Conditions: Helicobacter Pylori
Keywords: Drug Therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
To evaluate the safety, tolerability, and pharmacokinetics (PK) of quadruple therapy with bismuth, clarithromycin, amoxicillin, and TAK-438 versus quadruple therapy with bismuth, clarithromycin, amoxicillin, and lansoprazole.

Detailed description:
This is a phase 1, double-blind, parallel group study in participants with Helicobacter pylori (HP positive) who are, additionally, cytochrome P-450 (CYP)2C19 extensive metabolizers (EM) to evaluate the safety, tolerability and pharmacokinetics (PK) of a quadruple therapy with bismuth, clarithromycin, amoxicillin, and TAK-438 versus quadruple therapy with bismuth, clarithromycin, amoxicillin, and lansoprazole. The study will enroll 30 participants.

The treatment phase consists of quadruple therapy twice daily (BID) with tripotassium bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and TAK-438 (20 mg) (Group B) or quadruple therapy BID with tripotassium bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg),and lansoprazole (30 mg) (Group A) from Days 1 to 14. Participants will be discharged on Day 15 after final PK blood samples are collected and all procedures performed.

This single-center will be conducted in Korea. 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, twice daily, along with amoxicillin 1000 mg capsules, orally, twice daily, tripotassium bismuth dicitrate 600 mg, tablets, orally, twice daily, and lansoprazole 30 mg, capsules, orally, twice daily on Days 1 to 14. arm 2: Clarithromycin 500 mg, tablets, orally, twice daily, along with amoxicillin 1000 mg, capsules, orally, twice daily, tripotassium bismuth dicitrate 600 mg, tablets, orally, twice daily, and TAK-438 20 mg, tablets, orally, twice daily on Days 1 to 14.

Interventions: intervention 1: Clarithromycin intervention 2: Amoxicillin intervention 3: Tripotassium bismuth dicitrate intervention 4: Lansoprazole intervention 5: TAK-438
Intervention descriptions: intervention 1: Clarithromycin tablets intervention 2: Amoxicillin capsules intervention 3: Tripotassium bismuth dicitrate tablets intervention 4: Lansoprazole capsules intervention 5: TAK-438 tablets

Protocol document:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Double-Blind, Parallel Group Study to Evaluate the Safety and
Pharmacokinetics of Quadruple Therapy (Bismuth, Clarithromycin, and Amoxicillin) With
TAK-438 Versus Quadruple Therapy With Lansoprazole.
Phase 1 TAK-438 Bismuth Drug Interaction Study
NCT Number: NCT02892409
Protocol Approve Date: 21 November 2016
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.


TITLE PAGE
PROTOCOL
A Phase 1, Double-Blind, Parallel Group Study to Evaluate the Safety and 
Pharmacokinetics of Quadruple Therapy (Bismuth, Clarithromycin, and Amoxicillin) With 
TAK-438 Versus Quadruple Therapy With Lansoprazole.
Phase 1 TAK-438 Bismuth Drug Interaction Study
Sponsor:
Takeda Development Center Asia Pte. Ltd.
21 Biopolis Road
Nucleos North Tower, Level 4
Singapore 138567
Study Number:
TAK-438_115
IND Number:
Not Applicable
EudraCT Number:
Not Applicable
Compound:
TAK-438
Date:
21 November 2016
Amendment Number:
03
Amendment History
Date
Amendment Number
Region
22 Dec 2015
Initial Protocol
Asia Pacific
22 Apr 2016
01
Asia Pacific
20 July 2016
02
Asia Pacific
21 November 2016
03
Asia Pacific
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts 
A separate contact information list will be provided to each site.
Takeda Development Center Asia, Pte., Ltd (TDC Asia) sponsored Asian Pacific investigators will 
be provided with emergency medical contact information cards to be carried by each subject. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Issue
Asian Regional Contact
Serious adverse event, pregnancy and special interest adverse event 
reporting
Medical Monitor (medical advice on protocol and study drug)
Responsible Medical Officer (carries overall responsibility for the 
conduct of the study)
PPD


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


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1.3
Protocol Amendment 03 Summary of Changes
Rationale for Amendment 03
This document describes the changes in reference to the protocol incorporating Amendment 
No. 03. The primary reasons for this amendment are listed below.
Minor grammatical, editorial, and formatting changes are included for clarification purposes only. 
For specific descriptions of text changes and where the changes are located, see Appendix F.
Changes in Amendment 03
1. Removal of reference to CYP2C19 genotype status from study inclusion criteria.
2. For Exclusion criterion #20, permission for all investigators (including sub investigators) to 
enter subjects with non-clinically significant electrocardiogram (ECG) abnormalities.
3. For Exclusion Criterion No.22, glomerular filtration rate to be estimated using the Chronic 
Kidney Disease-Epidemiology Collaboration formula.
4. Clarification to indicate that the time point for pharmacokinetic (PK) analysis will be Day 14.
5. Rescreening and the process of rescreening subjects have been added.
6. Amendments to the CYP2C19 blood collection.
7. The screening procedure of Helicobacter pylori (HP) breath test is permitted to be performed 
at a satellite site.
8. Clarified liver function test monitoring.
9. Clarification of footnotes in the Schedule of Study Procedures (Appendix A).


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


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Principal Investigator...............................................................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Corporate Identification...........................................................................................16
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.2
Rationale for the Proposed Study.............................................................................19
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................20
5.1
Objectives................................................................................................................20
5.2
Endpoints.................................................................................................................20
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................21
6.1
Study Design ...........................................................................................................21
6.2
Justification for Study Design, Dose, and Endpoints ................................................22
6.3
Premature Termination or Suspension of Study or Investigational Site.....................23
6.3.1
Criteria for Premature Termination or Suspension of the Study...................23
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites ..23
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s).........................................................23
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............24
7.1
Inclusion Criteria .....................................................................................................24
7.2
Exclusion Criteria ....................................................................................................24
7.3
Excluded Medications, Dietary Products..................................................................26
7.4
Diet, Fluid, Activity Control ....................................................................................27
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................28
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................28
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................30
8.1
Study Medication and Materials...............................................................................30
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................30


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8.1.1.1
Investigational Drug ...............................................................................30
8.1.2
Storage........................................................................................................31
8.1.3
Dose and Regimen ......................................................................................31
8.1.4
Overdose.....................................................................................................32
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................32
8.3
Randomization Code Creation and Storage..............................................................33
8.4
Investigational Drug Blind Maintenance ..................................................................33
8.5
Unblinding Procedure..............................................................................................33
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................33
9.0
STUDY PLAN ..............................................................................................................36
9.1
Study Procedures.....................................................................................................36
9.1.1
Informed Consent Procedure.......................................................................36
9.1.1.1
Pharmacogenomic Informed Consent Procedure.....................................36
9.1.2
Demographics, Medical History, and Medication History Procedure...........36
9.1.3
Physical Examination Procedure .................................................................36
9.1.4
Weight, Height, and BMI............................................................................37
9.1.5
Vital Sign Procedure ...................................................................................37
9.1.6
Documentation of Concomitant Medications...............................................37
9.1.7
Documentation of Concurrent Medical Conditions......................................38
9.1.8
Procedures for Clinical Laboratory Samples................................................38
9.1.9
Contraception and Pregnancy Avoidance Procedure....................................40
9.1.10
Pregnancy ...................................................................................................41
9.1.11
ECG Procedure ...........................................................................................42
9.1.12
Pharmacogenetic Sample Collection for CYP2C19 Genotyping ..................42
9.1.13
PK Sample Collection.................................................................................42
9.1.13.1
Collection of Blood for PK Sampling .....................................................42
9.1.13.2
Collection of Urine for PK Sampling......................................................43
9.1.13.3
Bioanalytical Methods............................................................................43
9.1.14
PK Parameters.............................................................................................43
9.1.15
Documentation of Screen Failure ................................................................44
9.1.16
Documentation of Randomization ...............................................................44
9.2
Monitoring Subject Treatment Compliance..............................................................44
9.3
Schedule of Observations and Procedures................................................................45
9.3.1
Screening (Day -28 to -2)............................................................................45
9.3.2
Check-in (Day -1) .......................................................................................46


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9.3.3
Quadruple Therapy Dosing (Day 1 to 11)....................................................46
9.3.4
Quadruple Therapy Dosing/TAK-438 PK and Lansoprazole PK (Day 12 to 
13) ..............................................................................................................47
9.3.5
Quadruple Therapy Dosing/TAK-438 PK, Lansoprazole PK and Bismuth 
PK (Day 14)................................................................................................47
9.3.6
Check-out (Day 15).....................................................................................48
9.3.7
Early Termination .......................................................................................48
9.3.8
Follow-up Call (Day 17) .............................................................................49
9.3.9
Follow-up Visit (Day 42) ............................................................................49
9.4
Blood Volume .........................................................................................................49
9.5
Biological Sample Retention and Destruction ..........................................................50
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................51
10.1
Definitions...............................................................................................................51
10.1.1
PTEs...........................................................................................................51
10.1.2
AEs.............................................................................................................51
10.1.3
Additional Points to Consider for PTEs and AEs.........................................51
10.1.4
SAEs...........................................................................................................53
10.1.5
Severity of PTEs and AEs ...........................................................................54
10.1.6
Causality of AEs .........................................................................................54
10.1.7
Relationship to Study Procedures................................................................54
10.1.8
Start Date....................................................................................................55
10.1.9
Stop Date ....................................................................................................55
10.1.10
Frequency ...................................................................................................55
10.1.11
Action Concerning Study Medication..........................................................55
10.1.12
Outcome .....................................................................................................55
10.2
Procedures...............................................................................................................56
10.2.1
Collection and Reporting of AEs.................................................................56
10.2.1.1
PTE and AE Collection Period ...............................................................56
10.2.1.2
PTE and AE Reporting ...........................................................................56
10.2.2
Collection and Reporting of SAEs...............................................................57
10.2.3
Reporting of Abnormal Liver Function Tests ..............................................57
10.3
Follow-up of SAEs ..................................................................................................57
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................58
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................59
12.0
DATA HANDLING AND RECORDKEEPING............................................................60


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12.1
CRFs (Electronic)....................................................................................................60
12.2
Record Retention .....................................................................................................60
13.0
STATISTICAL METHODS..........................................................................................62
13.1
Statistical and Analytical Plans ................................................................................62
13.1.1
Analysis Sets...............................................................................................62
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................62
13.1.3
Pharmacokinetic Analysis ...........................................................................62
13.1.4
Safety Analysis ...........................................................................................63
13.2
Interim Analysis and Criteria for Early Termination ................................................63
13.3
Determination of Sample Size..................................................................................63
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................65
14.1
Study-Site Monitoring Visits ...................................................................................65
14.2
Protocol Deviations..................................................................................................65
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................66
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................67
15.1
IRB and/or IEC Approval ........................................................................................67
15.2
Subject Information, Informed Consent, and Subject Authorization .........................68
15.3
Subject Confidentiality ............................................................................................69
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................69
15.4.1
Publication and Disclosure..........................................................................69
15.4.2
Clinical Trial Registration...........................................................................70
15.4.3
Clinical Trial Results Disclosure .................................................................70
15.5
Insurance and Compensation for Injury....................................................................70
16.0
REFERENCES..............................................................................................................71
LIST OF IN-TEXT TABLES
Table 7.a
Prohibited Medications ......................................................................................26
Table 8.a
Investigational Drug...........................................................................................30
Table 8.b
Sponsor-Supplied Drug......................................................................................32
Table 9.a
Clinical Laboratory Tests...................................................................................39
Table 9.b
Collection of Blood Samples for PK Analysis ....................................................42
Table 9.c
Collection of Urine Samples for PK Analysis.....................................................43
Table 9.d
Approximate Blood Volume ..............................................................................49
Table 10.a
Takeda Medically Significant AE List................................................................54
Table 14.a
Windows for PK Blood Sample Collection ........................................................66


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LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................22
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................73
Appendix B
Responsibilities of the Investigator.....................................................................75
Appendix C
Elements of the Subject Informed Consent.........................................................77
Appendix D
Investigator Consent to Use of Personal Information..........................................79
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples..............................80
Appendix F
Detailed Description of Amendments to Text.....................................................84


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Asia Pte. Ltd.
Compound:
TAK-438
Title of Protocol: A Phase 1, Double-Blind, Parallel Group 
Study to Evaluate the Safety and Pharmacokinetics of 
Quadruple Therapy (Bismuth, Clarithromycin, and 
Amoxicillin) With TAK-438 Versus Quadruple Therapy 
With Lansoprazole.
IND No.: 
Not applicable
EudraCT No.:
Not applicable
Study Number: TAK-438_115
Phase: 1
Study Design:
This is a phase 1, double-blind, parallel group study in subjects with Helicobacter pylori (HP positive) to evaluate the 
safety, tolerability and pharmacokinetics (PK) of a quadruple therapy with bismuth, clarithromycin, amoxicillin, and 
TAK-438 versus quadruple therapy with bismuth, clarithromycin, amoxicillin, and lansoprazole. Thirty HP positive 
subjects aged 19 to 60 years, inclusive, and 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 2 treatment groups as indicated in the 
schematic below. 
The treatment phase consists of quadruple therapy twice daily (BID) with tripotassium bismuth dicitrate (600 mg), 
clarithromycin (500 mg), amoxicillin (1000 mg), and TAK-438 (20 mg) (Group B) or quadruple therapy BID with 
tripotassium bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg),and lansoprazole (30 mg) 
(Group A) from Days 1 to 14. Subjects will be discharged on Day 15 after final PK blood samples are collected and all 
procedures performed.
Schematic of Study Design
Pretreatment
Treatment Period
Follow
up
Screening
Check-in
Baseline
Confinement
Check-
out
Follow-up 
call
Follow-up 
visit
Days -28 
to -2
Day -1
Day 1-11
Day 12-13
Day 14
Day 15
Day 17 (+2 
days)
Day 42 
(+6 days)
Group A: CA + bismuth + lansoprazole dosing
HP breath 
test
Group B: CA + bismuth + TAK-438 dosing
TAK-438 PK or 
lansoprazole PK in 
plasma
Bismuth 
PK in 
plasma 
and urine
Bismuth: tripotassium bismuth dicitrate (600 mg BID, equivalent to bismuth 220 mg BID); CA: clarithromycin 
(500 mg BID), amoxicillin (1000 mg BID); TAK-438: 20 mg BID; lansoprazole: 30 mg BID. 
Blood PK samples for Bismuth: 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 morning dose.
Urine PK samples for Bismuth: Day 14 at 0 to 12 hours post–morning dose.
Blood PK samples for TAK-438 and lansoprazole: Day 12-14 predose (morning and evening) 
Analyte: Bismuth, TAK-438, and lansoprazole.
Comparison of Group A and Group B: maximum observed plasma concentration (Cmax) and area under the plasma 
concentration-time curve during a dosing interval, where tau (τ) is the length of the dosing interval (AUCτ).


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Primary Objective:
To evaluate the safety, tolerability, and PK of quadruple therapy with bismuth, clarithromycin, amoxicillin, and 
TAK-438 versus quadruple therapy with bismuth, clarithromycin, amoxicillin, and lansoprazole.
Subject Population: HP positive subjects aged 19 to 60 years, inclusive.
Number of Subjects:
Estimated total: 30 subjects.
Number of Sites:
Estimated total: 1 site in Asia.
Dose Level(s):
TAK-438 (20 mg) 
Tripotassium bismuth dicitrate (600 mg, equivalent to 
bismuth 220 mg) 
Clarithromycin (500 mg) 
Amoxicillin (1000 mg)
Lansoprazole (30 mg)
Route of Administration:
Oral
Duration of Treatment:
Quadruple therapy BID for 14 days (Days 1 to 14)
Period of Evaluation:
Approximately 70 days (including Screening, Day -1 
through Study Exit, Follow-up Call, and Follow-up 
Visit)
Main Criteria for Inclusion:
1.
HP positive male or female subjects aged 19 to 60 years.
2.
Subject has a body mass index between >18 and ≤30 kg/m2 and weighs ≥50 kg.
Main Criteria for Exclusion:
Subjects will be excluded who have: 
1.
A history of hypersensitivity to any excipients of TAK-438 and lansoprazole.
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 >upper limit of normal.
Main Criteria for Evaluation and Analyses:
- Safety: 
Standard safety assessments for phase 1 studies will be collected. 
- Laboratory tests: 
Standard laboratory tests will be assessed.
- Pharmacokinetics: 
Blood PK samples for TAK-438 and lansoprazole analysis will be collected on Day 12 to 14 at predose (morning and 
evening).
Blood PK samples for bismuth analysis will be collected on Day 14 at predose (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 post–morning dose.
Urine PK samples for bismuth analysis will be collected on Day 14 at 0 to 12 hours post–morning dose.
Sample Type
Dosing Day
Time Postdose (hours)
Plasma
12-14
Predose (morning and evening)
Plasma
14
Predose (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
Urine
14
0 to 12 hours post–morning dose


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PK variables will be derived from the plasma concentrations of bismuth as required. These will include, where 
appropriate, AUCτ, Cmax, time at which Cmax occurs (tmax), terminal elimination rate constant (z), terminal elimination 
half life (t1/2z), apparent clearance (CL/F), and apparent volume of distribution (Vz/F).
PK variables will be derived from the urine concentrations of bismuth as required. These will include amount excreted 
in urine (Aeτ), the fraction of the dose excreted unchanged in urine (fe), and renal clearance (CLR).
- Pharmacogenomics:
Mandatory blood samples will be collected for CYP2C19 genotyping. 
- Total volume of blood drawn:
Blood draw is expected to be 203 mL.
Statistical Considerations:
Adverse Events
All treatment-emergent adverse events (TEAEs) will be coded using the Medical Dictionary for Regulatory Activities. 
Data will be summarized using preferred term and primary system organ class. All TEAEs, drug-related TEAEs and 
serious TEAEs will be summarized by administration conditions (bismuth with the combination clarithromycin, 
amoxicillin, and TAK-438 [CAT] and bismuth with the combination clarithromycin, amoxicillin, and lansoprazole 
[CAL]).
Clinical Laboratory Evaluations, Vital Signs and 12-lead Electrocardiograms
Observed values and changes (from Baseline) for continuous variables will be summarized by administration 
conditions (bismuth with CAL and bismuth with CAT) over time using descriptive statistics.
For categorical variables, shift tables will be presented for administration conditions (bismuth with CAL and bismuth 
with CAT).
Pharmacokinetics
Plasma concentrations of bismuth will be summarized at each scheduled sampling point by administration condition 
(bismuth with CAT and bismuth with CAL) using descriptive statistics (arithmetic mean, SD, median, minimum and 
maximum). For Days 12 to 14, plasma concentrations of freebase of TAK-438 (TAK-438F) and lansoprazole will be 
summarized at each scheduled sampling point using descriptive statistics. The plasma and urine PK parameters of 
bismuth will be summarized by administration conditions (bismuth with CAT and bismuth with CAL) using 
descriptive statistics. Two-sided 90% and 95% confidence levels (CIs) of the ratio between administration conditions 
(bismuth with CAT and bismuth with CAL) will be calculated using an analysis of variance with natural 
log-transformed AUCτ and Cmax of bismuth to evaluate the impact of TAK-438 on the PK of bismuth compared with 
the impact of lansoprazole on the PK of bismuth. Statistical analyses of other plasma and urine PK parameters will be 
performed if appropriate.
Sample Size Justification:
A sample size of 30 (15 subjects per group) will be used in this exploratory study. 


