, nominal day and time, and either 
“SET 1” (for original sample) or “SET 2” (for duplicate sample).
5. Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately -20°C to -70°C or lower until shipment to the selected laboratory in China. No 
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Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 72 of 75
Protocol Amendment 1
23 June 2021
more than 45 to 60 minutes should elapse between blood collection and freezing the plasma 
sample.
Instructions for Processing of Urine Samples for PK Analysis of Bismuth
1. Collect urine into polypropylene containers. During the collection interval, the urine will be 
stored at approximately 2°C to 8ºC.
2. Stir the urine in the polypropylene container vigorously.
3. Measure the urine volume within 2 hours of the end of the collection period.
4. Transfer approximately 10 mL aliquots of urine in duplicate into appropriate polypropylene 
containers. Container should be filled to within 60% to 80% of the nominal value. Labeling 
may include protocol number (Vonoprazan-1001), sample matrix (ie, urine), analyte (bismuth), 
randomization sequence number, nominal day and time, and either “SET 1” (for original 
sample) or “SET 2” (for duplicate sample).
5. Freeze the urine sample immediately and store frozen at approximately -20°C to -70ºC or 
lower. Keep samples frozen at approximately -20°C to -70ºC or lower until shipment to the 
selected laboratory in China.
Shipping of Plasma and Urine Samples 
The following instructions are recommended unless they differ from the site’s standard operating 
procedures for labeling, packaging, or shipping of PK samples.
1. Plasma samples for vonoprazan, esomeprazole and bismuth will be collected separately and 
sent to different analytical labs.
2. Biological samples (ie, plasma or urine) should be shipped on dry ice to prevent thawing 
during transit. Samples should be shipped only on Monday, Tuesday, or Wednesday, and at 
least 2 days before 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.
3. Before shipping, make sure the sample tubes are tightly sealed. Separate each subject’s 
samples as follows:
!
Separate the duplicate SET 2 samples from the SET 1 samples.
!
Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc) containing 
additional absorbent material.
!
Using a permanent marker, write the 4-digit randomization sequence number, sample 
matrix (ie, plasma or urine), number of samples, and “SET 1” on each self-sealing bag.
!
Place the bags of individual subject’s samples into a larger plastic bag so that samples are 
double bagged. Duplicate SET 2 samples should be returned to the freezer for storage. 
Repeat the steps above when preparing duplicate samples for shipment, except self-sealing 
bags should be marked “SET 2.”
PI


Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 73 of 75
Protocol Amendment 1
23 June 2021
4. An inventory of individual samples should accompany each shipment and should include the 
sponsor’s name (Takeda), study medication (vonoprazan), protocol number 
(Vonoprazan-1001), investigator’s name, sample type (ie, plasma or urine), randomization 
sequence number, nominal collection day and time, and intended sample storage conditions. 
When duplicate SET 2 samples are being shipped, make a copy of the original SET 1 sample 
inventory and mark as “SET 2.” Place the inventory paperwork into a large self-sealing bag. 
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 analytical laboratory.
5. For sample packing, utilize dry ice generously (eg, 20-25 pounds per day of transit) to 
safeguard against longer than expected shipping times and delays. Use newspaper or other 
material to insulate the double-bagged samples from direct contact with the dry ice. Place the 
sample bundles into a Styrofoam container (or other suitable container) and fill the excess 
space with dry ice slabs or ice pellets (preferably the latter). Make a note of the estimated 
weight of the dry ice used per shipping container.
6. Place the inventory paperwork (in a large self-sealing bag) on top of the dry ice in the 
Styrofoam container. Place the lid on the Styrofoam container and seal completely with 
strapping tape. Place the Styrofoam container in a cardboard shipping carton and seal securely 
with strapping tape.
7. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
8. Follow Central Laboratory Manual for shipping samples. 
9. Affix a carbon dioxide label on each carton, specifically:
Carbon Dioxide Solid UN-1845
Class 9 PKG GR III
Quantity _____________________
(fill in weight to nearest lb/kg and specify unit of measure used)
10. Affix 2 dry ice symbol labels on opposite sides of the carton. Mark KEEP FROZEN on each 
carton. Specify a return address and contact person on the carton.
11. Obtain the airway bill number and a receipt of shipment from the carrier.
12. After shipping of the vonoprazan samples, please contact (name) at e-mail to notify her of next 
day delivery. When calling, provide the following information:
Name of courier or transport company
Time and date the shipment left the clinical site
Airway bill number
PI


Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 74 of 75
Protocol Amendment 1
23 June 2021
Collection of PGx Samples 
Sample Collection
1. Mandatory collection for CYP2C19 genotyping: 
During the screening period, each subject will provide one 3 mL whole blood sample for DNA 
isolation and CYP2C19 genotyping that should be collected in a plastic tube that has been 
spray-coated with potassium ethylenediamine tetraacetic acid.
PI


Vonoprazan (TAK-438)
Study No. Vonoprazan-1001
Page 75 of 75
Protocol Amendment 1
23 June 2021
Appendix F
Protocol History
Date
Amendment Number
Amendment Type
Region
23 June 2021
Amendment 1
Substantial
China
28 October 2020
Initial protocol
Not applicable
China
PI


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d6810f297b
Amendment 1 to A Phase 1, Double-Blind, Parallel Group Study to Evaluate the Safety, Tolerability, and
Pharmacokinetics of Quadruple Therapy (Bismuth, Clarithromycin, and Amoxicillin) With Vonoprazan Versus
Quadruple Therapy With Esomeprazole
Biostatistics Approval
23-Jun-2021 07:16 UTC
Clinical Science Approval
23-Jun-2021 08:04 UTC
Clinical Pharmacology Approval
23-Jun-2021 10:07 UTC