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator
Kyung-Sang Yu, MD, PhD
Professor
Seoul National University Hospital and College of Medicine
Seoul, Korea


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3.3
List of Abbreviations
λz
terminal elimination rate constant
%CV
percentage coefficient of variation
AE
adverse event
Aeτ
amount of drug excreted in urine during a dosing interval
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
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
AUC∞
area under the plasma concentration-time curve from 0 to infinity
BID
twice daily
BMI
body mass index
CAL
clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and lansoprazole (30 mg BID) 
CAT
clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and TAK-438 (20 mg BID)
CI
confidence interval
CL/F
apparent clearance
CLR 
renal clearance
Cmax
maximum observed plasma concentration
CRO
contract research organization
CS
Clinically Significant
CYP
cytochrome P450
DNA
deoxyribonucleic acid
DU
duodenal ulcer
ECG
electrocardiogram
eCRF
electronic case report form 
FDA
Food and Drug Administration
fe
fraction of drug excreted in urine
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GGT
-glutamyl transferase
GU
gastric ulcer
H+,K+-ATPase
hydrogen, potassium adenosine triphosphatase
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HP
Helicobacter pylori
ICH
International Conference on Harmonisation


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ID
identification
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
K2EDTA
potassium ethylenediamine tetraacetic acid
MedDRA
Medical Dictionary for Regulatory Activities
Med ID
medical identification
NCS
not clinically significant
NSAID
nonsteroidal anti-inflammatory drug
OTC
over-the-counter
PCAB
potassium-competitive acid blocker
PGx
pharmacogenomics
pH4 HTR
pH4 holding time ratio
PK
pharmacokinetic
PPI
proton pump inhibitors
PTE
pretreatment event
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reactions
t1/2z
terminal elimination half-life
TAK-438F
freebase of TAK-438
TEAE
treatment-emergent adverse event
tmax
time to reach Cmax
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal phase after extravascular 
administration
3.4
Corporate Identification 
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
Helicobacter pylori (HP) is a Gram-negative, microaerophilic bacteria mainly found in the gastric 
mucus and mucosa, whose causal relationships to gastrointestinal diseases have been extensively 
studied [1,2] since it has been isolated from the gastric mucosa of a patient with chronic gastritis in 
1983 [3]. Since then, HP eradication therapy has been shown to be effective in reducing the 
recurrence of gastric and duodenal ulcers [4,5], and HP 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 HP eradication in patients with gastric or duodenal 
ulcers, 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 HP eradication were approved in June 2010 also for gastric mucosa associated 
lymphoid tissue lymphoma, idiopathic thrombocytopenic purpura, and endoscopically-treated 
early gastric cancers. 
Developed at Takeda Pharmaceutical Company Ltd, TAK-438 belongs to a new class of 
acid-inhibitory agents called potassium-competitive acid blockers (PCABs). TAK-438 is shown 
not only to inhibit the hydrogen, potassium adenosine triphosphatase (H+,K+-ATPase) enzyme in 
the final step of acid secretion, as the PPIs do, but does not require the presence of acid for its 
activation and inhibits the H+,K+-ATPase enzyme in a potassium-competitive fashion. 
Furthermore, TAK-438 has been shown to be stable in the presence of acid and is water-soluble, 
requiring no particular pharmacological preparations, such as an enteric coating. Furthermore, 
TAK-438 is predominantly metabolized by cytochrome P-450 (CYP)3A4 and contribution of 
polymorphic CYP2C19 is considered to be limited. In contrast to the PPIs, which take 3 to 5 days 
to produce their maximum acid-inhibitory effects, due to its rapid accumulation in the gastric 
parietal cell and longer half-life, TAK-438 is expected to produce its maximum acid-inhibitory 
effects in a much shorter time and therefore have better potential clinical outcomes than the PPIs 
with its potent and sustained acid-inhibitory effects. TAK-438 is currently marketed in several 
indications in Japan, including the treatment of reflux esophagitis, gastric ulcer (GU), duodenal 
ulcer (DU), prevention of recurrence of a GU or DU during nonsteroidal anti-inflammatory drug 
(NSAID) or aspirin administration and as an adjunct to HP eradication. 
In Japan, a phase 1 single-dose study (TAK-438/CPH-001), with doses ranging from 1 mg up to 
120 mg, and a phase 1, 7-day repeat-dose study (TAK-438/CPH-002), with doses ranging from 
10 mg to 40 mg, have been conducted to evaluate safety, pharmacokinetics (PK), and 
acid-inhibitory effects of TAK-438. TAK-438 was well tolerated at the single daily dose of 40 mg 
in the 7-day repeat-dose study, and the pH4 holding time ratio (pH4 HTR) of TAK-438 10 mg on 
Day 7 was comparable to that of lansoprazole 30 mg once daily. TAK-438 exhibited a potent and 
sustained acid-inhibitory effect, with the pH4 HTR on Day 7 increasing dose dependently reaching 
over 90% at doses of 30 and 40 mg. Investigation of a possible effect of CYP2C19 on the PK of 
TAK-438, in the single-dose study, demonstrated no definite trend among the genotypes 


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examined; this suggested that the PK of TAK-438 is not affected by CYP2C19. In addition, a study 
evaluating interactions between TAK-438 and various NSAIDs (eg, loxoprofen sodium, 
diclofenac sodium, or meloxicam) or low-dose aspirin (TAK-438/CPH-003), showed that 
TAK-438 had no significant effect on the PK of these drugs and these drugs showed no significant 
effect on the PK of TAK-438 in the repeat dose study.
TAK-438 was also studied in a single-dose study (TAK-438_101) and a repeat-dose study 
(TAK-438_107) of TAK-438 in the United Kingdom. In the 7-day repeat-dose study to evaluate 
the safety, PK, and acid-inhibitory effects at doses ranging from 10 to 40 mg once daily, TAK-438 
was well tolerated at all doses studied, and the pH4 HTR on Day 7 was similar to that observed in 
the repeat-dose study conducted in Japan at comparable doses, supporting the potent and sustained 
acid-inhibitory effects of TAK-438. In a study conducted in the United Kingdom to evaluate 
interactions between TAK-438 and repeated doses of clarithromycin (TAK-438_110), the 
maximum observed plasma concentration (Cmax) and area under the plasma concentration-time 
curve (AUC) of TAK-438F (freebase of TAK-438) increased by 1.35-fold and by 1.58-fold, 
respectively, when used in combination with clarithromycin, a potent inhibitor of the CYP3A4, 
and TAK-438 was well tolerated. 
A 4×4 crossover study of PK drug-drug interactions of triple therapy twice a day (BID) with 
TAK-438/amoxicillin/clarithromycin or TAK-438/amoxicillin/metronidazole was conducted in 
healthy Japanese male subjects (TAK-438_CPH-401). In Cohort 1 (triple therapy BID with 
TAK-438, amoxicillin, and clarithromycin), compared with single-agent use of TAK-438, the 
mean area under the plasma concentration-time curve from time 0 to 12 hours (AUC0-12)and mean 
Cmax for TAK-438F increased approximately 1.8- and 1.9-fold, respectively, when TAK-438 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 was administered as triple therapy. In 
Cohort 2 (triple therapy BID with TAK-438, 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 TAK-438/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 
TAK-438/amoxicillin/clarithromycin or TAK-438/amoxicillin/metronidazole are not considered 
to be clinically significant.
In a phase 2 dose-ranging study of TAK-438 in Japanese patients with erosive esophagitis 
(TAK-438/CCT-001), TAK-438, given once daily at doses of 5, 10, 20, and 40 mg for 8 weeks, 
was evaluated for its dose-response efficacy and safety in a randomized, double-blind, 
parallel-group comparison with lansoprazole. The primary endpoint of the study was endoscopic 
healing rate of erosive esophagitis after 4 weeks treatment and was 92.3%, 92.5%, 94.4%, and 
97.0% with 5, 10, 20, and 40 mg of TAK-438, respectively, compared with 93.2% with 30 mg of 
lansoprazole, showing the noninferiority of TAK-438 to lansoprazole at any of the doses 
examined. No particular safety concerns were noted.


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TAK-438 has been studied in a number of acid-related diseases and noninferiority with 
lansoprazole has been confirmed in several phase 3 studies including reflux esophagitis healing 
and prevention of recurrence studies, GU/DU ulcer healing and for the prevention of recurrence of 
a gastric or duodenal ulcer during NSAID or aspirin administration and has subsequently been 
launched in Japan for these indications. Of note, in a phase 3 HP eradication study, 7-day treatment 
with TAK-438 20 mg (n=329) or lansoprazole 30 mg (n=321) in combination with amoxicillin 
750 mg plus clarithromycin 200 or 400 mg, HP eradication rates were 92.6% and 75.9%,
respectively. Furthermore, the first 50 treatment failures with good compliance received 
second-line triple-therapy with TAK-438 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
TAK-438 is a novel, orally active PCAB, which was launched for a number of acid-related 
diseases in Japan in February 2015. Unlike PPIs, TAK-438 is acid-stable and does not require an 
acid-protective formulation. The compound is metabolized mainly by CYP3A4, in contrast to 
PPIs, which are metabolized mainly by CYP2C19, an enzyme with genetic polymorphism. 
Therefore, the degree of interpatient variability in response to treatment is not expected to be as 
high with TAK-438.
TAK-438 was recently launched in Japan for several acid-related disease indications including 
adjunct to HP eradication and is currently in clinical development in Asia where there are 2 
ongoing studies (reflux esophagitis and prevention of recurrence) and 2 phase 3 studies planned 
(GU/DU healing) and 2 phase 1 trials planned. TAK-438_115 is one of the planned phase 1 trials 
planned in Asia. In China, HP eradication guidelines recommend quadruple therapy for HP 
eradication consisting of 2 antibiotics, a PPI and bismuth [6]. As a replacement for PPIs in China, 
TAK-438 would be expected to be used as part of a quadruple treatment regimen and a drug 
interaction study is required to confirm the tolerability of TAK-438 quadruple therapy for HP 
eradication. 
It has been reported that with increasing pH of the stomach 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 [7]. Increased levels of bismuth may be associated with 
increased potential for neurotoxicity [8]. As TAK-438 achieves high stomach pH over a full 
24-hour period, an evaluation of drug interaction potential and tolerability when TAK-438 and 
bismuth are coadministered is warranted.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
The objectives of this study are:

To evaluate the safety, tolerability, and PK of quadruple therapy BID with tripotassium 
bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and TAK-438 
(20 mg) versus quadruple therapy BID with tripotassium bismuth dicitrate (600 mg), 
clarithromycin (500 mg), amoxicillin (1000 mg), and lansoprazole (30 mg).
5.2
Endpoints

Percentage of subjects who experience at least 1 treatment-emergent adverse event (TEAE).

Percentage of subjects who discontinue due to an adverse event (AE).

Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at 
least once postdose.

Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at 
least once postdose.

Percentage of subjects who meet the markedly abnormal criteria for safety electrocardiogram 
(ECG) parameters at least once postdose.

Plasma PK parameters of tripotassium bismuth dicitrate (600 mg) when coadministered with 
clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and TAK-438 (20 mg BID) (CAT), 
and coadministered with clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and 
lansoprazole (30 mg BID) (CAL):
–
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.


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 1, double-blind, parallel group study in HP positive subjects to evaluate the safety, 
tolerability, and PK of quadruple therapy with bismuth, clarithromycin, amoxicillin, and TAK-438 
versus quadruple therapy with bismuth, clarithromycin, amoxicillin, and lansoprazole.
Thirty HP positive male or female subjects aged 19 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 as indicated in Figure 6.a. One site in 
Asia will be selected to conduct this study.
The treatment phase consists of quadruple therapy BID with tripotassium bismuth dicitrate 
(600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and TAK-438 (20 mg) or quadruple 
therapy BID with tripotassium bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin 
(1000 mg), and lansoprazole (30 mg) for 14 days (Days 1 to 14). Subjects will be discharged on 
Day 15 after final PK blood samples are collected and all procedures performed. 
Screening for potential subjects will occur between Days -28 and -2 prior to confinement at the 
phase 1 unit. Eligibility will be reconfirmed on Day -1. Having fasted for a minimum of 8 hours, 
oral doses of tripotassium bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin 
(1000 mg), and TAK-438 (20 mg) or tripotassium bismuth dicitrate (600 mg), clarithromycin 
(500 mg), amoxicillin (1000 mg), and lansoprazole (30 mg) will be administered BID from Days 1 
to 14. The last dose will be on the evening of Day 14. Blood sampling for TAK-438 and 
lansoprazole PK measurements will be taken on Days 12 to 14 (predose evening and morning) and 
for bismuth PK measurements on Day 14 (pre–morning dose to 12 hours post–morning dose). 
Urine sampling for bismuth PK measurements will be taken on Day 14 (pre–morning dose to 12 
hours post–morning dose). The subject will be confined to the phase 1 unit from Day -1 (Check-in) 
through to Day 15 (Check-out), and will be required to contact the study site once again for a 
follow-up call on Day 17 and a clinic visit on Day 42 for a HP breath test.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in
Appendix A.


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Figure 6.a
Schematic of Study Design
Pretreatment
Treatment Period
Follow
up
Screening
Check-in
Baseline
Confinement
Check-
out
Follow-up 
call
Follow-up 
visit
Days -28 
to -2
Day -1
Day 1-11
Day 12-13
Day 14
Day 15
Day 17 (+2 
days)
Day 42 
(+6 days)
Group A: CA + bismuth + lansoprazole dosing
HP breath 
test
Group B: CA + bismuth + TAK-438 dosing
TAK-438 PK or 
lansoprazole PK in 
plasma
Bismuth 
PK in 
plasma 
and urine
Bismuth: tripotassium bismuth dicitrate (600 mg BID, equivalent to bismuth 220 mg BID); CA: clarithromycin (500 mg BID), 
amoxicillin (1000 mg BID); TAK-438: 20 mg BID; lansoprazole: 30 mg BID.
Blood PK samples for Bismuth: 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 morning dose.
Urine PK samples for Bismuth: Day 14 at 0 to 12 hours post–morning dose.
Blood PK samples for TAK-438 and lansoprazole: Day 12-14 predose (morning and evening)
Analyte: bismuth, TAK-438, and lansoprazole.
Comparison of Group A and Group B: Cmax and AUCτ.
6.2
Justification for Study Design, Dose, and Endpoints
As bismuth is minimally absorbed and renally excreted, it is not expected to have an effect on the 
PK of TAK-438, clarithromycin or amoxicillin and the combination of clarithromycin and 
amoxicillin are not expected to have an effect on bismuth concentrations [9]. However, as an 
increase in bismuth concentration is observed when administered with PPIs, which is associated 
with increased stomach pH [7], it is expected that when bismuth is coadministered with TAK-438 
there may be an increase in bismuth exposure. Coadministration of clarithromycin and amoxicillin 
with TAK-438 has already been evaluated in study TAK-438/CPH-401 (TAK-438/CPH-401), 
where an approximate 2-fold increase in TAK-438 concentrations was observed in healthy male 
subjects. The absorption of bismuth is affected by intragastric pH, which in turn is affected by HP 
status. In HP-positive subjects, the intragastric pH could be increased and downstream effects on 
safety related to an increase in bismuth exposure could occur. HP positive subjects are also more 
representative of the HP status of the patient population to be treated. Therefore, HP positive only 
subjects will be included. 
This drug interaction study has also been designed to evaluate the relative impact of TAK-438 on 
the PK of bismuth compared with the impact of lansoprazole on the PK of bismuth. Bismuth PK on 
Day 14 administered with TAK-438 will be compared with bismuth coadministered with 
lansoprazole. The population will comprise of HP positive subjects. No clinically relevant 
difference in exposure between male and females has previously been established in study 
TAK-438_109, therefore the study will enroll both. 
According to the HP local treatment guideline for HP in China, the recommended dose of bismuth 
is 220 mg BID [6]. Therefore, tripotassium bismuth dicitrate 600 mg has been chosen in this study 


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as it is equivalent to bismuth 220 mg (hereafter referred to as bismuth 220 mg). Bismuth potassium 
citrate is the synonym of tripotassium bismuth dicitrate. Bismuth is minimally absorbed with 
bioavailability <0.3%, a time to reach Cmax (tmax) of 0.5 hour and is excreted through urinary and 
biliary routes. It is highly distributed throughout the body and displays multicompartment 
elimination with multiple half-lives: an initial half-life of 1-4 hours, a more prolonged half-life of 
5-11 days, and a more extended half-life [11,12]. There are several half-lives reported for bismuth, 
however, 1 article indicates that plasma level of bismuth approach an apparent steady-state after 30 
- 40 days after multiple dose of bismuth. This study could not be simulated using 
physiologically-based PK modeling due to the number of regimens used. 
The local treatment guidance in China proposes the use of quadruple therapy consisting of 
2 antibiotics, bismuth 220 mg BID, and PPI BID for 14 days. A number of different antibiotic 
regimens are proposed; however clarithromycin (500 mg BID) and amoxicillin (1000 mg BID) 
have been chosen in the upcoming phase 3 program as this regimen will offer optimal eradication 
rates [13,14]. TAK-438 20 mg BID is the chosen dose as at this dose there is good pH control and 
20 mg BID has been observed to give good HP eradication rates when administered as triple 
therapy in Japanese patients.
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 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 risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/ independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization or first dose or 
other. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures, including requesting that a subject fast for any laboratory evaluations. 
3. The subject is HP positive at Screening.
4. The subject is male or female and aged 19 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 and ≤30 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 1 month after last dose of the study medication.
*Definitions and acceptable methods of contraception are defined in Section 9.1.9
Contraception and Pregnancy Avoidance Procedure and reporting responsibilities 
are defined in Section 9.1.10 Pregnancy.
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 prior to providing their 
informed consent.
2. The subject has received TAK-438 in a previous clinical study or as a therapeutic agent.
3. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(eg, spouse, parent, child, sibling) or may consent under duress.
4. The subject has uncontrolled, clinically significant cardiovascular, or other abnormality (other 
than the disease being studied), which may impact the ability of the subject to participate or 
potentially confound the study results. 