SAP_001.pdf: 
NCT Number: 
Study Title: 
Study Number: 
A Phase 1, Double-Blind, Parallel Group Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Quadruple 
Therapy (Bismuth, Clarithromycin, and Amoxicillin) With 
Vonoprazan Versus Quadruple Therapy With Esomeprazole
NCT04753437
Vonoprazan-1001
STATISTICAL ANALYSIS PLAN
SAP Version and Date: Version 
Version 2.0: 10-November-2021 


STATISTICAL ANALYSIS PLAN
Study: Vonoprazan-1001
Study Title: A Phase 1, Double-Blind, Parallel Group Study to Evaluate the Safety, Tolerability, 
and Pharmacokinetics of Quadruple Therapy (Bismuth, Clarithromycin, and Amoxicillin) With 
Vonoprazan Versus Quadruple Therapy with Esomeprazole
Phase: 1
Version: 2.0
Date: 08-Nov-2021
Prepared by:
, Statistical & Quantitative Sciences Japan
Based on:
Protocol Version: 2 (Amendment 1)
Protocol Date: 23-June-2021
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Statistical Analysis Plan v2.0
08-Nov-2021
Electronic signatures can be found on the last page of this document.
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Statistical Analysis Plan v2.0
08-Nov-2021
REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
1.0
(Original version)
12-Apr-2021
[Not Applicable]
2.0
08-Nov-2021
2.0 STUDY DESIGN, 4.0 SAMPLE-SIZE DETERMINATION
Updated sample size from 34 to 42 (maximum 46) based on Protocol 
Amendment 1 from Version 1.
5.2 Pharmacokinetic Analysis Set
Clarified with that the additional / detail definition of PK Analysis 
Set is defined in CPAP.
9.2.3.2 Handling of Vital Signs and 12-Lead ECGs
Deleted Time Windows of Vistal Sign related evening dose, because 
vital sign is not captured at evening dose.
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Statistical Analysis Plan v2.0
08-Nov-2021
TABLE OF CONTENTS
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS..........................................................7
1.1
Objectives..................................................................................................................7
1.1.1
Primary Objective..............................................................................................7
1.1.2
Secondary Objective..........................................................................................7
1.1.3
Additional Objective..........................................................................................7
1.2
Endpoints...................................................................................................................7
1.2.1
Primary Endpoint...............................................................................................7
1.2.2
Secondary Endpoints .........................................................................................7
1.2.2.1
Key Secondary Endpoint ...........................................................................7
1.2.2.2
Other Secondary Endpoints .......................................................................7
1.2.3
Exploratory Endpoint.........................................................................................8
1.2.4
Safety Endpoints................................................................................................8
1.2.5
Other Endpoints.................................................................................................8
1.3
Estimand....................................................................................................................8
2.0
STUDY DESIGN............................................................................................................8
3.0
STATISTICAL HYPOTHESES AND DECISION RULES.............................................9
3.1
Statistical Hypotheses................................................................................................9
3.2
Statistical Decision Rules...........................................................................................9
3.3
Multiplicity Adjustment.............................................................................................9
4.0
SAMPLE-SIZE DETERMINATION.............................................................................10
5.0
ANALYSIS SETS.........................................................................................................10
5.1
Safety Analysis Set..................................................................................................10
5.2
Pharmacokinetic Analysis Set..................................................................................10
6.0
STATISTICAL ANALYSIS..........................................................................................10
6.1
General Considerations............................................................................................10
6.2
Disposition of Subjects ............................................................................................11
6.2.1
Study Information............................................................................................11
6.2.2
Screen Failures ................................................................................................11
6.2.3
Subject Eligibility............................................................................................11
6.2.4
Disposition of Subjects ....................................................................................12
6.2.5
Protocol Deviations and Analysis Sets.............................................................12
6.3
Demographic and Other Baseline Characteristics.....................................................13
6.3.1
Demographics..................................................................................................13
6.3.2
Medical History and Concurrent Medical Conditions.......................................13
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Statistical Analysis Plan v2.0
08-Nov-2021
6.4
Medication History and Concomitant Medications...................................................14
6.5
Study Drug Exposure and Compliance.....................................................................14
6.6
Efficacy Analysis.....................................................................................................14
6.7
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses................................14
6.8
Other Analyses ........................................................................................................15
6.9
Safety Analysis........................................................................................................15
6.9.1
Adverse Events................................................................................................15
6.9.2
Overview of Treatment-Emergent Adverse Events...........................................15
6.9.3
Displays of Treatment-Emergent Adverse Events ............................................16
6.9.4
Displays of Pretreatment Events ......................................................................17
6.9.5
Adverse Events of Special Interest...................................................................17
6.9.6
Other Safety Analysis ......................................................................................18
6.9.6.1
Clinical Laboratory Evaluations...............................................................18
6.9.6.2
Vital Signs...............................................................................................19
6.9.6.3
12-Lead ECGs.........................................................................................20
6.10
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis...................................................................................................................20
6.11
Interim Analyses......................................................................................................20
6.12
Data Monitoring Committee/Internal Review Committee.........................................20
7.0
REFERENCES..............................................................................................................20
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES ................................................21
9.0
APPENDIX...................................................................................................................21
9.1
Changes from the Previous Version of the SAP .......................................................21
9.2
Data Handling Conventions .....................................................................................21
9.2.1
General Data Reporting Conventions...............................................................21
9.2.1.1
Criteria for Markedly Abnormal Values...................................................22
9.2.1.2
12-lead ECG (Upper MAV Criteria of QTcF Interval).............................24
9.2.2
Definition of Baseline......................................................................................24
9.2.3
Definition of Visit Windows............................................................................25
9.2.3.1
Handling of HP Breath Test and Laboratory Test.....................................25
9.2.3.2
Handling of Vital Signs and 12-Lead ECGs.............................................25
9.3
Analysis Software....................................................................................................26
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Statistical Analysis Plan v2.0
08-Nov-2021
ABBREVIATIONS
AE
adverse event
Aeτ 
amount of drug excreted in urine during a dosing interval
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AUCτ
area under the concentration-time curve during a dosing interval
AST
aspartate aminotransferase
BID
twice daily
BMI
body mass index
Cmax
maximum observed plasma concentration
CYP
cytochrome P450
ECG
electrocardiogram
eCRF
electronic case report form
GGT
-glutamyl transferase
HP
Helicobacter pylori
LDH
lactate dehydrogenase
LLN
lower limit of normal
MAV
markedly abnormal values
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetic(s)
PT
Preferred Term (MedDRA)
PTE
pretreatment event
QTcF
QT interval corrected by Fridericia's method
SAE
serious adverse event
SAP
statistical analysis plan
SOC
System Organ Class (MedDRA)
TAK-438
Vonoprazan
TAK-438F
freebase of TAK-438
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WHO Drug
World Health Organization Drug Dictionary
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Statistical Analysis Plan v2.0
08-Nov-2021
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS
1.1
Objectives
1.1.1
Primary Objective
To evaluate the safety, tolerability, and PK of quadruple therapy with bismuth, clarithromycin, 
amoxicillin, and vonoprazan versus quadruple therapy with bismuth, clarithromycin, amoxicillin, 
and esomeprazole.
1.1.2
Secondary Objective
Not Applicable.
1.1.3
Additional Objective
Not Applicable.
1.2
Endpoints
1.2.1
Primary Endpoint
The primary endpoint of the study is:

To evaluate plasma PK parameters of bismuth potassium citrate (600 mg) when
coadministered with clarithromycin (500 mg BID), amoxicillin (1000 mg BID), 
andvonoprazan (20 mg BID), and when coadministered with clarithromycin (500 mg 
BID),amoxicillin (1000 mg BID), and esomeprazole (20 mg BID):
–
Cmax at Day 14.
–
The area under the plasma concentration-time curve during a dosing interval (area 
under the plasma concentration-time curve during a dosing interval, where tau (τ) is the 
length of the dosing interval [AUCτ]) at Day 14.
–
The amount of drug excreted in urine during a dosing interval (Aeτ) at Day 14. 
1.2.2
Secondary Endpoints
Key Secondary Endpoint
1.2.2.1
Not Applicable.
Other Secondary Endpoints
1.2.2.2
The secondary endpoints will be assessed through evaluation of the following parameters: 

Percentage of subjects who experience at least 1 treatment-emergent adverse event (TEAE).

Percentage of subjects who discontinue due to an adverse event (AE).
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Statistical Analysis Plan v2.0
08-Nov-2021
1.2.3
Exploratory Endpoint
Evaluation of plasma drug concentrations at the end of dosing intervals (Ctrough) of vonoprazan 
and esomeprazole.
1.2.4
Safety Endpoints
Safety endpoints are as follows:

Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests 
at least once post dose.

Percentage of subjects who meet the markedly abnormal criteria for vital sign 
measurements at least once post dose.

Percentage of subjects who meet the markedly abnormal criteria for safety 
electrocardiogram (ECG) parameters at least once post dose.
1.2.5
Other Endpoints
Not Applicable.
1.3
Estimand
Not Applicable.
2.0
STUDY DESIGN
A Phase 1, double-blind, parallel group study in healthy subjects with Helicobacter pylori 
(H pylori–positive) to evaluate the safety, tolerability, and pharmacokinetics (PK) of a quadruple 
therapy with bismuth, clarithromycin, amoxicillin, and vonoprazan versus quadruple therapy 
with bismuth, clarithromycin, amoxicillin, and esomeprazole. Approximately 42 (maximum 
46 subjects) H pylori–positive healthy subjects aged 18 to 60 years, inclusive, who are 
considered eligible based on the inclusion and exclusion criteria, will participate in this study. 
All subjects will be enrolled and randomized to 1 of the 2 treatment groups as indicated in the 
schematic in Protocol, Section2.0.
The treatment phase will consist of quadruple therapy twice daily (BID) with bismuth potassium 
citrate (600 mg [equivalent to 220 mg bismuth]), BID clarithromycin (500 mg), amoxicillin 
(1000 mg), and vonoprazan (20 mg) (Group B) or quadruple therapy BID with bismuth 
potassium citrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and esomeprazole 
(20 mg) (Group A) administered from Days 1 to 14. Subjects will be discharged on Day 15 after 
all procedures have been performed. The subjects who complete study treatment are to be 
followed-up at Week 4 post-treatment to provide a 13C urea breath test (13C UBT) for H pylori.
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Statistical Analysis Plan v2.0
08-Nov-2021
Study Schematic
Pretreatment
Treatment Period
Follow-Up
Screening
Check-
in 
Baseline
<--------------------Confinement----------------->
Check-
out
Follow-
up call
Follow-up 
visit
Days -28 to -2
Day -1
Days 1-11
Days 12-
13
Day 14
Day 15
Day 17 
(+2 days)
Day 42
(+ 6 days)
Group A: clarithromycin a + amoxycillin b + 
bismuth c + esomeprazole d
13C UBT
for 
H pylori
13C UBT for 
H pylori
Group B: clarithromycin a + amoxycillin b + 
bismuth c + vonoprazan e
Vonoprazan PK or 
esomeprazole PK in 
plasma f
Bismuth PK 
in plasma 
and urine g
13C: carbon 13 isotope; BID: twice daily; PK: pharmacokinetic(s); UBT: urea breath test.
a Clarithromycin 500 mg BID.
b Amoxycillin 1000 mg BID.
c Bismuth potassium citrate 600 mg BID.
d Esomeprazole 20 mg BID.
e Vonoprazan: 20 mg BID.
f Blood samples for vonoprazan and esomeprazole PK on Days 12-14 are to be taken predose (morning and 
evening).
g Blood samples for bismuth PK are to be taken on Day 14 predose (0 hours), 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 
5.0, 6.0, 8.0, 10.0, and 12.0 hours after the morning dose. Urine samples for bismuth PK are to be taken on Day 14 
at 0 to 12 hours after the morning dose.
3.0
STATISTICAL HYPOTHESES AND DECISION RULES 
3.1
Statistical Hypotheses
Not Applicable.
3.2
Statistical Decision Rules
Not Applicable.
3.3
Multiplicity Adjustment
Not Applicable.
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Statistical Analysis Plan v2.0
08-Nov-2021
4.0
SAMPLE-SIZE DETERMINATION
The study will randomize approximately 42 subjects(maximum 46 subjects, if drop-out rate from 
PK Analysis Set increases to more than 25%) to provide at least 80% power of showing no 
significant difference in plasma bismuth Cmax and AUCτ between vonoprazan and esomeprazole 
quadruple therapy.
5.0
ANALYSIS SETS
5.1
Safety Analysis Set
The safety analysis set will consist of subjects who received at least 1 dose of the study drug.
5.2
Pharmacokinetic Analysis Set 
The PK analysis set will consist of subjects who received the study drug, completed the minimum 
protocol specified procedures with no significant protocol deviations, and were evaluable for the 
PK.
Subjects who received the study drug 
(bismuth/vonoprazan/esomeprazole/clarithromycin/amoxicillin) and have at least 1 measurable 
plasma drug concentration, after start of dosing without protocol violations or events with 
potential to affect the PK concentrations and who have completed minimum protocol procedures 
will be evaluated. The detail definition of the minimum protocol specified procedures with the 
potential to affect the PK concentrations will be described in the clinical pharmacology analysis 
plan (CPAP).
6.0
STATISTICAL ANALYSIS
6.1
General Considerations
Definitions
The following definitions and calculation formulas will be used.

TEAE: An AE whose date of onset occurs on or after the start of study drug.

PTE: An AE whose date of onset occurs before the start of study drug.

Significant TEAE: any AEs (not including serious TEAEs) that led to an intervention, 
including withdrawal of drug treatment or significant additional concomitant therapy.

Study Day: The day before the first dose of the study medication will be defined as Study 
Day -1 and the day of the first dose will be defined as Study Day 1. Other study days are 
defined relative to Study Day 1, eg, the day prior to Study Day 1 is Day -1 and the day after 
Study Day 1 is Day 2.
As for complex data handling conventions and definition of visit windows, refer to 
Appendix section 9.2.
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Statistical Analysis Plan v2.0
08-Nov-2021
6.2
Disposition of Subjects
6.2.1
Study Information
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables:
Date First Subject Signed Informed Consent Form
Date of Last Subject’s Last Visit/Contact
MedDRA Version
WHO Drug Version
SAS Version Used for Creating the Datasets
Analytical Methods:
(1) Study Information
Study information shown in the analysis variables section will be provided.
6.2.2
Screen Failures
Analysis Set:
All Subjects Who Were Not Randomized
Analysis Variables:
Age (years) 
[Min<= - <30, 30<= - <50, 50<= - <=Max]
Gender
[Male, Female]
Race
[American Indian or Alaska Native, Asian, Black or African American,
Native Hawaiian or Other Pacific Islander, White, Not Reported]
Analytical Methods:
(1) Screen Failures
Frequency distributions for categorical variables and descriptive statistics for continuous 
variables will be provided.
6.2.3
Subject Eligibility
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables:
Eligibility Status
[Yes, No]
Primary Reason for Subject Not Being Eligible
[Pretreatment Event/Adverse Event,
Did Not Meet Inclusion Criteria or Did 
Meet Exclusion Criteria, 
Significant Protocol Deviation,
Lost to Follow-Up,
Voluntary Withdrawal,
Study Termination,
Other]
Analytical Methods:
(1) Eligibility for Randomization
Frequency distributions will be provided. When calculating the percentages for the primary 
reasons for subject not being eligible, the total number of ineligible subjects will be used as 
the denominator.
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Statistical Analysis Plan v2.0
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6.2.4
Disposition of Subjects
Analysis Set:
Randomized Set
Analysis Variables:
TAK-438/Esomeprazole Study Drug 
Administration Status
[No]
Reason for Not Being Treated
[Pretreatment Event/Adverse Event, 
Liver Function Test Abnormalities, 
Lost to Follow-Up, Pregnancy,
Significant Protocol Deviation,
Study Termination, Voluntary Withdrawal, 
Other]
TAK-438/Esomeprazole Study Drug 
Completion Status
[Completed Study Drug, 
Prematurely Discontinued Study Drug]
Reason for Discontinuation of TAK-
438/Esomeprazole Study Drug
[Pretreatment Event/Adverse Event, 
Liver Function Test Abnormalities, 
Lost to Follow-Up, Pregnancy,
Significant Protocol Deviation,
Study Termination, Voluntary Withdrawal, 
Other]
Analytical Methods:
(1) Disposition of Subjects
Frequency distributions will be provided for each treatment group and overall. When 
calculating percentages for the reasons for not being treated, the total number of subjects not 
treated by the study drug will be used as the denominator. When calculating percentages for 
the reasons for discontinuation of study drug, the total number of subjects who prematurely 
discontinued the study drug will be used as the denominator.
(2) Flow Chart of Subject Distribution
Flow chart will be provided.
6.2.5
Protocol Deviations and Analysis Sets
Protocol Deviations
Analysis Set:
Randomized Set
Analysis Variables:
Protocol Deviation
[Entry Criteria, Concomitant Medication, 
Procedure Not Performed Per Protocol, 
Study Medication, Withdrawal Criteria]
Analytical Methods:
(1) Protocol Deviations
Frequency distribution will be provided by treatment group and overall for each deviation 
category. A subject who has several deviations will be counted once in each appropriate 
category. A subject who has several deviations that can be classified into the same category 
will be counted only once.
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Statistical Analysis Plan v2.0
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Analysis Sets
Analysis Set:
Randomized Set
Analysis Variables:
Analysis Sets
PK Analysis Set
Safety Analysis Set
[Included]
[Included]
Analytical Methods:
(1) Analysis Sets
Frequency distributions will be provided by treatment group and overall.
6.3
Demographic and Other Baseline Characteristics
6.3.1
Demographics
Analysis Set:
PK Analysis Set
Safety Analysis Set
Analysis Variables:
Age (years)
[Min<= - <30, 30<= - <50, 50<= - <=Max]
Gender
[Male, Female]
Race
[American Indian or Alaska Native, Asian, 
Black or African American, 
Native Hawaiian or Other Pacific Islander, 
White]
Height (cm)
[Min<= - <150, 150<= - <160, 
160<= - <170, 170<= - <=Max]
Weight (kg) (Baseline)
[Min<= - <50.0, 50.0<= - <60.0, 
60.0<= - <70.0, 70.0<= - <80.0, 
80.0<= - <=Max]
BMI (kg/m2) (Baseline)
[Min<= - <18.5, 18.5<= - <25.0, 
25.0<= - <=Max]
Smoking Classification
[Never, Former, Current]
Consumption of Alcohol