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5. The subject has a known hypersensitivity to any component of the formulation of TAK-438, 
penicillins, macrolides, bismuths, and lansoprazole, for example, 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 prior to 
the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the 
study (up to Day 17).
8. The subject has taken any excluded medication, supplements, or food products listed in the 
Excluded Medications and Dietary Products table listed in Section 7.3 of the protocol, except 
where over-the-counter (OTC) medication has been pre-approved by Takeda.
9. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after participating in this study; or intending to donate ova during such time 
period.
10. The subject has evidence of current cardiovascular, central nervous system, hepatic, 
hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, 
asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the 
subject’s medical history, physical examination, or safety laboratory tests giving reasonable 
suspicion of a disease that would contraindicate taking TAK-438, 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.
11. The subject has a history of gastroesophageal reflux disease (GERD), symptomatic GERD, 
erosive esophagitis, DU, GU, 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.
12. Subjects who have undergone therapeutic upper gastrointestinal endoscopic therapy (eg, 
endoscopic hemostasis or excision including biopsy) within 30 days prior to Screening.
13. 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).
14. The subject has any known disease or is taking any medication that is contraindicated with 
bismuth, clarithromycin, or amoxicillin.
15. 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 prior to Day 1.


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16. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen at Screening. 
17. 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 prior to 
Check-in. Cotinine test is positive at Screening or Check-in.
18. The subject has poor peripheral venous access.
19. The subject has donated or lost 450 mL or more of his blood volume (including 
plasmapheresis), or had a transfusion of any blood product within 90 days prior to Day 1.
20. The subject has a Screening or Check-in abnormal (clinically significant) ECG. Entry of any 
subject with an abnormal (not clinically significant) ECG must be approved, and documented 
by signature by both the investigator and the contract research organization (CRO) medical 
monitor.
21. 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 >the upper limit 
of normal (ULN).
22. 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, Dietary Products 
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until completion of all study activities (Day 17). 
Table 7.a
Prohibited Medications
6 weeks prior to 
Check-in 
(Day -1)
28 days prior to Check-in 
(Day -1)
7 days prior to Check-in 
(Day -1)
72 hours prior to 
Check-in 
(Day -1)
Nicotine-containing 
products
Prescription medications
OTC medications including salicylates 
(a)
Products containing 
caffeine or xanthine
Immunization/vacci
nes
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
(a) Occasional use of acetaminophen/paracetamol (1 g/day) or other medication is allowed. 


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Subjects must be instructed not to take any medications including 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 Control 
Subjects will be confined to the clinic for the duration of the treatment period (Day -1 until 
check-out on Day 15).
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 prior to the 
start of the study.
If a blood draw or any study procedure coincides with a meal, the study procedure will take 
precedence followed by the blood draw and then the meal.
Subjects should be fasted overnight for a minimum of 8 hours prior to dosing. Breakfast and dinner 
should be given at approximately the same time each day on Days 1 to 14. TAK-438, lansoprazole 
and bismuth should be administered 0.5 hours before breakfast/dinner. Breakfast and dinner 
should be completed within 0.5 hours and then clarithromycin and amoxicillin should be 
administered 0.5 hours after the start of breakfast/dinner on Days 1 to 14. They should take all 
doses with 240 mL water (120 mL with bismuth and TAK-438 or lansoprazole 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.
Subjects will refrain from strenuous exercise from 72 hours prior to 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 therapy, and should communicate with the medical institution 
about the subject’s participation in the study.


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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. For screen failure 
subjects, refer to Section 9.1.15.
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.

Liver Function Test Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any time 
during study medication treatment:
–
ALT or AST or total bilirubin >2×ULN.
2. Significant protocol deviation. The discovery postrandomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 


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the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. 
Discontinued or withdrawn subjects will not be replaced.


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to TAK-438, lansoprazole, tripotassium bismuth 
dicitrate, clarithromycin and amoxicillin.
8.1.1.1
Investigational Drug
The chemical name of TAK-438 is: 
1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrrol-3-yl]-N-methyl methanamine 
monofumarate. Note that the generic name assigned to TAK-438 is vonoprazan. 
The chemical name of lansoprazole (AG-1749) is:
(RS)-2-({[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridylmethyl]sulfinyl} benzimidazole.
TAK-438 and lansoprazole investigational drug will be foil/foil blistered packaged into 1-dose 
child-resistant blister cards. Each blister card will contain 1 tablet and 1 capsule. Each dose 
consists of 1 tablet and 1 capsule. 30 blister cards with the same medication identification (Med 
ID) will be dispensed to each subject.
The carton box and each blister card will be labeled in a blinded fashion with a single panel label. 
The labels will include pertinent study information and country-specific regulatory caution 
statement.
Amoxicillin, clarithromycin, and tripotassium bismuth dicitrate will be purchased by the clinical
site, or provided by sponsor or CRO.
Table 8.a
Investigational Drug
Name, Strength, and Dose Form
Description
Manufacturer
TAK-438 20 mg tablets
Pale red film-coated tablet scored on both 
sides
Takeda Pharmaceutical Company 
Limited, Osaka, Japan
TAK-438 20 mg matching placebo tablet
Pale red film-coated tablet scored on both 
sides
Takeda Pharmaceutical Company 
Limited, Osaka, Japan
Lansoprazole 30 mg capsule
White capsule
Takeda Pharmaceutical Company 
Limited, Osaka, Japan
Lansoprazole 30 mg matching placebo 
capsule
White capsule
Takeda Pharmaceutical Company 
Limited, Osaka, Japan
Tripotassium bismuth dicitrate 300 mg 
(equivalent to bismuth 110 mg) tablets
Locally sourced
Clarithromycin 500 mg tablets
Locally sourced
Amoxicillin 500 mg capsules
Locally sourced


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8.1.2
Storage
TAK-438, lansoprazole and each matching placebo investigational drug should be stored at 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.
Tripotassium bismuth dicitrate, clarithromycin, and amoxicillin should be stored as instructed on 
the label.
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.
8.1.3
Dose and Regimen
Each subject who qualified to enter into the double-blind treatment on Day 1 will be assigned to 1 
of 2 treatment groups (Group A or Group B). 
Subjects will be dosed the morning and evening of Day 1 to 14 for each BID dosing. The last dose 
will be on the evening of Day 14.
Breakfast and dinner should be given at approximately the same time each day on Days 1 to 14 and 
completed within 0.5 hour. Tripotassium bismuth dicitrate, TAK-438, and lansoprazole should be 
administered 0.5 hour before breakfast/dinner. Clarithromycin and amoxicillin should be 
administered 0.5 hour after the start of breakfast/dinner on Days 1 to 14. 
Water, 240 mL, will be accompanied with each study medication administration for all dosing 
(120 mL with bismuth and TAK-438 or lansoprazole dosing and 120 mL with clarithromycin and 
amoxicillin doses) and the subjects will refrain from drinking for at least 1 hour 
post–clarithromycin and amoxicillin dose, after which water can be given freely. Subjects must 
drink all of the water provided with the dose of study drug. Following administration of the study 
drug, hand and mouth checks will be performed to ensure that the dose was swallowed.
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. 
Table 8.b describes the dose and tablet count that will be provided to each subject.


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Table 8.b
Sponsor-Supplied Drug
Day 1-11
Day 12-13
Day 14
Group A: CA + Bismuth + Lansoprazole Dosing
Group B: CA + Bismuth + TAK-438 Dosing
TAK-438 or 
Lansoprazole PK
TAK-438 or 
Lansoprazole 
PK
Bismuth PK
Bismuth: tripotassium bismuth dicitrate (600 mg BID, equivalent to bismuth 220 mg BID); CA: clarithromycin
(500 mg BID), amoxicillin (1000 mg BID); TAK-438: 20 mg BID; lansoprazole: 30 mg BID.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0, Pretreatment 
Events and Adverse Events.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Investigational Drug Assignment and Dispensing Procedures
Subjects will be assigned, in the order in which they are randomized into the study, to receive their 
treatment according to the blinded randomization schedule allocated to the site. The 
Randomization Sequence Number and Med ID will be entered onto the eCRF.
Subjects will be assigned to receive a 4-digit randomization sequence number. The number will be 
assigned by the clinic site personnel in sequential order beginning with 1001 and ending with 
1030. This 4-digit number will be used by the clinical site to facilitate the prelabeling of PK 
samples, and will be the only subject identifier used on all PK sample collections. It should also be 
contained on the PK transport vials shipped to the bioanalytical laboratory, and will be used by the 
laboratory to report the subject data results. This 4-digit number should only be used for the 
purposes described in this section. It does not replace the 3-digit subject number that is assigned at 
the time the informed consent is obtained and that is used for all other procedures to identify the 
subjects throughout the study.


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8.3
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.
A blinded randomization schedule will be provided to the site pharmacist or authorized study 
designee prior to the start of this study. The medical identification (Med ID) to be dispensed to 
each subject will be provided in this schedule.
8.4
Investigational Drug Blind Maintenance
The investigator will receive the subject’s investigational drug blind information in the form of a 
sealed envelope which 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.
8.5
Unblinding Procedure
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. All study 
assessments and causality should be performed, if possible, prior to 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.
8.6
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 and matching placebo; lansoprazole 30 mg and 
matching placebo) and locally sourced study drugs (tripotassium bismuth dicitrate 600 mg; 


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clarithromycin 500 mg and amoxicillin 1000 mg), the 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 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 
and locally sourced drugs received and dispensed during his or her entire participation in the study. 
Proper drug accountability includes, but is not limited to:

Continuously monitoring expiration dates 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 prior to 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 
tablets and matching placebo; lansoprazole 30 mg capsule and matching placebo; tripotassium 
bismuth dicitrate 600 mg; clarithromycin 500 mg and amoxicillin 1000 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, including initials of the person 
dispensing the drug, and the date and amount returned to the site by the subject, including the 
initials of the person receiving the sponsor-supplied drug. The log should include all required 
information as a separate entry for each subject to whom sponsor-supplied drug is dispensed.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform 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.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. The Schedule of 
Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed, including requesting that a subject fast for laboratory 
evaluations.
If the subject is to undergo the urea breath test (one of the screening procedures) at a satellite site, 
the subject must sign the informed consent form prior to 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 in order 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
Demographics, Medical History, and Medication History Procedure
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 prior to 
signing of informed consent. Ongoing conditions are considered concurrent medical conditions 
(see Section 9.1.7).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 28 days prior to signing of informed consent.
9.1.3
Physical Examination Procedure
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system*; (10) lymph nodes; 
(11) genitourinary system; and (12) other.
* A neurological examination of the nervous system will be performed daily.


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Any abnormal finding on a pretreatment physical examination assessment must be assessed as not 
clinically significant (NCS) or clinically significant (CS) by the investigator and recorded in the 
source document and eCRF. All CS 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 9.1.7. 
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately prior to the start of the investigational drug (Day 1) must be 
assessed as NCS or CS by the investigator and recorded in the source document and eCRF. Any 
CS change or new diagnosis as a result of a CS 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. 
9.1.4
Weight, Height, and BMI
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.
The Takeda standard for collecting height is centimeters without decimal places and for weight it 
is kilograms (kg) 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, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.6 kg/m2 
9.1.5
Vital Sign Procedure
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. 
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw. 
9.1.6
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study (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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9.1.7
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at screening examination. The condition (ie, diagnosis) should be 
described.
9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 106 mL, and the approximate total volume of 
blood for the study is 203 mL for safety laboratory samples. Laboratory samples will be taken 
following a minimum 8-hour overnight fast on the days stipulated in the Schedule of Study 
Procedures (Appendix A).
Table 9.a lists the tests that will be obtained for each laboratory specimen.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBCs
WBCs (with differential:
neutrophils, eosinophils, 
basophils, monocytes, 
lymphocytes) 
Hemoglobin
Hematocrit
Platelets
PT/INR
aPTT
Reticulocyte count 
ALT (a, b)
Albumin
Alkaline phosphatase (a)
Amylase
AST (a, b)
GGT
Total bilirubin (a, b, c)
Direct bilirubin (a, b)
Uric acid
Total protein
Triglycerides (a)
Serum creatinine
Blood urea nitrogen
Creatine kinase
Creatine kinase MB
Potassium
Sodium
Glucose
Chloride
Calcium
Magnesium
Cholesterol (HDL and LDL) (a)
LDH (d)
pH
Specific gravity
Protein
Glucose
Nitrites
Bilirubin
Hemoglobin
Ketones
Leucocytes
Urobilinogen
Microscopic Analysis (for 
abnormal urinalysis 
result): 
RBC/high power field
WBC/high power field,
Epithelial cells, casts, 
crystals and organisms)
Diagnostic Screening:
Serum
Urine
HIV test
Hepatitis panel, including HBsAg and anti-HCV
Drug screen, including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, cotinine, 
methadone, and opiates.
Female subjects of child-bearing potential only:
hCG (for pregnancy)
Breath Test
HP (e)
Alcohol
aPPT=activated partial thromboplastin time, GGT=γ-glutamyl transferase, hCG=human chorionic gonadotropin, 
HDL=high-density lipoprotein, INR=international normalized ratio, LDH=lactate dehydrogenase, LDL=low-density 
lipoprotein, PT=prothrombin time, RBC=red blood cell, WBC=white blood cell.
(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×ULN.
(d) LDH1/LDH5 (in % and total) will be measured if clinically significant increase in LDH is reported.
(e) A breath test will be performed at the Screening and must be positive at Screening. A follow-up breath test will be 
performed on Day 42.
The phase 1 unit’s local laboratory will perform laboratory tests for hematology, serum 
chemistries, and urinalysis. The results of laboratory tests will be returned to the investigator, who 
is responsible for reviewing and filing these results.


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If subjects experience an increase in any one of ALT, AST or total bilirubin >2×ULN then trial 
medication should be stopped due to the criteria for discontinuation has been met (please refer to 
Section 7.5 for discontinuation criteria). Follow-up laboratory tests (at a minimum, serum alkaline 
phosphatase, ALT, AST, total bilirubin, GGT, and INR) to monitor recovery should be performed 
within a maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted.
Please refer to Section 10.2.3 for the appropriate guidance on Reporting of Abnormal Liver 
Function Tests 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 prior to 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.
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.
9.1.9
Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 4 weeks after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as at least 1 year since last regular menses with a follicle-stimulating hormone>40 IU/L or at least 
5 years since last regular menses, confirmed before any study medication is implemented).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, the only acceptable methods of contraception are: 


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Barrier methods (each time the subject has 
intercourse):
Intrauterine devices (IUDs):

Cap (plus spermicidal cream or jelly) PLUS male 
condom.

Diaphragm (plus spermicidal cream or jelly) 
PLUS male condom.

Copper T.
*Barrier methods are only applicable in countries where spermicide is commercially available.
Subjects can continue to use contraceptive medications and/or devices as long as they use 
additional contraceptive precautions as highlighted above. Subjects will be provided with 
information on acceptable methods of contraception as part of the subject informed consent 
process and will be asked to sign a consent form stating that they understand the requirements for 
avoidance of pregnancy, donation of ova during the course of the study.
During the course of the study, regular serum or 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 (Appendix A). In addition to a negative 
hCG pregnancy test at Screening, subjects must also have a negative hCG pregnancy test at 
Randomization prior to receiving first dose of double blind investigational drug. 
9.1.10
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (vonoprazan, lansoprazole, bismuth, clarithromycin, and amoxicillin)
should be immediately discontinued. 
If the pregnancy occurs during administration of active study medication, eg, after Day 1 
(Randomization) or within 4 weeks of the last dose of active study medication, the pregnancy 
should be reported immediately, using a pregnancy notification form, to the contact listed in 
Section 1.0.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time 
she became pregnant and provide details of treatment the subject received (blinded or unblinded, 
as applicable).
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.


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9.1.11
ECG Procedure
12-lead ECGs printed in standard format will be collected at Screening, Check-in, and on Days 1, 
3 and 7 at pre–morning dose, Day 14 at pre–morning dose and 1, 2 and 4 hours post–morning dose, 
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.
9.1.12
Pharmacogenetic Sample Collection for CYP2C19 Genotyping 
The sample of whole blood for CYP2C19 genotyping analysis is mandatory. Every subject must 
sign the informed consent in order to participate in this study. If subjects who initially screen fail 
this study have performed deoxyribonucleic acid (DNA) blood collection for CYP2C19 
genotyping analysis, it is not required to be collected again.
One whole blood sample (3 mL) for DNA isolation will be collected at Day -1 from each subject in 
the study, into plastic potassium ethylenediamine tetraacetic acid (K2EDTA) spray-coated tubes, 
and stored under frozen condition. A second aliquot of blood may be taken if isolation of DNA 
from the first sample was not successful or possible.
The DNA sample collected from each subject will be used for CYP2C19 genotyping analysis. 
Genetic variation into the CYP2C19 gene may lead to changes in metabolic activity of the 
CYP2C19 enzyme that may contribute to the variability in the PK/clinical efficacy of TAK-438 
and lansoprazole.
9.1.13
PK Sample Collection
9.1.13.1 Collection of Blood for PK Sampling
Blood samples for PK analysis of TAK-438F, lansoprazole, and bismuth will be collected into 
Vacutainers containing anticoagulant sodium heparin according to the schedule in Appendix A. 
Instructions for sample processing and shipment are provided in Appendix E.
Serial blood samples for determination of TAK-438F, lansoprazole, and bismuth will be collected 
according to Table 9.b.
Table 9.b
Collection of Blood Samples for PK Analysis
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-438F
Plasma
12-14
Predose (morning and evening).
Lansoprazole
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.
The actual time of sample collection will be recorded on the source document and eCRF.