[Never, Former, Current]
Consumption of Caffeine
[Never, Former, Current]
CYP2C19 Genotype
[*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, *3/*3]
Analytical Methods:
(1) Summary of Demographics and Other Baseline Characteristics
Frequency distributions for categorical variables and descriptive statistics for continuous 
variables will be provided by treatment group and overall.
6.3.2
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases that stopped at or prior to the time 
of informed consent. Concurrent medical conditions are defined as significant conditions 
ongoing or present at the time of informed consent.
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA, version 23.0) coding system.
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Statistical Analysis Plan v2.0
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There will be no analysis of medical history and concurrent medical conditions.
6.4
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped 
prior to signing of informed consent. Concomitant medications are recorded on the eCRF and 
include any medications, other than the study drug, taken at any time between informed consent 
and on or prior to the last dose of study drug.
Medication history and concomitant medications will be coded using the World Health 
Organization Drug Dictionary (WHO Drug) version Global B3 March 2021.
There will be no analysis of medication history and concomitant medications.
6.5
Study Drug Exposure and Compliance
TAK-438/Esomeprazole and Bismuth Exposure and Compliance
Analysis Set:
Safety Analysis Set
Analysis Variables:
Duration of Exposure to Study Drug (days)
Study Drug Compliance (%)
[Min<= - <50.0, 50.0<= - <70.0, 
70.0<= - <90.0, 90.0<= - <=Max]
Analytical Methods:
(1) Study Drug Exposure and Compliance
Frequency distributions for categorical variables and descriptive statistics for continuous 
variables will be provided by treatment group and overall.
Clarithromycin and Amoxicillin Exposure and Compliance
Analysis Set:
Safety Analysis Set
Analysis Variables:
Duration of Exposure to Study Drug (days)
Study Drug Compliance (%)
[Min<= - <50.0, 50.0<= - <70.0, 
70.0<= - <90.0, 90.0<= - <=Max]
Analytical Methods:
(1) Study Drug Exposure and Compliance
Frequency distributions for categorical variables and descriptive statistics for continuous 
variables will be provided by treatment group and overall.
6.6
Efficacy Analysis
Not applicable.
6.7
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses
The contents of PK analysis will be described in the clinical pharmacology analysis plan (CPAP).
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Statistical Analysis Plan v2.0
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6.8
Other Analyses
H Pylori Urea Breath Test
Analysis Set:
Safety Analysis Set
Analysis Variable:
H Pylori Urea Breath Test
[Positive, Negative]
Visit
Screening and Day 42
Analytical Methods:
(1) Summary of H Pylori Urea Breath Test
Frequency distributions will be provided by treatment group and overall.
6.9
Safety Analysis
6.9.1
Adverse Events
6.9.2
Overview of Treatment-Emergent Adverse Events
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Relationship to Study Drug
Relationship to TAK-438/ 
Esomeprazole
[Related, Not Related]
Relationship to Bismuth
[Related, Not Related]
Relationship to Clarithromycin
[Related, Not Related]
Relationship to Amoxicillin
[Related, Not Related]
Intensity
[Mild, Moderate, Severe]
Analytical Methods: The following summaries will be provided for each treatment group.
(1) Overview of Treatment-Emergent Adverse Events
1) All Treatment-Emergent Adverse Events (number of events, number and percentage of 
subjects) 
2) Relationship of Treatment-Emergent Adverse Events to Study Drug [TAK-
438/Esomeprazole, Bismuth, Clarithromycin, Amoxicillin] (number of events, number and 
percentage of subjects) 
3) Intensity of Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects) 
4) Treatment-Emergent Adverse Events Leading to TAK-438/Esomeprazole Study Drug 
Discontinuation (number of events, number and percentage of subjects) 
5) Relationship of Treatment-Emergent Adverse Events Leading to TAK-438/Esomeprazole 
Study Drug Discontinuation (number of events, number and percentage of subjects) 
6) Serious Treatment-Emergent Adverse Events (number of events, number and percentage of 
subjects) 
7) Relationship of Serious Treatment-Emergent Adverse Events to Study Drug [TAK-
438/Esomeprazole, Bismuth, Clarithromycin, Amoxicillin] (number of events, number and 
percentage of subjects) 
8) Serious Treatment-Emergent Adverse Events Leading to TAK-438/Esomeprazole Study 
Drug Discontinuation (number of events, number and percentage of subjects) 
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Statistical Analysis Plan v2.0
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9) Treatment-Emergent Adverse Events Resulting in Death (number of events, number and 
percentage of subjects) 
10) Significant Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)
11) Relationship of Significant Treatment-Emergent Adverse Events to Study Drug 
[TAK-438/Esomeprazole, Bismuth, Clarithromycin, Amoxicillin] (number of events, 
number and percentage of subjects)
TEAEs will be counted according to the rules below.
Number of subjects

Summaries for 2), 7) and 11)
A subject with occurrences of TEAE in both categories (ie, Related and Not Related) will 
be counted once in the Related category.

Summary for 3)
A subject with multiple occurrences of TEAE will be counted once for the TEAE with the 
maximum intensity.

Summaries other than 2), 3), 7) and 11)
A subject with multiple occurrences of TEAE will be counted only once.
Number of events
For each summary, the total number of events will be calculated.
6.9.3
Displays of Treatment-Emergent Adverse Events
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Intensity
[Mild, Moderate, Severe]
Analytical Methods: The following summaries will be provided using frequency distribution for each treatment 
group.
TEAEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency for tables provided 
by SOC and PT. SOC and PT will be sorted in decreasing frequency for tables provided by 
SOC only or PT only.
Drug-related TEAEs will be summarized for TAK-438/Esomeprazole, Bismuth, 
Clarithromycin and Amoxicillin, respectively.
(1) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
(2) Treatment-Emergent Adverse Events by System Organ Class
(3) Treatment-Emergent Adverse Events by Preferred Term
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term [TAK-438/Esomeprazole, Bismuth, Clarithromycin, Amoxicillin]
(5) Intensity of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class, and Preferred Term [TAK-438/Esomeprazole, Bismuth, Clarithromycin, 
Amoxicillin]
(7) Treatment-Emergent Adverse Events Leading to TAK-438/Esomeprazole Study 
Drug Discontinuation by System Organ Class and Preferred Term
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(8) Drug-Related Treatment-Emergent Adverse Events Leading to TAK-
438/Esomeprazole Study Drug Discontinuation by System Organ Class and Preferred 
Term
(9) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term
(10) Significant Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(11) Drug-Related Significant Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term [TAK-438/Esomeprazole, Bismuth, Clarithromycin, 
Amoxicillin]
The frequency distribution will be provided according to the rules below.
Number of subjects

Summary tables other than (5), and (6)
A subject with multiple occurrences of TEAE within a SOC will be counted only once in 
that SOC. A subject with multiple occurrences of TEAE within a PT will be counted only 
once in that PT. Percentages will be based on the number of subjects in the safety analysis 
set.