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9.1.13.2 Collection of Urine for PK Sampling
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 to12 hours post–morning dose.
Instructions for sample processing and shipment are provided in Appendix E.
9.1.13.3 Bioanalytical Methods
Plasma concentrations of TAK-438F and lansoprazole will be measured by high-performance 
liquid chromatography with tandem mass spectrometry.
Plasma and urine concentrations of bismuth will be measured by inductively coupled plasma mass 
spectrometry.
9.1.14
PK Parameters 
The PK parameters of bismuth will be determined from the concentration-time profiles for all 
evaluable subjects. Actual sampling times, rather than scheduled sampling times, will be used in 
all computations involving sampling times. The following PK parameters will be calculated for 
plasma concentration values of bismuth:
Symbol/Term
Definition
Plasma
AUCτ
Area under the plasma 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 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.


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The following urine PK parameters of bismuth will be derived from urine 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.
9.1.15
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.

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 stand-alone 
subject.
9.1.16
Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
Study medication will be administered while subjects are under observation in the clinical research 
unit. Following administration of the study medication, appropriate mouth and/or hand checks will 


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be performed to ensure that the dose is swallowed and noted in the source document. The date and 
time of each dose will be recorded in the source documents and on the eCRF. An inventory of the 
study medication supplies dispensed will be performed by the site pharmacist or authorized study 
designee and recorded onto the Drug Accountability Log in the subject’s source document records 
or equivalent. The exact dose time of consecutive subjects may be staggered to facilitate logistics 
at the site.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening (Day -28 to -2)
Subjects will be screened within 28 days prior to randomization. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.15 for procedures for documenting screening failures. Subjects who initially screen 
fail for the study are permitted to rescreen following re-consent, with the exception of subjects 
who at the initial screening visit failed due to abnormal clinical laboratory values that were 
investigator-defined as clinically significant. All screening procedures with the possible exception 
of DNA blood collection for CYP2C19 genotyping analysis (if this has been collected it is not 
required to be collected again) will be repeated. The subject must meet all inclusion and none of 
the exclusion criteria at the time of rescreening in order to qualify for the study. Procedures to be 
completed at Screening include:

Informed consent.

Inclusion/exclusion criteria assessment.

Demographics, medical history, and medication history.

Physical examination.

Vital signs.

Weight, height, and BMI.

Concomitant medications.

Concurrent medical conditions.

PTE assessment.

Fasting clinical laboratory tests (hematology, clinical chemistry, and urinalysis).

Fasting liver function tests.

Hepatitis and HIV panel assessment.

ECG procedure.


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
Breath test for alcohol.

Urine drug screen.

Urine pregnancy test (in female subjects of childbearing potential only).
HP breath test. Providing the subject has signed the informed consent form, sites can choose to 
conduct the urea breath test at a satellite site. The urea breath test may only be performed at a 
satellite site after the Sponsor has reviewed and approved the site’s procedures. All other screening 
procedures, and all other study visits are required to be conducted at the main Phase 1 unit.
9.3.2
Check-in (Day -1)
Screening will be completed at the Check-in Day -1 visit. If a subject has previously undergone 
DNA blood collection for CYP2C19 genotyping analysis, it is not required to be collected again. 
The following procedures will be performed and documented during this Check-in Visit:

Inclusion/exclusion criteria assessment.

Physical examination, including baseline neurological examination of the nervous system.

Vital signs.

Weight and BMI.

Concomitant medications.

Concurrent medical conditions.

PTE assessment.

Fasting clinical laboratory tests (hematology, clinical chemistry, and urinalysis).

Fasting liver function tests.

DNA blood collection for CYP2C19 genotyping analysis.

ECG procedure. 

Urine drug screen.

Urine pregnancy test (in female subjects of childbearing potential only).

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 
remains confined to the phase 1 unit.
9.3.3
Quadruple Therapy Dosing (Day 1 to 11)
The following procedures will be performed and documented after randomization while the 
subject remains in confinement:

Vital signs.


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
Neurological examination of the nervous system.

Concomitant medications.

ECG procedure (pre–morning dose on Days 1, 3, and 7).

Fasting clinical laboratory tests (hematology, clinical chemistry, and urinalysis) at Day 5 and
Day 8 pre–morning dose.

Fasting liver function tests at Day 5 and Day 8 pre–morning dose.

AE assessment.

Study drug dispense and administration.
9.3.4
Quadruple Therapy Dosing/TAK-438 PK and Lansoprazole PK (Day 12 to 13)
The following procedures will be performed and documented during Days 12 to 13 while subject 
remains in confinement:

Vital signs.

Neurological examination of the nervous system.

Concomitant medications.

AE assessment.

Predose blood PK sampling collection (morning and evening).

Fasting clinical laboratory tests (hematology, clinical chemistry, and urinalysis).

Fasting liver function tests.

Study drug dispense and administration.
9.3.5
Quadruple Therapy Dosing/TAK-438 PK, Lansoprazole PK and Bismuth PK 
(Day 14)
The following procedures will be performed and documented during Day 14 while the subject 
remains in confinement:

Vital signs and weight.

Neurological examination of the nervous system.

Concomitant medications.

Fasting clinical laboratory tests (hematology, clinical chemistry, and urinalysis).

Fasting liver function tests.

ECG procedure (predose and 1, 2, and 4 hours post–morning dose).

AE assessment.


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
Predose blood PK sampling collection for TAK-438 and lansoprazole (morning and evening).

Pre– and post–morning dose blood PK sampling collection for bismuth.

Post–morning dose urine PK sampling collection for bismuth.

Study drug dispense and administration.
9.3.6
Check-out (Day 15)
The Check-out Visit will be performed on Day 15.
The following procedures will be performed and documented:

Vital signs.

Physical examination.

Concomitant medications.

Fasting clinical laboratory tests (hematology, clinical chemistry, and urinalysis including 
pregnancy test).

Fasting liver function tests.

ECG procedure.

AE assessment.
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page. Subjects should avoid antibiotics, PPIs, bismuth preparations until Day 42 (HP breath test).
9.3.7
Early Termination
The reason for discontinuation must be documented in the source document and eCRF. The 
following procedures will be performed and documented:

Vital signs.

Physical examination.

Fasting clinical laboratory tests (hematology, clinical chemistry, and urinalysis including 
pregnancy test).

Concomitant medications.

ECG procedure.

AE assessment.
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.


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9.3.8
Follow-up Call (Day 17)
A follow-up phone call will be made after the Final Visit or Early Termination and will continue at 
approximately 2 days after Check-out to update safety information 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 or 
Early Termination Visit.
9.3.9
Follow-up Visit (Day 42)
Subjects will be invited back to the phase 1 unit for a follow-up visit on Day 42 (4 weeks after last 
dose of quadruple therapy) for a HP breath test. The following procedure will be performed and 
documented:

HP breath test.
9.4
Blood Volume
Total blood sampling volume for an individual subject is shown in Table 9.d
Table 9.d
Approximate Blood Volume
Volume per Period (mL)
Sample Type
Sample 
Volume 
(mL)
Screening
Check-in/
Baseline
CA + Bismuth 
+ TAK-438 or 
Lansoprazole 
Dosing
CA + Bismuth + 
TAK-438 or 
Lansoprazole 
Dosing/TAK-438 
or Lansoprazole 
PK
CA + Bismuth + 
TAK-438 or 
Lansoprazole 
Dosing/ 
TAK-438 or 
Lansoprazole 
and Bismuth PK
Check-out
Total 
Volume
Days -28 to 
-2
Day -1
Day 1 to 11
Day 12-13
Day 14
Day 15
Safety laboratory 
samples
10
10
10
20
(Day 5 and 8 
only)
20
10
10
80
Pharmacokinetic 
samples: bismuth
6
-
-
-
-
84
-
84
Pharmacokinetic 
samples: 
TAK-438/lansoprazole
6
-
-
-
24
12
-
36
CYP2C19 samples
3
-
3
-
-
-
-
3
Total blood volume
203
- = not applicable.
The maximum volume of blood at any single day is approximately 106 mL, and the approximate 
total volume of blood for the study is 203 mL.
Direct venipuncture is the preferred method of blood collection; however, a catheter with a single 
saline flush may be used. 


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If a catheter with a normal saline flush is used, the 203 mL total blood volume does not include 
discarded blood from predraws (assuming minimally the catheter dead volume plus 1 mL of blood 
is discarded each time a sample is collected from a catheter). Should a catheter be used, the total 
blood volume taken during the study must not exceed 203 mL.
9.5
Biological Sample Retention and Destruction
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.12. 
The genetic material will be sent to a testing laboratory to determine the CYP2C19 metabolic
status of each subject. Any remaining sample after 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.


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1
PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug.
10.1.3
Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason. 

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 


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


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Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5
Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6
Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.1.7
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as not related.


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10.1.8
Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.9
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.10 Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.11 Action Concerning Study Medication 
Drug withdrawn – a study medication is stopped due to the particular AE.
Dose not changed – the particular AE did not require stopping a study medication.
Unknown – only to be used if it has not been possible to determine what action has been taken.
Not Applicable – a study medication was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study medication was already stopped 
before the onset of the AE.
10.1.12 Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death.

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.


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10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication 
(Day 1) or until screen failure. For subjects who discontinue prior to study medication
administration, PTEs are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication (Day 1). Routine collection of AEs will continue until the Follow-up telephone call.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date.
3. 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.


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10.2.2
Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0. 
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3
Reporting of Abnormal Liver Function Tests 
If during the treatment or follow-up period a subject is noted to have ALT or AST >3×ULN and
total bilirubin >2×ULN for which an alternative etiology has not been identified, the event should 
be recorded as an SAE and reported as per Section 10.2.2. The investigator must contact the 
Medical Monitor for discussion of the relevant subject details and possible alternative etiologies, 
such as acute viral hepatitis A or B or other acute liver disease. Follow-up laboratory tests as 
described in Section 9.1.8 must also be performed. In addition, a Liver Function Test Abnormality 
Form must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information is not available at the time of the first report and becomes available at a later date, 
the investigator should complete a follow-up SAE form or provide other written documentation 
and transmit it immediately within 24 hours of receipt. Copies of any relevant data from the 
hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent 
to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.


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10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including investigators and 
IRBs or IECs, as applicable, in accordance with national regulations in the countries where the 
study is conducted. Relative to the first awareness of the event by/or further provision to the 
sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory authorities as 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events, unless otherwise required by national regulations. The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of an investigational medicinal product or that would be sufficient to consider changes 
in the investigational medicinal products administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.


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


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
Drug Dictionary.
12.1
CRFs (Electronic)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by 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.
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by study monitors. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 


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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 Phase 1 Site Specifications document for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor before 
disposing of any such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
13.1.1
Analysis Sets
In this study, 2 kinds of analysis sets are defined: safety analysis set and PK analysis set. The safety 
analysis set used for primary analysis will consist of subjects who received at least 1 dose of the 
study drug. 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. The definition of each analysis set will be described in the SAP. 
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized using the safety analysis set 
and PK analysis set.
13.1.3
Pharmacokinetic Analysis
The following analyses will be performed in the PK analysis set.
Plasma concentrations of bismuth will be summarized at each scheduled sampling point on Day 14 
by administration condition (bismuth with the combination CAL and bismuth with the 
combination CAT) using descriptive statistics (arithmetic mean, SD, median, minimum and 
maximum, geometric mean, and %CV). For Days 12 to 14, plasma concentrations of TAK-438F
and lansoprazole will be summarized at each scheduled sampling point using descriptive statistics. 
Concentration-time profiles of bismuth for individual subjects and mean concentration-time 
profiles with standard deviations will be provided for both administration conditions (bismuth 
with CAL and bismuth with CAT). Individual plasma concentration data versus time will be 
presented in a data listing. 
The plasma and urine PK parameters of bismuth will be summarized by administration conditions 
(bismuth with CAL and bismuth with CAT) using descriptive statistics. In addition, geometric 
mean and coefficient of variation will be computed for Cmax and AUCs from plasma PK. 
Two-sided 90% and 95% confidence levels (CIs) of the ratio between administration conditions 
(bismuth with CAL and bismuth with CAT) will be calculated using an analysis of variance with 
natural log-transformed AUCτ and Cmax of bismuth to evaluate the impact of TAK-438 on the PK 
of bismuth compared with the impact of lansoprazole on the PK of bismuth. Statistical analyses of 
other plasma and urine PK parameters will be performed if appropriate.
A more detailed analysis will be presented in the SAP.


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13.1.4
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.
Adverse Events
A TEAE is defined as an AE whose date of onset occurs on or after the start of study drug.
All TEAEs will be coded using MedDRA. Data will be summarized using preferred term and 
primary system organ class. All TEAEs, drug-related TEAEs and serious TEAEs will be 
summarized by administration conditions (bismuth with CAL and bismuth with CAT).
Clinical Laboratory Evaluations, Vital Signs, and 12-lead ECGs
Observed values and changes (from Baseline) for continuous variables will be summarized by 
administration conditions (bismuth with CL and bismuth with CAT) over time using descriptive 
statistics.
For categorical variables, shift tables will be presented for administration conditions (bismuth with 
CAL and bismuth with CAT).
Method of Data Conversion and Handling of Missing Data
No imputation of missing data or of excluded data in accordance with the SAP will be applied. 
Values below the lower limit of quantification will be handled as 0.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
A sample size of 30 (15 subjects per group) will be used in this exploratory study. Although this 
planned sample size is not primarily based on statistical considerations, it will allow precise 
estimation of the relative treatment effect of TAK-438 versus lansoprazole on bismuth exposure as 
follows:
Estimated Ratio 
TAK-438/Lansoprazole
%CV
Expected 90% CI
Expected 95% CI 
1.5
0.40
1.15, 1.96
1.09, 2.07
1.5
0.50
1.07, 2.10
1.00, 2.25
1.5
0.60
1.00, 2.24
0.92, 2.44
2.0
0.40
1.53, 2.62
1.45, 2.76
2.0
0.50
1.43, 2.80
1.33, 3.00
2.0
0.60
1.34, 2.99
1.23, 3.25
%CV=percentage coefficient of variation.


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These calculations allow for up to 2 dropouts per group and are based on estimates of %AUC of 
0.40 to 0.60 for PK parameters (area under the plasma concentration-time curve from time 0 to 
infinity [AUC∞] and Cmax) [15].


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol. 
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. However, 
blood samples not collected within the interval specified for the scheduled sample time should be 
reported to Takeda using the Protocol Deviation Form.
Protocol Deviation Forms are to be completed for PK samples collected outside of the following 
intervals:


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Table 14.a
Windows for PK Blood Sample Collection
Minutes
Nominal Sampling Time
no more than 10 minutes predose (a)
0 hour
±5 (b)
immediately postdose to ≤6 hours
±10 (b)
>6 hours to 12 hours postdose
(a) For TAK-438, lansoprazole, and bismuth PK samples.
(b) For bismuth PK samples only.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the 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 and institution guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1.


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


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


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


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15.4.2
Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on www.ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, country, and recruiting status will be registered 
and available for public viewing. For some registries, Takeda will assist callers in locating trial 
sites closest to their homes by providing the investigator name, address, and phone number to the 
callers requesting trial information. Once subjects receive investigator contact information, they 
may call the site requesting enrollment into the trial. The investigative sites are encouraged to 
handle the trial inquiries according to their established subject screening process. If the caller asks 
additional questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site.
15.4.3
Clinical Trial Results Disclosure 
Takeda will minimally post the results of clinical trials conducted in patients, regardless of 
outcome, on www.ClinicalTrials.gov or other publicly accessible websites, as required by Takeda 
Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.


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16.0
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. Klotz U. Pharmacokinetic considerations in the eradication of Helicobacter pylori. Clin 
Pharmacokinet 2000;38(3):243-70.
8. Hillemand P, Palliere M, Laquais B, Bouvet P. [Bismuth treatment and blood bismuth levels]. 
Sem Hop 1977;53(31-32):1663-9.
9. 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.
10. Furuta T, Shirai N, Sugimoto M, Nakamura A, Hishida A, Ishizaki T. Influence of CYP2C19 
pharmacogenetic polymorphism on proton pump inhibitor-based therapies. Drug Metab 
Pharmacokinet 2005;20(3):153-67.
11. Benet LZ. Safety and pharmacokinetics: colloidal bismuth subcitrate. Scand J Gastroenterol 
Suppl 1991;185:29-35.
12. Froomes PR, Wan AT, Keech AC, McNeil JJ, McLean AJ. Absorption and elimination of 
bismuth from oral doses of tripotassium dicitrato bismuthate. Eur J Clin Pharmacol 
1989;37(5):533-6.
13. Sun Q, Liang X, Zheng Q, Liu W, Xiao S, Gu W, et al. High efficacy of 14-day triple 
therapy-based, bismuth-containing quadruple therapy for initial Helicobacter pylori 
eradication. Helicobacter 2010;15(3):233-8.
14. Xu X, Sun Q, Liao J, Liang X, Zheng Q, Liu W, et al. Evaluation of 
bismuth-clarithromycin-containing quadruple therapy for initial Helicobacter pylori 
eradication. Chinese J Gastroenterol 2012(1):5-9.


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15. Zhou Q, Ruan ZR, Yuan H, Jiang B, Xu DH. Pharmacokinetics and bioequivalence of 
ranitidine and bismuth derived from two compound preparations. World J Gastroenterol 
2006;12(17):2742-8.


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Appendix A
Schedule of Study Procedures
Study Phase
Screening
Check-in 
Baseline
Quadruple 
Therapy Dosing 
(Group A or B)
Quadruple 
Therapy 
Dosing/ 
TAK-438 PK 
or Lanso PK
Quadruple 
Therapy 
Dosing 
/Bismuth PK 
and TAK-438 
PK or Lanso 
PK
Check-out/E
arly 
Termination 
(j)
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) 
(k)
Day 42 
(+6 days) 
(l)
Confinement
X
X
X
X
X
X
Informed consent
X
Inclusion/exclusion 
criteria assessment
X
X
Medical history and 
demographics (a) 
X
Medication history and 
concurrent medical 
conditions
X
X
Physical examination
X
X
X
Neurological 
examination
X
X
X
X
X
X
X
Vital signs (b)
X
X
X
X
X
X
X
Body weight and height 
(c) 
X
X
X
BMI calculation
X
X
Clinical laboratory tests 
(d)
X
X
X
X 
X
X
Liver function tests (e)
X
X
X
X 
X
X
Urine drug screen (f)
X
X
Urine pregnancy test 
(hCG) (g)
X
X
X
HP breath test
X
X
Alcohol breath test
X
Hepatitis panel and 
HIV panel 
X
Randomization
X
12-lead ECG (h)
X
X
X
X
X
X
PTEs monitoring
X
X
X
AE monitoring
X
X
X
X
X
X
Concomitant 
medication
X
X
X
X
X
X
X
X
PK sampling (i)
X
X
CYP2C19 sample 
collection (m)
X
Dispense study 
medication
X
X
X
X
Footnotes are on the following page.


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Lanso=lansoprazole.
(a) Demographics are collected at Screening only. All medical history updates should include tobacco, alcohol, and caffeine use.
(b) 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 Day 1 to 15.
(c) Height is only collected at the Screening Visit.
(d) 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.
(e) Liver function tests are comprised of AST, ALT, 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.
(f)Drug screen including: amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, cotinine, methadone, and opiates.
(g) Urine hCG test to be performed only in female subjects of childbearing potential.
(h) ECGs will be collected on Screening, Check-in, and on dosing Days 1, 3, and 7 at pre–morning dose, Day 14 at pre–morning dose and 
1, 2, and 4 hours post–morning dose, and at Check-out.
(i) Blood PK samples for TAK-438 or lansoprazole analysis will be collected on Day 12 to Day 14 at predose (morning and evening). 
Blood PK samples for bismuth analysis will be collected on Day 14 at 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, and 12.0 hours post–morning dose. Urine PK samples for bismuth analysis will be collected on Day 14 at 0 to 12 
hours post–morning dose.
(j) In the event of Early Termination, all Check-out procedures should be done at the time of withdrawal.
(k) 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.
(l) A Follow-up Visit will be arranged after approximately 4 weeks for HP breath test.
(m) Mandatory collection of 1 whole blood sample (3 mL) for DNA CYP2C19 genotyping will be taken at Day -1. If subjects who initially 
screen fail for this study have performed DNA blood collection for CYP2C19 genotyping analysis, it is not required again.


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


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


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


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


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Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples
Instructions for Processing of Plasma Samples for PK Analysis of TAK-438 or Lansoprazole
1. Collect 6 mL of venous blood for the plasma into a Becton-Dickinson Vacutainer at room 
temperature. All TAK-438 or lansoprazole 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 prior to 
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 (TAK-438_115), sample matrix (ie, 
plasma), analyte (TAK-438F or lansoprazole), 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 -70°C or lower until shipment to the correct laboratory as noted in Step 12 of 
the shipping instructions. No more than 45-60 minutes will elapse between blood collection 
and freezing the plasma sample.
Instructions for Processing of Plasma Samples for PK Analysis of Bismuth
1. Collect 6 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 prior to 
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 (TAK-438_115), 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 -70°C or lower until shipment to 
, Osaka, 
Japan. No more than 45-60 minutes will elapse between blood collection and freezing the 
plasma sample.
PPD


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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 4ºC,
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 (TAK-438_115), 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 -70ºC or lower. Keep 
samples frozen at approximately -70ºC or lower until shipment to 
 
, Osaka, Japan.
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 TAK-438, lansoprazole 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 prior to a national holiday, in order 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:
4. Separate the duplicate SET 2 samples from the SET 1 samples.
5. Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc) containing additional 
absorbent material.
6. 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.
7. 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 
steps 3 through 6 above when preparing duplicate samples for shipment, except self-sealing 
bags should be marked “SET 2.”
8. An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study medication (TAK-438), protocol number (TAK-438_115), 
PPD
PPD


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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.
9. 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.
10. 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.
11. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
12. Follow Central Laboratory Manual for shipping samples. 
Plasma Samples for TAK-438
Plasma Samples for Lansoprazole
Plasma and Urine Samples for Bismuth
13. 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)
PPD
PPD
PPD


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14. 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.
15. Obtain the airway bill number and a receipt of shipment from the carrier.
16. After shipping of the TAK-438 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
Collection of PGx Samples 
Sample Collection
1. Mandatory Collection for CYP2C19 Genotyping: 
One 3 mL whole blood sample for DNA isolation and CYP2C19 genotyping will be collected 
from each subject during the screening period, into a plastic tube spray coated with K2EDTA.


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Appendix F
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 03 are indicated. 
The corresponding text has been revised throughout the protocol
Change 1: Removal of reference to CYP2C19 genotype status from study inclusion criteria.
The primary change occurs in: Section 7.1 Inclusion Criteria:
Initial 
wording:
3. The subject is HP positive and a CYP2C19 EM (genotypes 1/*1, *1/*2, and *1/*3)
at Screening.
Amended 
or new 
wording:
3. The subject is HP positive and a CYP2C19 EM (genotypes 1/*1, *1/*2, and *1/*3)
at Screening.
Rationale for Change:
The inclusion criterion #3 has been extended to permit all subjects, regardless of CYP2C19 
genotype to be eligible to enter the study. TAK-438 is predominantly metabolized by CYP3A4, 
therefore, CYP2C19 status does not have an impact on plasma concentrations of TAK-438. 
Secondly, although exposure to lansoprazole has been shown to be several fold higher in subjects 
who lack a functional CYP2C19 gene (poor metabolizers), approved dosing information for 
lansoprazole does not state dose adjustment based on CYP2C19 status. Taken together, the 
enrolment of subjects with all CYP2C19 genotypes is not anticipated to have an impact on the 
safety of the subjects or on the objectives and scientific value of the study. 
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 6.1 Study Design

Section 6.2 Justification for Study Design, Dose, and Endpoints


TAK-438
Study No. TAK-438_115
Page 85 of 90
Protocol Incorporating Amendment No. 03
21 November 2016
CONFIDENTIAL
Change 2: For Exclusion criterion #20, permission for all investigators (including sub 
investigators) to enter subjects with non-clinically significant electrocardiogram (ECG) 
abnormalities.
The primary change occurs in: Section 7.2 Exclusion Criteria
Initial 
wording:
20. The subject has a Screening or Check-in abnormal (clinically significant) ECG. 
Entry of any subject with an abnormal (not clinically significant) ECG must be 
approved, and documented by signature by both the principal investigator and the 
contract research organization (CRO) medical monitor.
Amended 
or new 
wording:
20. The subject has a Screening or Check-in abnormal (clinically significant) ECG. 
Entry of any subject with an abnormal (not clinically significant) ECG must be 
approved, and documented by signature by both the principal investigator and the 
contract research organization (CRO) medical monitor.
Rationale for Change:
A site request to allow all appropriately-trained investigators involved in the study to permit entry 
in case of principal investigator unavailability.
Change 3: For Exclusion Criterion No.22, glomerular filtration rate to be estimated using the 
Chronic Kidney Disease-Epidemiology Collaboration formula.
The primary change occurs in: Section 7.2 Exclusion Criteria
Initial 
wording:
22. The subject has reduced renal function assessed by having an estimated 
glomerular filtration rate <90 mL/min/1.73 m2 (as estimated by Modification of 
Diet in Renal Disease) at Screening or Check-in.
Amended 
or new 
wording:
22. The subject has reduced renal function assessed by having an estimated 
glomerular filtration rate <90 mL/min/1.73 m2 (as estimated by Modification of 
Diet in Renal Disease Chronic Kidney Disease-Epidemiology Collaboration) at 
Screening or Check-in.
Rationale for Change:
Compared with the Modification of Diet in Renal Disease equation for estimating glomerular 
filtration rate, the Chronic Kidney Disease-Epidemiology Collaboration equation has been shown 
to be similarly accurate at estimating the glomerular filtration rate in subjects with an estimated 
glomerular filtration rate of <60 ml/min/1.73m2 and substantially more accurate in subjects with 
eGFR of >60 ml/min/1.73m2(Misuk Ji, Yoon-Hee Lee, Mina Hur, Hyesun Kim, Han-Ik Cho, 
Hyun Suk Yang, et al. Comparing results of five glomerular filtration rate-estimating equations in 
the Korean general population: MDRD Study, Revised Lund-Malmӧ, and three CKD-EPI 
equations. Ann Lab Med 2016;36:521-528.)


TAK-438
Study No. TAK-438_115
Page 86 of 90
Protocol Incorporating Amendment No. 03
21 November 2016
CONFIDENTIAL
Change 4: Clarification to indicate that the time point for pharmacokinetic (PK) analysis will be 
Day 14.
The primary change occurs in Section 5.2 Endpoints:
Initial 
wording:
–
Cmax at Day 14.
–
The area under the plasma concentration-time curve during a dosing interval 
(AUCτ).
–
The amount of drug excreted in urine during a dosing interval (Aeτ).
Amended 
or new 
wording:
–
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.
Rationale for Change:
A clarification to indicate the time point for PK analysis.


TAK-438
Study No. TAK-438_115
Page 87 of 90
Protocol Incorporating Amendment No. 03
21 November 2016
CONFIDENTIAL
Change 5: Rescreening and the process of rescreening subjects have been added.
The primary change occurs in Section 9.3.1 Screening (Day -28 to -2):
Initial 
wording:
Subjects will be screened within 28 days prior to randomization. Subjects will be 
screened in accordance with predefined inclusion and exclusion criteria as described 
in Section 7.0. See Section 9.1.15 for procedures for documenting screening failures.
Amended 
or new 
wording:
Subjects will be screened within 28 days prior to randomization. Subjects will be 
screened in accordance with predefined inclusion and exclusion criteria as described 
in Section 7.0. See Section 9.1.15 for procedures for documenting screening failures. 
Subjects who initially screen fail for the study are permitted to rescreen 
following re-consent, with the exception of subjects who at the initial screening 
visit failed due to abnormal clinical laboratory values that were 
investigator-defined as clinically significant. All screening procedures with the 
possible exception of DNA blood collection for CYP2C19 genotyping analysis (if 
this has been collected it is not required to be collected again) will be repeated. 
The subject must meet all inclusion and none of the exclusion criteria at the time 
of rescreening in order to qualify for the study.
Rationale for Change:
Given that the inclusion criteria has changed to permit the inclusion of all HP positive subjects, 
regardless of CYP2C19 status (see Change 1), and the equation for estimating glomerular filtration 
rate has also changed (see Change 3), the protocol has been updated to provide guidance for the 
possible rescreening of subjects who had previously been found to be ineligible.
The following sections also contain this change:

Section 9.1.12 Pharmacogenetic Sample Collection for CYP2C19 Genotyping.

Section 9.1.15 Documentation of Screen Failure.


TAK-438
Study No. TAK-438_115
Page 88 of 90
Protocol Incorporating Amendment No. 03
21 November 2016
CONFIDENTIAL
Change 6: Amendments to the CYP2C19 blood collection.
The primary change occurs in Section 9.1.12 Pharmacogenetic Sample Collection for CYP2C19 
Genotyping:
Initial 
wording:
One whole blood sample (3 mL) for DNA isolation will be collected during the 
screening period from each subject in the study, into plastic potassium 
ethylenediamine tetraacetic acid (K2EDTA) spray-coated tubes, and stored under 
frozen condition. A second aliquot of blood may be taken if isolation of DNA from the 
first sample was not successful or possible.
The DNA sample collected from each subject will be used for CYP2C19 genotyping 
analysis. Genetic variation into the CYP2C19 gene may lead to changes in metabolic 
activity of the CYP2C19 enzyme that may contribute to the variability in the 
PK/clinical efficacy of TAK-438 and lansoprazole. CYP2C19 metabolic status 
information will be confirmed with the investigators prior to Day -1.
Amended 
or new 
wording:
One whole blood sample (3 mL) for DNA isolation will be collected during the 
screening period at Day-1 from each subject in the study, into plastic potassium 
ethylenediamine tetraacetic acid (K2EDTA) spray-coated tubes, and stored under 
frozen condition. A second aliquot of blood may be taken if isolation of DNA from the 
first sample was not successful or possible.
The DNA sample collected from each subject will be used for CYP2C19 genotyping 
analysis. Genetic variation into the CYP2C19 gene may lead to changes in metabolic 
activity of the CYP2C19 enzyme that may contribute to the variability in the 
PK/clinical efficacy of TAK-438 and lansoprazole. CYP2C19 metabolic status 
information will be confirmed with the investigators prior to Day -1.
Rationale for Change:
To clarify study procedures.
The following section also contains one of these changes:

Table 9.d Approximate Blood Volume.

Appendix A Schedule of Study Procedures.


TAK-438
Study No. TAK-438_115
Page 89 of 90
Protocol Incorporating Amendment No. 03
21 November 2016
CONFIDENTIAL
Change 7: The screening procedure of Helicobacter pylori (HP) breath test is permitted to be 
performed at a satellite site.
The primary change occurs in Section 9.3.1 Screening (Day -28 to -2):
Initial 
wording:
HP breath test.
Amended 
or new 
wording:
HP breath test. Providing the subject has signed the informed consent form, sites 
can choose to conduct the urea breath test at a satellite site. The urea breath test 
may only be performed at a satellite site after the Sponsor has reviewed and 
approved the site’s procedures. All other screening procedures, and all other 
study visits are required to be conducted at the main Phase 1 unit.
Rationale for Change:
This update to the study protocol has been included to improve the recruitment process by 
allowing a satellite site to test for HP status, before a subject must travel to the main Phase 1 unit to 
confirm other eligibility criteria. Satellite sites will use the same urea breath test as the main 
Phase 1 unit, and staff will be appropriately trained. Therefore, allowing satellite sites to conduct 
this test will not have an impact on the scientific integrity of the study or subject safety. 
The following section also contains this change:

Section 9.1.1 Informed Consent Procedure.


TAK-438
Study No. TAK-438_115
Page 90 of 90
Protocol Incorporating Amendment No. 03
21 November 2016
CONFIDENTIAL
Change 8: Clarified liver function test monitoring.
The primary change occurs in Table 9.a Clinical Laboratory Tests:
Description 
of change:
In the column Serum Chemistry: alanine aminotransferase, aspartate 
aminotransferase, total bilirubin, and direct bilirubin have been highlighted as being 
included in liver function tests, with a new footnote:
(b) Included in liver function tests.
Rationale for Change:
Highlight the tests involved in liver function monitoring.
The following sections also contain this change:

Section 9.3 Schedule of Observations and Procedures.

Appendix A Schedule of Study Procedures.
Change 9: Clarification of footnotes in the Schedule of Study Procedures (Appendix A).
The primary change occurs in Appendix A Schedule of Study Procedures:
Description 
of change:
In the footnote (b): 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 Day 1 to Day 15. An orthostatic 
blood pressure measurement will be made at Screening and Check-in (Day -1) based 
on the difference between sitting and standing [1 minute] systolic blood pressure 
measurements.
Rationale for Change:
To clarify study procedures.


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PPD


TAK-438
Study No. TAK-438_115
Page 85 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
Appendix F
Detailed Description of Amendments to Text
This document describes changes in reference to the original Protocol (22 December 2015).
Page 2, Section 1.1 Contacts
Existing text
A separate contact information list will be provided to each site.
TDC sponsored Asian Pacific investigators will be provided with emergency medical contact 
information cards to be carried by each subject. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Issue
Asian Regional Contact
Serious adverse event, pregnancy and special interest adverse event
reporting
To be confirmed
Medical Monitor (medical advice on protocol, compound, and medical 
management of subjects)
To be confirmed
Responsible Medical Officer (carries overall responsibility for the 
conduct of the study)
To be confirmed
Revised Text
A separate contact information list will be provided to each site.
TDC sponsored Asian Pacific investigators will be provided with emergency medical contact 
information cards to be carried by each subject. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Issue
Asian Regional Contact
Serious adverse event, pregnancy and special interest adverse event
reporting
Medical Monitor (medical advice on protocol, compound, and medical 
management of subjects)
Responsible Medical Officer (carries overall responsibility for the 
conduct of the study)
PPD


TAK-438
Study No. TAK-438_115
Page 86 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
Rationale for Amendment
Appropriate contacts have been identified for reporting of adverse events, Medical Monitoring, 
and the Responsible Medical Officer.
Page 3, Section 1.2 Approvals
Existing Text
SIGNATURES
Electronic Signatures may be found on the last page of this document.
ate
Date
Date
Date
Revised Text
SIGNATURES
Electronic Signatures may be found on the last page of this document.
Date
Date
Date
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


TAK-438
Study No. TAK-438_115
Page 87 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
Rationale for Amendment
According to changes in the Takeda process for approval of Protocols and Protocol Amendments, 
the document should be approved by the Study Clinical Science Lead. As such,
replaces
.
Page 20, Section 5.1 Objectives
Existing Text
The objectives of this study are:
!
To evaluate the safety, tolerability, and PK of quadruple therapy BID with tripotassium 
bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and TAK-438
(20 mg) versus quadruple therapy BID with tripotassium bismuth dicitrate (600 mg), 
clarithromycin (500 mg), amoxicillin (1000 mg), and lansoprazole (30 mg).
!
To evaluate the PK of quadruple therapy BID with tripotassium bismuth dicitrate (600 mg), 
clarithromycin (500 mg), amoxicillin (1000 mg), and TAK-438 (20 mg) versus quadruple 
therapy BID with tripotassium bismuth dicitrate (600 mg), clarithromycin (500 mg), 
amoxicillin (1000 mg), and lansoprazole (30 mg). 
Revised Text
The objectives of this study are:
!
To evaluate the safety, tolerability, and PK of quadruple therapy BID with tripotassium 
bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and TAK-438
(20 mg) versus quadruple therapy BID with tripotassium bismuth dicitrate (600 mg), 
clarithromycin (500 mg), amoxicillin (1000 mg), and lansoprazole (30 mg).
Rationale for Amendment
The first, bulleted objective stated that the objectives of the study were to evaluate the safety, 
tolerability, and PK of study drug administration. The second, bulleted objective in the original 
text was a duplicate of this for PK evaluation and, as such, has been deleted.
Page 25, Section 7.2 Exclusion Criteria
Existing Text
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 prior to providing their 
informed consent.
2. The subject has received TAK-438 in a previous clinical study or as a therapeutic agent.
3. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(eg, spouse, parent, child, sibling) or may consent under duress.
PPD
PPD


TAK-438
Study No. TAK-438_115
Page 88 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
4. The subject has uncontrolled, clinically significant cardiovascular, or other abnormality (other 
than the disease being studied), which may impact the ability of the subject to participate or 
potentially confound the study results.
5. The subject has a known hypersensitivity to any component of the formulation of TAK-438, 
penicillins, macrolides, and bismuths, for example, 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 prior to 
the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the 
study (1 unit=12 oz/300 mL beer, 1.5 oz/25 mL hard liquor/spirits, or 5 oz/100 mL wine).
8. The subject has taken any excluded medication, supplements, or food products listed in the 
Excluded Medications and Dietary Products table listed in Section 7.3 of the protocol, except 
where over-the-counter (OTC) medication has been pre-approved by Takeda.
9. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after participating in this study; or intending to donate ova during such time 
period.
10. The subject has evidence of current cardiovascular, central nervous system, hepatic, 
hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, 
asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the 
subject’s medical history, physical examination, or safety laboratory tests giving reasonable 
suspicion of a disease that would contraindicate taking TAK-438, 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.
11. The subject has a history of gastroesophogeal reflux disease (GERD), symptomatic GERD, 
erosive esophagitis, DU, GU, dyspepsia, 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.
12. The subject has any known disease or is taking any medication that is contraindicated with 
bismuth, clarithromycin, or amoxicillin.
13. 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 prior to Day 1.
14. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen at Screening.