Summary tables for (5) and (6)
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted only 
once for the TEAE with the maximum intensity. Percentages will be based on the number 
of subjects in the safety analysis set.
6.9.4
Displays of Pretreatment Events
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables: PTE
Analytical Methods: The following summaries will be provided using frequency distribution.
PTEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC will 
be sorted alphabetically and PT will be sorted in decreasing frequency.
(1) Pretreatment Events by System Organ Class and Preferred Term
(2) Serious Pretreatment Events by System Organ Class and Preferred Term
The frequency distribution will be provided according to the rules below.
Number of subjects
A subject with multiple occurrences of PTE within a SOC will be counted only once in that 
SOC. A subject with multiple occurrences of PTE within a PT will be counted only once in 
that PT.
6.9.5
Adverse Events of Special Interest
Not applicable.
Additionally, as for Significant TEAE, refer to section 6.1.
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Statistical Analysis Plan v2.0
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6.9.6
Other Safety Analysis
Clinical Laboratory Evaluations
6.9.6.1
Hematology and Serum Chemistry
Analysis Set:
Safety Analysis Set
Analysis Variables: Hematology
RBCs (×1012/L)
WBCs (×109/L)
Hemoglobin (g/L)
Hematocrit (%)
Platelets (×109/L)
White Blood Cell Fractions (Neutrophils (%), Eosinophils (%), Basophils (%), Monocytes
(%), Lymphocytes (%))
PT/INR
aPTT (sec)
Reticulocyte count (×1012/L)
Serum Chemistry
ALT (U/L)
Alkaline phosphatase (U/L)
AST (U/L)
GGT (U/L)
Total Bilirubin (μmol/L)
Direct Bilirubin (μmol/L)
Creatine kinase (U/L)
Creatine kinase MB (ng/mL) Albumin (g/L)
Total Protein (g/L)
Serum creatinine (μmol/L)
LDH (U/L)
Uric Acid (μmol/L)
HDL Cholesterol (mmol/L)
LDL Cholesterol (mmol/L)
Triglycerides (mmol/L)
Glucose (mmol/L)
Potassium (mmol/L)
Sodium (mmol/L)
Magnesium (mmol/L)
Calcium (mmol/L)
Chloride (mmol/L)
Amylase (U/L)
Blood urea nitrogen (mmol/L)
Visit:
Baseline, Day 5, 8, 12, 13, 14, 15
Analytical Methods: The following summaries will be provided for each treatment group.
(1) Summary of Laboratory Test Results and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline (each post-baseline 
visit - baseline) will be provided for each visit.
(2) Summary of Shifts of Laboratory Test Results
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided. For each laboratory test, the laboratory values will be 
classified as "Low", "Normal" or "High" relative to the normal reference range provided by 
the central laboratory. The shift tables will be based on these classifications.
(3) Number and Percentage of Subjects with Markedly Abnormal Values of Laboratory 
Test results
Overall frequency distributions of MAV during treatment phase will be provided. If a 
laboratory test result has both lower and upper MAV criteria, analysis will be performed for 
each. Further details are given in Appendix.
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Statistical Analysis Plan v2.0
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Urinalysis
Analysis Set:
Safety Analysis Set
Analysis Variables: pH
[Min<= - <5.0, 5.0<= - <=8.5, 8.5< - <=Max]
Specific gravity [Min<= - <1.005, 1.005<= - <=1.030, 1.030< - <=Max]
Protein
[Negative, Positive]
Glucose
[Negative, Positive]
Nitrites
[Negative, Positive]
Bilirubin
[Negative, Positive]
Hemoglobin
[Negative, Positive]
Ketones
[Negative, Positive]
Leucocytes
[Negative, Positive]
Urobilinogen
[Negative, Positive]
Visit:
Baseline, Day 5, 8, 12, 13, 14, 15
Analytical Methods: The following summaries will be provided for each treatment group.
(1) Summary of Shifts of Urine Laboratory Test Results
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided.
Vital Signs
6.9.6.2
Analysis Set:
Safety Analysis Set
Analysis Variables:
Body Temperature (C)
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Respiratory Rate (bpm)
Pulse (bpm)
Visit:
Baseline, Day 1 to 15 at Predose
Analytical Methods: For each variable, following summary will be provided by treatment group.
(1) Summary of Vital Signs Parameters and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline (each post-baseline 
visit – baseline) will be provided for each visit.
(2) Number and Percentage of Subjects with Markedly Abnormal Values of Vital Signs 
Parameters
Overall frequency distributions of MAV during treatment phase will be provided. If a vital 
sign parameter has both lower and upper MAV criteria, analysis will be performed for 
each. Further details are given in Appendix.
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12-Lead ECGs
6.9.6.3
Analysis Set:
Safety Analysis Set
Analysis Variables:
Heart Rate (bpm)
RR Interval (msec)
PR Interval (msec)
QT Interval (msec)
QTcF Interval (msec)
QRS Interval (msec)
12-Lead ECG Interpretation
["Within Normal Limits",
"Abnormal, Not Clinically Significant",
"Abnormal, Clinically Significant",
"Not Evaluable"]
Visit:
Baseline, Day 3, Day 7 at Pre–morning dose, Day 14 at Pre–morning dose, 1, 2, 4 hour Post-
morning dose, Day 15
Analytical Methods: For each variable other than 12-lead ECG interpretations, summary (1) will be provided by 
treatment group.
For 12-lead ECG interpretations, summary (3) will be provided by treatment group.
(1) Summary of ECG Parameters and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline (each post-baseline 
visit – baseline) will be provided for each visit.
(2) Number and Percentage of Subjects with Markedly Abnormal Values of ECG 
Parameters
Overall frequency distributions of MAV during treatment phase will be provided. If an 
ECG parameter has both lower and upper MAV criteria, analysis will be performed for 
each. Further details are given in Appendix.
(3) Summary of Shifts of ECG Parameters
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided.
6.10
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis
Not applicable.
6.11
Interim Analyses
Not applicable.
6.12
Data Monitoring Committee/Internal Review Committee
Not applicable.
7.0
REFERENCES
Not applicable.
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8.0
CHANGES TO PROTOCOL PLANNED ANALYSES
Not applicable.
9.0
APPENDIX 
9.1
Changes from the Previous Version of the SAP
Changes made from the previous version of the SAP that have a material impact to the 
planned statistical analysis methods are described below. In addition, there were textual 
changes purely to improve the flow, organization and clarity. As these represent cosmetic 
changes with no impact to the planned statistical analyses, they are not included in the table 
below. 
SAP Section 
Impacted Text 
(shown in bold)
Change 
Rationale for Change
(Not applicable)
The other changes from Statistical Analysis Plan version 1 are as follows:

5.2 Clarified with the additional / detail definition of PK Analysis Set is in CPAP 
–
Old text: The definition of PK analysis set will be described in the clinical pharmacology
analysis plan (CPAP).
–
Revised text: The detail definition of PK analysis set that completed the minimum 
protocol specified procedures with no significant protocol deviations that is potentially to 
affect the PK concentration will be described in the clinical pharmacology analysis plan 
(CPAP).

9.2.3.2 Deleted Time Windows of Vistal Sign related evening dose, because vital sign is not 
captured at evening dose.
9.2
Data Handling Conventions 
9.2.1
General Data Reporting Conventions 

Descriptive statistics: number of subjects, mean, standard deviation, maximum, minimum, 
and quartiles

Duration of exposure to study medication (days): date of last dose of study medication - date 
of first dose of study medication + 1

Study drug compliance (%): (number of times “Dose Start Time” was collected) / (2* 
Duration of exposure to study medication) *100 (rounded to 1 decimal place). Study drug 
compliance will be calculated each group of study drugs, 1) TAK438/Esomeprazole and 
Bismuth or 2) Clarithromycin and Amoxicillin.
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
QTcF interval (msec): QT interval (msec) / (RR interval (msec) / 1000) 0.33 (rounded to the 
nearest whole number)