TAK-438
Study No. TAK-438_115
Page 89 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
15. 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 prior to 
Check-in. Cotinine test is positive at Screening or Check-in.
16. The subject has poor peripheral venous access.
17. The subject has donated or lost 450 mL or more of his blood volume (including 
plasmapheresis), or had a transfusion of any blood product within 90 days prior to Day 1.
18. The subject has a Screening or Check-in abnormal (clinically significant) ECG. Entry of any 
subject with an abnormal (not clinically significant) ECG must be approved, and documented 
by signature by both the principal investigator and the contract research organization (CRO)
medical monitor.
19. 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 >the upper limit 
of normal (ULN).
20. The subject has reduced renal function assessed by having an estimated glomerular filtration 
rate <90 mL/min/1.73 m2 (as estimated by Modification of Diet in Renal Disease) at Screening 
or Check-in.
Revised Text
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 prior to providing their 
informed consent.
2. The subject has received TAK-438 in a previous clinical study or as a therapeutic agent.
3. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(eg, spouse, parent, child, sibling) or may consent under duress.
4. The subject has uncontrolled, clinically significant cardiovascular, or other abnormality (other 
than the disease being studied), which may impact the ability of the subject to participate or 
potentially confound the study results.
5. The subject has a known hypersensitivity to any component of the formulation of TAK-438, 
penicillins, macrolides, and bismuths, for example, 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 prior to 


TAK-438
Study No. TAK-438_115
Page 90 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the 
study (1 unit=12 oz/300 mL beer, 1.5 oz/25 mL hard liquor/spirits, or 5 oz/100 mL wine).
8. The subject has taken any excluded medication, supplements, or food products listed in the 
Excluded Medications and Dietary Products table listed in Section 7.3 of the protocol, except 
where over-the-counter (OTC) medication has been pre-approved by Takeda.
9. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after participating in this study; or intending to donate ova during such time 
period.
10. The subject has evidence of current cardiovascular, central nervous system, hepatic, 
hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, 
asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the 
subject’s medical history, physical examination, or safety laboratory tests giving reasonable 
suspicion of a disease that would contraindicate taking TAK-438, 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.
11. The subject has a history of gastroesophogeal reflux disease (GERD), symptomatic GERD, 
erosive esophagitis, DU, GU, 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.
12. Subjects who have undergone therapeutic upper gastrointestinal endoscopic therapy (eg, 
endoscopic hemostasis or excision including biopsy) within 30 days prior to visit 1.
13. 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).
14. The subject has any known disease or is taking any medication that is contraindicated with 
bismuth, clarithromycin, or amoxicillin.
15. 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 prior to Day 1.
16. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen at Screening.
17. 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 prior to 
Check-in. Cotinine test is positive at Screening or Check-in.
18. The subject has poor peripheral venous access.
19. The subject has donated or lost 450 mL or more of his blood volume (including 
plasmapheresis), or had a transfusion of any blood product within 90 days prior to Day 1.


TAK-438
Study No. TAK-438_115
Page 91 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
20. The subject has a Screening or Check-in abnormal (clinically significant) ECG. Entry of any 
subject with an abnormal (not clinically significant) ECG must be approved, and documented 
by signature by both the principal investigator and the contract research organization (CRO)
medical monitor.
21. 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 >the upper limit 
of normal (ULN).
22. The subject has reduced renal function assessed by having an estimated glomerular filtration 
rate <90 mL/min/1.73 m2 (as estimated by Modification of Diet in Renal Disease) at Screening 
or Check-in.
Rationale for Amendment
In order to ensure that subjects are recruited with an intact luminal gastrointestinal tract, so that 
absorption of investigational medicinal product is not compromised, 2 additional criteria (#12 and 
#13) have been added to Section 7.2 Exclusion Criteria. The additions will exclude subjects with a 
history of upper gastrointestinal endoscopic therapy (within 30 days of Visit 1) and exclude 
subjects who have undergone (within 1 month prior to recruitment), or will be undergoing, major 
surgical procedures that may affect gastric acid secretion. Additionally, as dyspepsia is a common 
symptom of H. pylori infection, this term has been removed as an exclusion criteria.
Page 28, Section 7.3 Excluded Medication, Dietary Products
Existing Text
Concomitant medications will include all medications the subject has taken from signing of 
informed consent to the end of the study (Day 17).
Revised Text
Concomitant medications will include all medications the subject has taken from signing of 
informed consent to the Follow-up call (Day 17).
Rationale for Amendment
The study end has been corrected to Day 42 from Day 17.


TAK-438
Study No. TAK-438_115
Page 92 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
Page 74, Appendix A Schedule of Study Procedures
Existing Text
Study Phase
Screening
Check-in 
Baseline
Quadruple 
Therapy Dosing 
(Group A or B)
Quadruple 
Therapy 
Dosing/ 
TAK-438 PK 
or Lanso PK
Quadruple 
Therapy 
Dosing
/Bismuth PK 
and TAK-438 
PK or Lanso 
PK
Check-out/Early 
termination (i)
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) (j)
Day 42 
(k)
Confinement
X
X
X
X
X
X
Informed consent
X
Inclusion/exclusion 
criteria assessment
X
X
Medical history and 
demographics (a) 
X
Medication history and 
concurrent medical 
conditions
X
X
Physical examination
X
X
X
Neurological 
examination
X
X
X
X
X
X
X
Vital signs (b)
X
X
X
X
X
X
X
Body weight and height 
(c) 
X
X
X
BMI calculation
X
X
Clinical laboratory tests 
(d)
X
X
X
X 
X
X
Urine drug screen (e)
X
X
Urine pregnancy test 
(hCG) (f)
X
X
X
X
HP breath test
X
X
Alcohol breath test
X
Hepatitis panel and HIV 
panel 
X
Randomization
X
12-lead ECG (g)
X
X
X
X
X
X
PTEs monitoring
X
X
X
AE monitoring
X
X
X
X
X
X
Concomitant 
medication
X
X
X
X
X
X
X
X
PK sampling (h)
X
X
CYP2C19 sample 
collection (l)
X
Dispense study 
medication
X
X
X
X


TAK-438
Study No. TAK-438_115
Page 93 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
Revised Text
Study Phase
Screening
Check-in 
Baseline
Quadruple 
Therapy Dosing 
(Group A or B)
Quadruple 
Therapy 
Dosing/ 
TAK-438 PK 
or Lanso PK
Quadruple 
Therapy 
Dosing 
/Bismuth PK 
and TAK-438 
PK or Lanso 
PK
Check-out/Early 
termination (i)
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) (j)
Day 42 
(+6 
days) 
(k)
Confinement
X
X
X
X
X
X
Informed consent
X
PGx informed consent
X
Inclusion/exclusion 
criteria assessment
X
X
Medical history and 
demographics (a) 
X
Medication history and 
concurrent medical 
conditions
X
X
Physical examination
X
X
X
Neurological 
examination
X
X
X
X
X
X
X
Vital signs (b)
X
X
X
X
X
X
X
Body weight and height 
(c) 
X
X
X
BMI calculation
X
X
Clinical laboratory tests 
(d)
X
X
X
X 
X
X
Urine drug screen (e)
X
X
Urine pregnancy test 
(hCG) (f)
X
X
X
HP breath test
X
X
Alcohol breath test
X
Hepatitis panel and HIV 
panel 
X
Randomization
X
12-lead ECG (g)
X
X
X
X
X
X
PTEs monitoring
X
X
X
AE monitoring
X
X
X
X
X
X
Concomitant 
medication
X
X
X
X
X
X
X
X
PK sampling (h)
X
X
CYP2C19 sample 
collection (l)
X
Dispense study 
medication
X
X
X
X


TAK-438
Study No. TAK-438_115
Page 94 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
Rationale for Amendment
A separate PGx informed consent form must be obtained in order to store the remaining DNA 
sample from the CYP2C19 genotyping. The provision of consent to store the sample for future 
analysis is independent of consent to the other aspects of the study and any randomized subjects 
will be provided with a separate PGx informed consent form at Randomization. As such, this will 
be collected at Day 1, in the Schedule of Study Procedures. Additionally, the procedure for urine 
pregnancy test on Day 14 has been deleted, as this was included in error. The qualifier (+6 days) 
has been added to the Follow-up at Day 42, in order to be aligned with the study schematic 
(Figure 6.a).
Page 81, Appendix E Collection, Storage, and Shipment of Bioanalytical Samples
Existing Text
Instructions for Processing of Plasma Samples for PK Analysis of TAK-438 or Lansoprazole
1. Collect 6 mL of venous blood for the plasma into a Becton-Dickinson Vacutainer at room 
temperature. All TAK-438 or lansoprazole 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 prior to 
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 (TAK-438_115), sample matrix (ie, plasma), 
analyte (TAK-438F or lansoprazole), subject number, period, 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 -70°C or lower until shipment to the correct laboratory as noted in Step 12 of the 
shipping instructions. No more than 45-60 minutes will elapse between blood collection and 
freezing the plasma sample.
Instructions for Processing of Plasma Samples for PK Analysis of Bismuth
1. Collect 6 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 prior to 
centrifugation and place immediately on ice.


TAK-438
Study No. TAK-438_115
Page 95 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
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 (TAK-438_115), sample matrix (ie, plasma), 
analyte (Bismuth), enrollment number, period, 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 -70°C or lower until shipment to
 Osaka, Japan. 
No more than 45-60 minutes will 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 4ºC,
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 (TAK-438_115), sample matrix (ie, urine), analyte (bismuth), enrollment 
number, period, 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 -70ºC or lower. Keep 
samples frozen at approximately -70ºC or lower until shipment to 
 Osaka, Japan.
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 TAK-438, lansoprazole 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 
prior to a national holiday, in order 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:
PPD
PPD
PPD


TAK-438
Study No. TAK-438_115
Page 96 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
4. Separate the duplicate SET 2 samples from the SET 1 samples.
5. Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc) containing additional 
absorbent material.
6. Using a permanent marker, write the 4-digit enrollment number, sample matrix (ie, plasma or 
urine), number of samples, and “SET 1” on each self-sealing bag.
7. 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 steps 3 
through 6 above when preparing duplicate samples for shipment, except self-sealing bags should 
be marked “SET 2.”
8. An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study medication (TAK-438), protocol number (TAK-438_115), 
investigator’s name, sample type (ie, plasma or urine), subject enrollment number, period, 
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.
9. 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.
10. 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.
11. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
12. Follow Central Laboratory Manual for shipping samples. The PK samples will be shipped to 
the central laboratory and the central laboratory will ship to the designated laboratories for 
analysis of TAK-438, lansoprazole or bismuth.
Plasma Samples for TAK-438
PPD


TAK-438
Study No. TAK-438_115
Page 97 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
Plasma and Urine Samples for Bismuth
13. 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)
14. 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.
15. Obtain the airway bill number and a receipt of shipment from the carrier.
16. After shipping of the TAK-438 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
Revised Text
Instructions for Processing of Plasma Samples for PK Analysis of TAK-438 or Lansoprazole
1. Collect 6 mL of venous blood for the plasma into a Becton-Dickinson Vacutainer at room 
temperature. All TAK-438 or lansoprazole 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 prior to 
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.
PPD
PPD


TAK-438
Study No. TAK-438_115
Page 98 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
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 (TAK-438_115), sample matrix (ie, plasma), 
analyte (TAK-438F or lansoprazole), 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 -70°C or lower until shipment to the correct laboratory as noted in Step 12 of the 
shipping instructions. No more than 45-60 minutes will elapse between blood collection and 
freezing the plasma sample.
Instructions for Processing of Plasma Samples for PK Analysis of Bismuth
1. Collect 6 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 prior to 
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 (TAK-438_115), 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 -70°C or lower until shipment to
 Osaka, Japan. 
No more than 45-60 minutes will 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 4ºC,
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 (TAK-438_115), 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).
PPD


TAK-438
Study No. TAK-438_115
Page 99 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
5. Freeze the urine sample immediately and store frozen at approximately -70ºC or lower. Keep 
samples frozen at approximately -70ºC or lower until shipment to 
 
 Osaka, Japan.
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 TAK-438, lansoprazole 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 
prior to a national holiday, in order 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:
4. Separate the duplicate SET 2 samples from the SET 1 samples.
5. Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc) containing additional 
absorbent material.
6. 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.
7. 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 steps 3 
through 6 above when preparing duplicate samples for shipment, except self-sealing bags should 
be marked “SET 2.”
8. An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study medication (TAK-438), protocol number (TAK-438_115), 
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.
9. 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.
PPD
PPD


TAK-438
Study No. TAK-438_115
Page 100 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
10. 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.
11. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
12. Follow Central Laboratory Manual for shipping samples. 
Plasma Samples for TAK-438
Plasma and Urine Samples for Bismuth
13. 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)
14. 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.
15. Obtain the airway bill number and a receipt of shipment from the carrier.
16. After shipping of the TAK-438 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
PPD
PPD
PPD


TAK-438
Study No. TAK-438_115
Page 101 of 101
Protocol Incorporating Amendment No. 01
22 April 2016
CONFIDENTIAL
Rationale for Amendment
In order to align with Section 8.2, Investigational Drug Assignment and Dispensing Procedures, 
the term ‘randomization sequence number’ has replaced ‘enrollment number, period’, where 
appropriate. Additionally, for the shipping of PK samples to the designated laboratories (for 
TAK-438, lansoprazole, and bismuth analysis), the specific names of individuals have been 
deleted in order to minimize any further protocol amendments.


TAK-438
Study No. TAK-438_115
Page 84 of 99
Protocol Incorporating Amendment No. 02
20 July 2016
CONFIDENTIAL
Appendix F
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Amendment 01 (22 April 2016).
Throughout the Protocol Amendment 02
Revised Text
Wording that references measurement of bismuth PK parameters (in both plasma and urine) at 
steady state (eg, Cmax ss) has been removed (eg, Cmax).
Rationale for Amendment
In the original protocol, and protocol amendment 01, the sponsor stated that, following oral 
administration, bismuth is highly distributed throughout the body and displays multicompartment 
elimination with an effective half-life of 10.2 hours [15], indicating that the plasma concentration 
could almost reach steady state in a few days after multiple dosing. However, following 
discussions with the Korean agency (MFDS), in which the time for bismuth to reach steady state 
could vary from 5 to 28 days, in some literature, it has been agreed that measurement of PK 
parameters (in both plasma and urine) will now not be calculated on the assumption that steady 
state has been reached.
Throughout the Protocol Amendment 02
Revised Text
(up to Day 17)
Rationale for Amendment
Qualification of study end as Day 17 regarding prohibited medications for exclusion criteria 
(Section 7.2), excluded medications/dietary products (Section 7.3), blood draw (Diet, Fluid, and 
Activity Control, Section 7.4), and documentation of concomitant medications (Section 9.1.6). 
Page 2, Section 1.1 Contacts
Existing Text
Medical Monitor (medical advice on protocol, compound, and medical management of subjects)
Revised Text
Medical Monitor (medical advice on protocol and study drug)
Rationale for Amendment
Adopted the protocol template language.
Page 3, Section 1.2 Approval
Existing Text
Richard Jenkins, PhD
Global Development Lead, GI TAU, Senior Scientific Director


TAK-438
Study No. TAK-438_115
Page 85 of 99
Protocol Incorporating Amendment No. 02
20 July 2016
CONFIDENTIAL
Revised Text
Richard Jenkins, DPhil
Global Development Lead, GI TAU, Senior Scientific Director
Rationale for Amendment
Correct qualification assigned.
Page 13, Section 2.0 Study Summary
Existing Text
Main Criteria for Exclusion
A history of hypersensitivity to any excipients of TAK-438.
Pharmacogenomics:
Mandatory blood samples will be collected for CYP2C19 genotyping. The storage of remaining DNA samples from 
the CYP2C19 genotyping test for future analysis will be optional.
- Total volume of blood drawn:
Blood draw is expected to be 206 mL.
Revised Text
Main Criteria for Exclusion
A history of hypersensitivity to any excipients of TAK-438 and lansoprazole.
Pharmacogenomics:
Mandatory blood samples will be collected for CYP2C19 genotyping. 
- Total volume of blood drawn:
Blood draw is expected to be 203 mL.
Rationale for Amendment
The requirement for an optional blood draw (3 mL) for storage purposes for later DNA analysis 
has been removed.
Page 21, Section 5.2 Endpoints
Existing Text

Additional safety endpoints will be examined.

Plasma PK parameters of tripotassium bismuth dicitrate (600 mg) when coadministered with 
clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and TAK-438 (20 mg BID) (CAT), 
and coadministered with clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and 
lansoprazole (30 mg BID) (CAL):
–
The maximum observed steady-state plasma concentration (Cmax,ss) at Day 14.
–
The area under the plasma concentration-time curve during a dosing interval (AUCτ).
–
The amount of drug excreted in urine during a dosing interval (Aeτ).