As for laboratory test values, below the lower limit of quantification will be handled as zero.
Criteria for Markedly Abnormal Values
9.2.1.1
Hematology, Serum Chemistry, Vital Signs, and 12-lead ECG (except Upper MAV Criteria of 
QTcF Interval)
For each parameter, all evaluable data (ie, non-missing data) obtained up to Day 15 will be 
classified as a MAV or not. The criteria in the table below will be used. 
For each parameter and subject, classifications will be made according to the conditions i) to 
iii) provided below. The lower and the upper criteria will be considered separately.
i)
A subject with at least one evaluable data after baseline that meets the MAV criteria will be 
classified as a subject with MAV.
ii)
A subject who does not meet condition i) and has at least one evaluable data after baseline 
that doesn't meet the MAV criteria will be considered as a subject without MAV.
iii) A subject who does not meet conditions i) or ii) will be excluded from the analysis of MAV 
for that parameter.
Hematology
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
RBCs (×1012/L)
<0.8×LLN
>1.2×ULN
WBCs (×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
aPTT (sec)
>1.5×ULN
PT/INR
>1.5
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Statistical Analysis Plan v2.0
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Serum Chemistry
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
ALT (U/L)
-
>3×ULN
Alkaline phosphatase (U/L)
-
>3×ULN
AST (U/L)
-
>3×ULN
GGT (U/L)
-
>3×ULN
Total Bilirubin (μmol/L)
-
>34.2
Creatine kinase (U/L)
-
>5×ULN
Albumin (g/L)
<25
-
Total Protein (g/L)
<0.8×LLN
>1.2×ULN
Blood urea nitrogen (mmol/L)
-
>10.7
Uric acid (mmol/L)
-
>0.773
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
Chloride (mmol/L)
<75
>126
Amylase (U/L)
-
>2×ULN
Serum creatinine (μmol/L)
-
>177
*For Uric acid, there is unit discrepancy between measurement as “Uric Acid (μmol/L)” and MAV criteria as “Uric 
acid (mmol/L)”
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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Statistical Analysis Plan v2.0
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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
-
12-lead ECG (Upper MAV Criteria of QTcF Interval)
9.2.1.2
All evaluable data (ie, non-missing data) obtained up to Day 15 will be classified as a MAV or 
not. The criteria in the table below will be used. Note that the observed value and the change 
from baseline used for classification should be measurements taken on the same day.
For each subject, classifications will be made according to the conditions i) to iii) provided 
below.
i)
A subject with at least one evaluable data after baseline that meets the MAV criteria will be 
classified as a subject with MAV.
ii)
A subject who does not meet condition i) and has at least one evaluable data after baseline 
that meets any of the following will be considered as a subject without MAV.

Observed value is less than 450 msec and not missing.

Change from baseline is less than 30 msec and not missing, and observed value is less 
than 500 msec and not missing.
iii) A subject who does not meet conditions i) or ii) will be excluded from the analysis of MAV.
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
QTcF Interval (msec)
-
If either of the following conditions is met:

observed value >=500

change from baseline >= 30 and observed value >=450
9.2.2
Definition of Baseline 
Baseline and Screening values: The last evaluable observation (ie, non-missing) before the first 
dose of study medication. If no evaluable observation is obtained before the first dose, the 
baseline value will be missing.
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Statistical Analysis Plan v2.0
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9.2.3
Definition of Visit Windows 
Handling of HP Breath Test and Laboratory Test
9.2.3.1
For each visit, all evaluable observation (ie, non-missing) obtained in the corresponding time 
interval will be used. If more than one observation lies within the same visit window, the 
observation with the closest sampling day to the scheduled study day will be used. If there are
two observations equidistant to the scheduled study day, the later observation will be used.
HP Breath Test
Visit
Scheduled Study Day
(days)
Time Interval (days)
Study Day
Screening
-2
-28 – -2
Day 42
42
Post dose – 48
Laboratory Test
Visit
Scheduled Study Day (days)
Time Interval (days)
Study Day
Baseline
Study Day: -1
-28 – -1
Day 5
Study Day: 5
1 – 6
Day 8
Study Day: 8
7 – 9
Day 12
Study Day: 12
10 – 12
Day 13
Study Day: 13
13
Day 14
Study Day: 14
14
Day 15
Study Day: 15
15
Handling of Vital Signs and 12-Lead ECGs
9.2.3.2
For each visit, all evaluable observation (ie, non-missing) obtained in the corresponding time 
interval will be used. If more than one observation lies within the same time window, the 
observation with the closest sampling time to the scheduled time will be used. If there are two 
observations equidistant to the scheduled time, the later observation will be used.
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Statistical Analysis Plan v2.0
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Vital Signs
Visit
Time
Scheduled Study Day
(days)
Scheduled Time
from Dose* (min)
Time Interval (min)
/ Study Day (days)
Assessment Time
from Dose*
Baseline
Pre-morning 
dose
Study Day: 1
Morning
0
Study Day: -28 – 1
Day 2 to 14
Pre-morning 
dose
Study Day: 2 to 14
Morning
0
Time: -60 – 0
Day 15
Study Day: 15
Study Day: 
Post dose – 15
* Start Time of bismuth, TAK-438, Esomeprazole
12-Lead ECGs
Visit
Time
Scheduled Study Day
(days)
Scheduled Time
from Dose*
(min)
Time Interval (min)
/ Study Day (days)
Assessment Time
from Dose*
Baseline
Pre-morning 
dose
Study Day: 1
Morning
0
Study Day: -28 – 1
Day 3
Pre-morning 
dose
Study Day: 3
Morning
0
Time: -60 – 0
Day 7
Pre-morning 
dose
Study Day: 7
Morning
0
Time: -60 – 0
Day 14
Pre-morning 
dose
Study Day: 14
Morning
0
Time: -60 – 0
1 hour post-
morning dose
Morning
60
Time: 0< – 90
2 hours post-
morning dose
Morning
120
Time: 90< – 180
4 hours post-
morning dose
Morning
240
Time: 180< – 300
Day 15
Study Day: 15
Study Day: 
Post dose – 15
* Start Time of bismuth, TAK-438, Esomeprazole
9.3
Analysis Software 
SAS 9.4
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d681215682
Vonoprazan-1001 Statistical Analysis Plan 2021-11-08
Biostatistics Approval
10-Nov-2021 00:17 UTC
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