TAK-438
Study No. TAK-438_115
Page 86 of 99
Protocol Incorporating Amendment No. 02
20 July 2016
CONFIDENTIAL

Additional PK endpoints for tripotassium bismuth dicitrate (600 mg), TAK-438 and 
lansoprazole.
Revised Text

Plasma PK parameters of tripotassium bismuth dicitrate (600 mg) when coadministered with 
clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and TAK-438 (20 mg BID) (CAT), 
and coadministered with clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and 
lansoprazole (30 mg BID) (CAL):
–
Cmax at Day 14.
–
The area under the plasma concentration-time curve during a dosing interval (AUCτ).
–
The amount of drug excreted in urine during a dosing interval (Aeτ).
Rationale for Amendment
As a consequence of lack of specificity, 2 endpoints (‘Additional safety endpoints will be 
examined.’ and ‘Additional PK endpoints for tripotassium bismuth dicitrate (600 mg), TAK-438 
and lansoprazole.’) have been removed.
Page 24, Section 6.2 Justification for Study Design, Dose, and Endpoints
Existing Text
According to the HP local treatment guideline for HP in China, the recommended dose of bismuth 
is 220 mg BID [6]. Therefore, tripotassium bismuth dicitrate 600 mg has been chosen in this study 
as it is equivalent to bismuth 220 mg (hereafter referred to as bismuth 220 mg). Bismuth potassium 
citrate is the synonym of tripotassium bismuth dicitrate. Bismuth is minimally absorbed with 
bioavailability <0.3%, a time to reach Cmax (tmax) of 0.5 hour and is excreted through urinary and 
biliary routes. It is highly distributed throughout the body and displays multicompartment 
elimination with an effective half-life of 10.2 hours [11], indicating that the plasma concentration 
could almost reach steady state in a few days after multiple dosing. This study could not be 
simulated using physiologically-based PK modeling due to the number of regimens used.
Revised Text
According to the HP local treatment guideline for HP in China, the recommended dose of bismuth 
is 220 mg BID [6]. Therefore, tripotassium bismuth dicitrate 600 mg has been chosen in this study 
as it is equivalent to bismuth 220 mg (hereafter referred to as bismuth 220 mg). Bismuth potassium 
citrate is the synonym of tripotassium bismuth dicitrate. Bismuth is minimally absorbed with 
bioavailability <0.3%, a time to reach Cmax (tmax) of 0.5 hour and is excreted through urinary and 
biliary routes. It is highly distributed throughout the body and displays multicompartment 
elimination with multiple half-lives: an initial half-life of 1-4 hours, a more prolonged half-life 
of 5-11 days, and a more extended half-life [11,12]. There are several half-lives reported for 
bismuth, however, one article indicates that plasma level of bismuth approach an apparent 
steady-state after 30 - 40 days after multiple dose of bismuth. This study could not be simulated 
using physiologically-based PK modeling due to the number of regimens used.


TAK-438
Study No. TAK-438_115
Page 87 of 99
Protocol Incorporating Amendment No. 02
20 July 2016
CONFIDENTIAL
Rationale for Amendment
Following extended literature review, the half-life for bismuth has been revised and supported by 
2 new references (Benet 1991; Froomes et al. 1989).
Page 27, Section 7.2 Exclusion Criteria
Existing Text
5. The subject has a known hypersensitivity to any component of the formulation of TAK-438, 
penicillins, macrolides, and bismuths, for example, D-mannitol, crystalline cellulose, 
hydroxypropyl cellulose, fumaric acid, croscarmellose sodium, magnesium stearate, 
hypromellose, macrogol 6000, titanium oxide, yellow iron sesquioxide, and iron sesquioxide.
7. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse (defined as regular consumption of 21 units or more units per week) at any time prior to the 
Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the study (1 
unit=12 oz/300 mL beer, 1.5 oz/25 mL hard liquor/spirits, or 5 oz/100 mL wine).
12. Subjects who have undergone therapeutic upper gastrointestinal endoscopic therapy (eg, 
endoscopic hemostasis or excision including biopsy) within 30 days prior to Day -28.
Revised Text
5. The subject has a known hypersensitivity to any component of the formulation of TAK-438, 
penicillins, macrolides, bismuths, and lansoprazole, for example, D-mannitol, crystalline 
cellulose, hydroxypropyl cellulose, fumaric acid, croscarmellose sodium, magnesium stearate, 
hypromellose, macrogol 6000, titanium oxide, yellow iron sesquioxide, and iron sesquioxide.
7. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse (defined as regular consumption of 21 units or more units per week) at any time prior to the 
Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.
12. Subjects who have undergone therapeutic upper gastrointestinal endoscopic therapy (eg, 
endoscopic hemostasis or excision including biopsy) within 30 days prior to Screening.
Rationale for Amendment
The exclusion criterion regarding known hypersensitivity to medicines provided by the sponsor 
for administration during the study has been expanded to include lansoprazole, which will be 
administered as an active comparator.
The qualification for alcohol units will now be calculated by the study site.
To be consistent with other exclusion criteria, Day -28 was rephrased to Screening.
Page 34, Section 8.2 Investigational Drug Assignment and Dispensing Procedures
Existing Text
Subjects will be assigned, in the order in which they are randomized into the study, to receive their 
treatment according to the randomization schedule allocated to the site. The Randomization 
Sequence Number will be entered onto the eCRF. Med ID will be assigned by the Site Pharmacist 


TAK-438
Study No. TAK-438_115
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CONFIDENTIAL
or authorized study designee based on the randomization schedule and medication schedule 
allocated to the site.
Revised Text
Subjects will be assigned, in the order in which they are randomized into the study, to receive their 
treatment according to the blinded randomization schedule allocated to the site. The 
Randomization Sequence Number and Med ID will be entered onto the eCRF. 
Rationale for Amendment
The randomization schedule and Med ID list will be provided to a blinded pharmacist at the site in 
order to dispense the drug.
Page 35, Section 8.3 Randomization Code Creation and Storage
Existing Text
Randomization personnel of the sponsor or designee will generate the randomization schedule and 
will provide it to the site pharmacist or authorized study designee prior to the start of this study. 
All randomization information will be stored in a secured area, accessible only by authorized 
personnel.
Revised Text
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 prior to the start of this study. The Med ID to be dispensed to each subject 
will be provided in this schedule.
Rationale for Amendment
A blinded randomization schedule (includes the subject sequence number and which Med ID each 
subject should receive) will be provided to the pharmacist or designee.
Page 38, Section 9.1.1.1 Pharmacogenomic Informed Consent Procedure
Existing Text
The sampling of whole blood for CYP2C19 genotyping analysis is mandatory; every subject must 
sign the informed consent in order to participate in this study. The informed consent for the 
CYP2C19 genotyping analysis is a component of the overall study informed consent.
A separate pharmacogenomic (PGx) informed consent form pertaining to storage of the sample 
must be obtained in order to store the sample after the study related PGx analysis described in the 
protocol is completed. The provision of consent to store the sample for future analysis is 
independent of consent to the other aspects of the study and any randomized subjects will be 
provided with a separate PGx informed consent form at Randomization. The requirements are
described in Section 15.2.


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Study No. TAK-438_115
Page 89 of 99
Protocol Incorporating Amendment No. 02
20 July 2016
CONFIDENTIAL
Revised Text
The sampling of whole blood for CYP2C19 genotyping analysis is mandatory; every subject must 
sign the informed consent in order to participate in this study. The informed consent for the 
CYP2C19 genotyping analysis is a component of the overall study informed consent.
Rationale for Amendment
The requirement for an optional blood draw (3 mL) for storage purposes for later DNA analysis 
has been removed. Therefore, there is no longer the need to obtain PGx informed consent.
Page 40, Section 9.1.8 Procedures for Clinical Laboratory Samples
Existing Text
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 106 mL, and the approximate total volume of 
blood for the study is 206 mL for safety laboratory samples. Laboratory samples will be taken 
following a minimum 8-hour overnight fast on the days stipulated in the Schedule of Study 
Procedures (Appendix A).
Revised Text
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 106 mL, and the approximate total volume of 
blood for the study is 203 mL for safety laboratory samples. Laboratory samples will be taken 
following a minimum 8-hour overnight fast on the days stipulated in the Schedule of Study 
Procedures (Appendix A).
Rationale for Amendment
The requirement for an optional blood draw (3 mL) for storage purposes for later DNA analysis 
has been removed, which has reduced the total blood draw from 206 mL to 203 mL.


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Study No. TAK-438_115
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Page 40, Table 9.a Clinical Laboratory Assessments
Existing Text
Serum Chemistry
ALT (a)
Albumin
Alkaline phosphatase
Amylase
AST
GGT
Total bilirubin (a) (b)
Direct bilirubin (a)
Uric acid
Total protein
Triglycerides
Serum creatinine
Blood urea nitrogen
Creatine kinase
Creatine kinase MB
Potassium
Sodium
Glucose
Chloride
Calcium
Magnesium
Cholesterol (HDL and LDL)
LDH (c)
Revised Text
Serum Chemistry
ALT (a)
Albumin
Alkaline phosphatase (a)
Amylase
AST
GGT
Total bilirubin (a) (b)
Direct bilirubin (a)
Uric acid
Total protein
Triglycerides (a)
Serum creatinine
Blood urea nitrogen
Creatine kinase
Creatine kinase MB
Potassium
Sodium
Glucose
Chloride
Calcium
Magnesium
Cholesterol (HDL and LDL) (a)
LDH (c)


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Study No. TAK-438_115
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CONFIDENTIAL
Rationale for Amendment
To be consistent with other protocols in the clinical development program for TAK-438, 
assessment of alkaline phosphatase, triglycerides, and cholesterol will be measured under fasting 
conditions, as denoted by the footnote (a).
Page 44, Section 9.1.12 Pharmacogenetic Sample Collection for CYP2C19 Genotyping
Existing Text
The sample of whole blood for CYP2C19 genotyping analysis is mandatory. Every subject must 
sign the informed consent in order to participate in this study.
Two whole blood samples (3 mL per sample) for DNA isolation will be collected during the 
screening period from each subject in the study, into plastic K2EDTA spray-coated tubes, and 
stored under frozen condition. A second aliquot of blood may be taken if isolation of DNA from 
the first sample was not successful or possible.
The DNA sample collected from each subject will be used for CYP2C19 genotyping analysis. 
Genetic variation into the CYP2C19 gene may lead to changes in metabolic activity of the 
CYP2C19 enzyme that may contribute to the variability in the PK/clinical efficacy of TAK-438 
and lansoprazole. CYP2C19 metabolic status information will be provided to investigators prior to 
Day -1.
Revised Text
The sample of whole blood for CYP2C19 genotyping analysis is mandatory. Every subject must 
sign the informed consent in order to participate in this study.
One whole blood sample (3 mL) for DNA isolation will be collected during the screening period 
from each subject in the study, into plastic K2EDTA spray-coated tubes, and stored under frozen 
condition. A second aliquot of blood may be taken if isolation of DNA from the first sample was 
not successful or possible.
The DNA sample collected from each subject will be used for CYP2C19 genotyping analysis. 
Genetic variation into the CYP2C19 gene may lead to changes in metabolic activity of the 
CYP2C19 enzyme that may contribute to the variability in the PK/clinical efficacy of TAK-438 
and lansoprazole. CYP2C19 metabolic status information will be confirmed with the
investigators prior to Day -1.
Rationale for Amendment
The requirement for an optional blood draw (3 mL) for storage purposes for later DNA analysis 
has been removed.


TAK-438
Study No. TAK-438_115
Page 92 of 99
Protocol Incorporating Amendment No. 02
20 July 2016
CONFIDENTIAL
Page 44, Section 9.1.13 PGx Sample Collection for Storage
Existing Text
A separate PGx informed consent form must be obtained in order to store the remaining DNA 
sample from the CYP2C19 genotyping. The provision of consent to store the sample for future 
analysis is independent of consent to the other aspects of the study and any randomized subjects 
will be provided with a separate PGx informed consent form at Randomization.
DNA forms the basis for the genes that make the body produce proteins such as enzymes, drug 
transporters or drug targets, and may be evaluated for the genetic contribution how the drug is 
broken down, or how the drug affects the body. This is called a “Pharmacogenomics research 
study.” Specific purposes of this study include:

Identifying genetic reasons why certain people respond differently to vonoprazan

Finding out more information about how vonoprazan works.

Generating information needed for research, development, and regulatory approval of tests to 
predict response to vonoprazan.

Identifying variations in genes related to the biological target of vonoprazan.
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of vonoprazan and other study medications, understanding of disease/condition being 
studied and for improving the efficiency, design and study methods of future research studies. 
Each PGx sample for a study subject should be identifiable on the requisition form with a subject 
identification number.
The samples will be stored for no longer than 15 years after completion of the study and/or until 
the drug development of TAK-438 is no longer actively pursued by Takeda or its collaborators. No 
samples will be stored for longer than permitted by the applicable law and samples will be 
destroyed upon notification from Takeda. “Stored samples” are defined as samples that are 
key-coded (the samples are stripped of all personal identifying information but a key links the 
samples to the clinical data collected from the sample donor) and are used in the analysis of 
investigational drug or related drugs.
Detailed instructions for the handling and shipping of samples are provided in Appendix E.
Rationale for Amendment
Section 9.1.13 PGx Sample Collection for Storage has been removed. The requirement for an 
optional blood draw (3 mL) for storage purposes for later DNA analysis has been removed. 
Therefore, there is no longer the need to obtain PGx informed consent.


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Study No. TAK-438_115
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Protocol Incorporating Amendment No. 02
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CONFIDENTIAL
Page 48, Section 9.3.2 Check-in (Day -1)
Existing Text

Urine pregnancy test (in female subjects of childbearing potential only).

Informed consent for long-term storage of DNA blood collection.

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 
remains confined to the phase 1 unit.
Revised Text

Urine pregnancy test (in female subjects of childbearing potential only).

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 
remains confined to the phase 1 unit.
Rationale for Amendment
The requirement for an optional blood draw (3 mL) for storage purposes for later DNA analysis 
has been removed. Therefore, there is no longer the need to obtain PGx informed consent.
Page 49, Section 9.3.6 Check-out (Day 15)
Added Text
Subjects should avoid antibiotics, PPIs, bismuth preparations until Day 42 (HP breath test)
Rationale for Amendment
Provision of advice to avoid gastrointestinal disease treatments until the final study procedure (HP 
breath test), on Day 42, as these may interact with TAK-438, affecting the breath test result.


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Study No. TAK-438_115
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CONFIDENTIAL
Page 51, Section 9.4 Blood Volume
Existing Text
Table 9.d
Approximate Blood Volume
Volume per Period (mL)
Sample Type
Sample 
Volume 
(mL)
Screening
Check-in/
Baseline
CA + Bismuth 
+ TAK-438 or 
Lansoprazole 
Dosing
CA + Bismuth + 
TAK-438 or 
Lansoprazole 
Dosing/TAK-438 
or Lansoprazole 
PK
CA + Bismuth + 
TAK-438 or 
Lansoprazole 
Dosing/ 
TAK-438 or 
Lansoprazole 
and Bismuth PK
Check-out
Total 
Volume
Days -28 to 
-2
Day -1
Day 1 to 11
Day 12-13
Day 14
Day 15
Safety laboratory 
samples
10
10
10
20
(Day 5 and 8 
only)
20
10
10
80
Pharmacokinetic 
samples: bismuth
6
-
-
-
-
84
-
84
Pharmacokinetic 
samples: 
TAK-438/lansoprazole
6
-
-
-
24
12
-
36
CYP2C19 samples
6
6
-
-
-
-
-
6
Total blood volume
206
- = not applicable.
The maximum volume of blood at any single day is approximately 106 mL, and the approximate 
total volume of blood for the study is 206 mL.
Direct venipuncture is the preferred method of blood collection; however, a catheter with a single 
saline flush may be used. 
If a catheter with a normal saline flush is used, the 206 mL total blood volume does not include 
discarded blood from predraws (assuming minimally the catheter dead volume plus 1 mL of blood 
is discarded each time a sample is collected from a catheter). Should a catheter be used, the total 
blood volume taken during the study must not exceed 206 mL.


TAK-438
Study No. TAK-438_115
Page 95 of 99
Protocol Incorporating Amendment No. 02
20 July 2016
CONFIDENTIAL
Revised Text
Table 9.d
Approximate Blood Volume
Volume per Period (mL)
Sample Type
Sample 
Volume 
(mL)
Screening
Check-in/
Baseline
CA + Bismuth 
+ TAK-438 or 
Lansoprazole 
Dosing
CA + Bismuth + 
TAK-438 or 
Lansoprazole 
Dosing/TAK-438 
or Lansoprazole 
PK
CA + Bismuth + 
TAK-438 or 
Lansoprazole 
Dosing/ 
TAK-438 or 
Lansoprazole 
and Bismuth PK
Check-out
Total 
Volume
Days -28 to 
-2
Day -1
Day 1 to 11
Day 12-13
Day 14
Day 15
Safety laboratory 
samples
10
10
10
20
(Day 5 and 8 
only)
20
10
10
80
Pharmacokinetic 
samples: bismuth
6
-
-
-
-
84
-
84
Pharmacokinetic 
samples: 
TAK-438/lansoprazole
6
-
-
-
24
12
-
36
CYP2C19 samples
3
3
-
-
-
-
-
3
Total blood volume
203
- = not applicable.
The maximum volume of blood at any single day is approximately 106 mL, and the approximate 
total volume of blood for the study is 203 mL.
Direct venipuncture is the preferred method of blood collection; however, a catheter with a single 
saline flush may be used. 
If a catheter with a normal saline flush is used, the 203 mL total blood volume does not include 
discarded blood from predraws (assuming minimally the catheter dead volume plus 1 mL of blood 
is discarded each time a sample is collected from a catheter). Should a catheter be used, the total 
blood volume taken during the study must not exceed 203 mL.
Rationale for Amendment
The requirement for an optional blood draw (3 mL) for storage purposes for later DNA analysis 
has been removed. Thus, the total blood draw volume will be 203 mL, instead of 206 mL.
Page 51, Section 9.5 Biological Sample Retention and Destruction
Existing Text
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.12. 
The genetic material will be sent to a testing laboratory to determine the CYP2C19 metabolic 
status of each subject. If subjects consent for long-term storage, the remaining PGx samples will 
be preserved and retained at
, Greenfield, IN, USA for up to but not longer 
than 15 years or as required by applicable law. The sponsor has put into place a system to protect 
PPD


TAK-438
Study No. TAK-438_115
Page 96 of 99
Protocol Incorporating Amendment No. 02
20 July 2016
CONFIDENTIAL
the subjects’ personal information to ensure optimal confidentiality and defined standard 
processes for sample and data collection, storage, analysis, and destruction.
The Sponsor and researchers working with the Sponsor will have access to the samples collected 
and any test results. All samples collected during the study will be stored securely with limited 
access and the Sponsor will require anyone who works with the samples to agree to hold the 
research information and any results in confidence.
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical 
test results collected in the study. The sample and data are linked to personal health information 
with code numbers; the samples are stripped of all personal identifying information but a key 
linking the samples to clinical analysis data exists. This link means that the subject may be 
identified but only indirectly. The code numbers will be kept secure by or on behalf of the Sponsor.
Subjects who consented and provided a PGx sample for DNA analysis can withdraw their consent 
and request disposal of a stored sample at any time prior to analysis. Notify sponsor of consent 
withdrawal.
Revised Text
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.12. 
The genetic material will be sent to a testing laboratory to determine the CYP2C19 metabolic 
status of each subject. Any remaining sample after 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.
Rationale for Amendment
The requirement for an optional blood draw (3 mL) for storage purposes for later DNA analysis 
has been removed. Thus, the need for storage and retention no longer applies. After DNA analysis 
for CYP2C19 genotyping, any remaining sample will be destroyed.
Page 54, Section 10.1.4 SAEs
Existing Text
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


TAK-438
Study No. TAK-438_115
Page 97 of 99
Protocol Incorporating Amendment No. 02
20 July 2016
CONFIDENTIAL
Revised Text
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).
Rationale for Amendment
The wording for ‘congenital anomaly/birth defect’ has been amended to be in line with the 
definition in ICH E2A.
Page 55, Section 10.1.6 Causality of AEs
Existing Text
The relationship of each AE to each study medication(s) will be assessed using the following 
categories:
Revised Text
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Rationale for Amendment
To provide clarity.


TAK-438
Study No. TAK-438_115
Page 98 of 99
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CONFIDENTIAL
Page 73, Appendix A Schedule of Study Procedures
Existing Text
Study Phase
Screening
Check-in 
Baseline
Quadruple 
Therapy Dosing 
(Group A or B)
Quadruple 
Therapy 
Dosing/ 
TAK-438 PK 
or Lanso PK
Quadruple 
Therapy 
Dosing 
/Bismuth PK 
and TAK-438 
PK or Lanso 
PK
Check-out/Early 
termination (i)
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) (j)
Day 42 
(k)
Confinement
X
X
X
X
X
X
Informed consent
X
PGx Informed consent
X
Inclusion/exclusion 
criteria assessment
X
X
(l) Mandatory collection of 2 whole blood samples (3 mL each) for DNA CYP2C19 genotyping will be taken during Screening. 
Long-term storage for the remaining sample after testing is optional.
Revised Text
Study Phase
Screening
Check-in 
Baseline
Quadruple 
Therapy Dosing 
(Group A or B)
Quadruple 
Therapy 
Dosing/ 
TAK-438 PK 
or Lanso PK
Quadruple 
Therapy 
Dosing 
/Bismuth PK 
and TAK-438 
PK or Lanso 
PK
Check-out/Early 
termination (i)
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) (j)
Day 42
(+6 
days) 
(k)
Confinement
X
X
X
X
X
X
Informed consent
X
Inclusion/exclusion 
criteria assessment
X
X
(l) Mandatory collection of 1 whole blood sample (3 mL) for DNA CYP2C19 genotyping will be taken during Screening.
Rationale for Amendment
The requirement for an optional blood draw (3 mL) for storage purposes for later DNA analysis 
has been removed. Therefore, there is no longer the need to obtain PGx informed consent.
Page 83, Appendix E Collection, Storage, and Shipment of Bioanalytical Samples
Existing Text
Collection, Shipment, and Storage of PGx Samples 
Sample Collection
1. Mandatory Collection for CYP2C19 Genotyping


TAK-438
Study No. TAK-438_115
Page 99 of 99
Protocol Incorporating Amendment No. 02
20 July 2016
CONFIDENTIAL
Two 3 mL whole blood samples for DNA isolation and genotyping will be collected from each 
subject during the screening period, into a plastic tube spray coated with K2EDTA. Note 
long-term storage of the sample is optional.
Sample Shipment
1. DNA PGx samples will be shipped frozen at -20°C after collection.
2. Ship samples only on Monday, Tuesday, or Wednesday, and at least 2 days prior to a national 
holiday, to minimize the possibility of samples in transit over a weekend or holiday.
3. The laboratory must confirm arrival of the shipped samples. Storage at the site prior to shipping 
must be at -20°C or colder.
4. For instructions on shipping, both ambient and refrigerated, and packing follow the laboratory 
manual and shipping instructions provided by the central laboratory.
5. Before shipping, ensure the sample tubes are tightly sealed. Ship samples to the Central 
Laboratory Services. Shipping information can be found in the PGx laboratory manual.
Sample Storage
The central laboratory will initially store the DNA samples in a secure storage space with 
adequate measures to protect confidentiality. The samples that have consent for storage and future 
use will be retained at 
 for up to but not longer than 15 years or as required 
by applicable law.
Revised Text
Collection of PGx Samples 
Sample Collection
1. Mandatory Collection for CYP2C19 Genotyping:
One 3 mL whole blood sample for DNA isolation and CYP2C19 genotyping will be collected 
from each subject during the screening period, into a plastic tube spray coated with K2EDTA.
Rationale for Amendment
The requirement for an optional blood draw (3 mL) for storage purposes for later DNA analysis 
has been removed. Thus, the need for shipment, storage and retention no longer applies. After 
DNA analysis for CYP2C19 genotyping, any remaining sample will be destroyed.
PPD

SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Double-Blind, Parallel Group Study to Evaluate the Safety and 
Pharmacokinetics of Quadruple Therapy (Bismuth, Clarithromycin, and Amoxicillin) With 
TAK-438 Versus Quadruple Therapy With Lansoprazole.
NCT Number: NCT02892409
SAP Approve Date: 15MAY2017
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.


CROSS-REGIONAL TEMPLATE
Template Number:
C-TMPL-DO-801
Page:
1 of 31
Version Number:
1.2
Effective Date:
14 Sep 2015
This version replaces:
1.1
Parent Document:
C-SOP-DO-800
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Printed or downloaded documents must be verified against the effective version.
CONFIDENTIAL INFORMATION
Do not distribute outside of Takeda without a confidentiality agreement.
TAKEDA DEVELOPMENT CENTER
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-438_115
A Phase 1, Double-Blind, Parallel Group Study to Evaluate the Safety and
Pharmacokinetics of Quadruple Therapy (Bismuth, Clarithromycin, and Amoxicillin) With
TAK-438 Versus Quadruple Therapy With Lansoprazole.
PHASE 1
Version: 2.0
Date: 15MAY2017
Prepared by:
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


CROSS-REGIONAL TEMPLATE
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Page:
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Version Number:
1.2
Effective Date:
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This version replaces:
1.1
Parent Document:
C-SOP-DO-800
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Printed or downloaded documents must be verified against the effective version.
CONFIDENTIAL INFORMATION
Do not distribute outside of Takeda without a confidentiality agreement.
1.0
APPROVAL SIGNATURES
Electronic signatures can be found on the last page of this document.
Study Title:
A Phase 1, Double-Blind, Parallel Group Study to Evaluate the Safety and
Pharmacokinetics of Quadruple Therapy (Bismuth, Clarithromycin, and 
Amoxicillin) With TAK-438 Versus Quadruple Therapy With 
Lansoprazole.
TDC Approvals:
Date
Date
Date
Date
Date
PPD
PPD
PPD
PPD
PPD


CROSS-REGIONAL TEMPLATE
Template Number:
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Page:
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Version Number:
1.2
Effective Date:
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Parent Document:
C-SOP-DO-800
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Printed or downloaded documents must be verified against the effective version.
CONFIDENTIAL INFORMATION
Do not distribute outside of Takeda without a confidentiality agreement.
2.0
TABLE OF CONTENTS
1.0
APPROVAL SIGNATURES........................................................................................................2
2.0
TABLE OF CONTENTS..............................................................................................................3
3.0
LIST OF ABBREVIATIONS........................................................................................................5
4.0
OBJECTIVES.............................................................................................................................7
4.1.
PRIMARY OBJECTIVES.................................................................................................7
4.2.
SECONDARY OBJECTIVES............................................................................................7
4.3.
ADDITIONAL OBJECTIVES.............................................................................................7
4.4.
STUDY DESIGN ..........................................................................................................7
5.0
ANALYSIS ENDPOINTS ............................................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE ......................................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION................................................................... 11
7.1
GENERAL PRINCIPLES...............................................................................................11
7.1.1
Definitions..............................................................................................................11
7.1.2
Handling of Plasma Bismuth Concentrations at Day 14...........................................11
7.1.3
Handling of Plasma TAK-438F/ Lansoprazole Concentrations ................................13
7.1.4
Handling of Laboratory Test ...................................................................................13
7.1.5
Handling of Vital Signs ...........................................................................................14
7.1.6
Handling of 12-Lead ECGs.....................................................................................14
7.1.7
Handling of HP Breath Test....................................................................................15
7.2
ANALYSIS SETS........................................................................................................15
7.3
DISPOSITION OF SUBJECTS........................................................................................16
7.3.1
Study Information................................................................................................... 16
7.3.2
Screen Failures...................................................................................................... 16
7.3.3
Subject Eligibility .................................................................................................... 16
7.3.4
Disposition of Subjects...........................................................................................17
7.3.5
Protocol Deviations and Analysis Sets.................................................................... 17
Protocol Deviations............................................................................................................17
Analysis Sets.....................................................................................................................18
7.4
DEMOGRAPHIC AND BASELINE CHARACTERISTICS........................................................18
7.5
MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS........................................19
7.6
MEDICATION HISTORY AND CONCOMITANT MEDICATIONS .............................................19


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7.7
STUDY DRUG EXPOSURE AND COMPLIANCE ................................................................19
TAK-438/ Lansoprazole and Bismuth Exposure and Compliance .......................................19
Clarithromycin and Amoxicillin Exposure and Compliance..................................................19
7.8
EFFICACY ANALYSIS ................................................................................................. 20
7.9
PHARMACOKINETIC ANALYSIS ....................................................................................20
Plasma Bismuth Concentration ..........................................................................................20
Plasma TAK-438F/ Lansoprazole Concentration ................................................................20
Plasma PK Parameters of Bismuth ....................................................................................21
Urine PK parameters of Bismuth........................................................................................21
7.10
OTHER OUTCOMES................................................................................................... 21
HP Breath Test ..................................................................................................................21
7.11
SAFETY ANALYSIS .................................................................................................... 22
7.11.1 Adverse Events...................................................................................................... 22
7.11.1.1
Overview of Treatment-Emergent Adverse Events............................................22
7.11.1.2
Displays of Treatment-Emergent Adverse Events .............................................23
7.11.1.3
Displays of Pretreatment Events.......................................................................24
7.11.2 Clinical Laboratory Evaluations...............................................................................24
Hematology and Serum Chemistry.....................................................................................24
Urinalysis...........................................................................................................................25
7.11.3 Vital Signs..............................................................................................................26
7.11.4 12-Lead ECGs .......................................................................................................26
7.11.5 Other Observations Related to Safety..................................................................... 27
7.12
INTERIM ANALYSIS.................................................................................................... 27
7.13
CHANGES IN THE STATISTICAL ANALYSIS PLAN ............................................................27
8.0
REFERENCES .........................................................................................................................28
9.0
APPENDIX ...............................................................................................................................29
9.1
CRITERIA FOR MARKEDLY ABNORMAL VALUES.............................................................29
9.1.1
Hematology, Serum Chemistry, Vital Signs, and 12-lead ECG (except Upper MAV 
Criteria of QTcF Interval) .......................................................................................29
9.1.2
12-lead ECG (Upper MAV Criteria of QTcF Interval)...............................................30


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3.0
LIST OF 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
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AST
aspartate aminotransferase
BID 
twice daily
BMI
body mass index
CAL
clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and lansoprazole (30 mg 
BID)
CAT
clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and TAK-438 (20 mg 
BID)
CL/F
apparent clearance after extravascular administration, calculated using the observed 
value of the last quantifiable concentration
CLR
renal clearance
Cmax
maximum observed plasma concentration
CRF
case report form
CV
coefficient of variation
CYP
cytochrome P450
ECG
electrocardiogram
fe,τ
Fraction of administered dose of drug excreted in urine during a dosing interval. 
Molecular weight adjustment needed for metabolites.
GGT
-glutamyl transferase
HP
Helicobacter pylori
LDH
lactate dehydrogenase
LLN
lower limit of normal
λz
terminal disposition phase rate constant
MAV
markedly abnormal values
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PK
pharmacokinetics
PTE
pretreatment event
QTcF
QT interval corrected by Fridericia's method
SAP
statistical analysis plan
TAK-438F
freebase of TAK-438
TEAE
treatment-emergent adverse event
t1/2z
terminal disposition phase half-life


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tmax
time of first occurrence of Cmax
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal disposition phase after 
extravascular administration, calculated using the observed value of the last 
quantifiable concentration
WHO Drug
World Health Organization Drug Dictionary


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4.0
OBJECTIVES
4.1.
PRIMARY OBJECTIVES
The primary objective is to evaluate the safety, tolerability, and PK of quadruple therapy BID with tripotassium
bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and TAK-438 (20 mg) versus 
quadruple therapy BID with tripotassium bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 
mg), and lansoprazole (30 mg).
4.2.
SECONDARY OBJECTIVES
Not applicable
4.3.
ADDITIONAL OBJECTIVES
Not applicable
4.4.
STUDY DESIGN
This is a phase 1, double-blind, parallel group study in HP positive subjects to evaluate the safety, tolerability, and 
PK of quadruple therapy with bismuth, clarithromycin, amoxicillin, and TAK-438 versus quadruple therapy with 
bismuth, clarithromycin, amoxicillin, and lansoprazole.
Thirty HP positive male or female subjects aged 19 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 as indicated in Figure 1. One site in Asia will be selected to conduct this study.
The treatment phase consists of quadruple therapy BID with tripotassium bismuth dicitrate (600 mg), clarithromycin 
(500 mg), amoxicillin (1000 mg), and TAK-438 (20 mg) or quadruple therapy BID with tripotassium bismuth 
dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and lansoprazole (30 mg) for 14 days (Days 1 
to 14). Subjects will be discharged on Day 15 after final PK blood samples are collected and all procedures 
performed.
Screening for potential subjects will occur between Days -28 and -2 prior to confinement at the phase 1 unit. 
Eligibility will be reconfirmed on Day -1. Having fasted for a minimum of 8 hours, oral doses of tripotassium 
bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and TAK-438 (20 mg) or tripotassium 
bismuth dicitrate (600 mg), clarithromycin (500 mg), amoxicillin (1000 mg), and lansoprazole (30 mg) will be 
administered BID from Days 1 to 14. The last dose will be on the evening of Day 14. Blood sampling for TAK-438 
and lansoprazole PK measurements will be taken on Days 12 to 14 (predose evening and morning) and for bismuth 
PK measurements on Day 14 (pre–morning dose to 12 hours post–morning dose). Urine sampling for bismuth PK 
measurements will be taken on Day 14 (pre–morning dose to 12 hours post–morning dose). The subject will be 
confined to the phase 1 unit from Day -1 (Check-in) through to Day 15 (Check-out), and will be required to contact 
the study site once again for a follow-up call on Day 17 and a clinic visit on Day 42 for a HP breath test.
A schematic of the study design is included as Figure 1.
Figure 1. Schematic of Study Design


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Bismuth: tripotassium bismuth dicitrate (600 mg BID, equivalent to bismuth 220 mg BID); CA: clarithromycin (500 
mg BID), amoxicillin (1000 mg BID); TAK-438: 20 mg BID; lansoprazole: 30 mg BID.
Blood PK samples for Bismuth: 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 morning dose.
Urine PK samples for Bismuth: Day 14 at 0 to 12 hours post–morning dose.
Blood PK samples for TAK-438 and lansoprazole: Day 12-14 predose (morning and evening) 
Analyte: bismuth, TAK-438F, and lansoprazole.
Comparison of Group A and Group B: Cmax and AUCτ.


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5.0
ANALYSIS ENDPOINTS
・
Percentage of subjects who experience at least 1 treatment-emergent adverse event (TEAE).
・
Percentage of subjects who discontinue due to an adverse event (AE).
・
Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at least 
once postdose.
・
Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at least 
once postdose.
・
Percentage of subjects who meet the markedly abnormal criteria for safety electrocardiogram (ECG) 
parameters at least once postdose.
・
Plasma PK parameters of tripotassium bismuth dicitrate (600 mg) when coadministered with
clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and TAK-438 (20 mg BID) (CAT), and 
coadministered with clarithromycin (500 mg BID), amoxicillin (1000 mg BID), and lansoprazole (30 
mg BID) (CAL):
–
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.


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6.0
DETERMINATION OF SAMPLE SIZE
A sample size of 30 (15 subjects per group) will be used in this exploratory study. Although this planned sample size 
is not primarily based on statistical considerations, it will allow precise estimation of the relative treatment effect of 
TAK-438 versus lansoprazole on bismuth exposure as follows:
These calculations allow for up to 2 dropouts per group and are based on estimates of CV of 0.40 to 0.60 for PK 
parameters (area under the plasma concentration-time curve from time 0 to infinity [AUC∞] and Cmax)


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
GENERAL PRINCIPLES 
7.1.1
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.
- Descriptive statistics: number of subjects, mean, standard deviation, maximum, minimum, and quartiles
- 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, e.g., the 
day prior to Study Day 1 is Day -1 and the day after Study Day 1 is Day 2.
- 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/ lansoprazole and bismuth or 2)clarithromycin and amoxicillin.
- QTcF interval (msec): QT interval (msec) / (RR interval (msec)/1000)0.33 (rounded to the nearest whole 
number)
-
Baseline and Screening values: The last evaluable observation (i.e., 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.  
7.1.2
Handling of Plasma Bismuth Concentrations at Day 14
For each time, all evaluable observation (i.e., 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.
Time
Scheduled Time
From Morning Dose* at Day 14
(min) 
Time Interval
(min)
Sampling Time
From Morning Dose* at Day 14
Pre–morning dose (0 
hours)
0
-10 – 0 
0.25 hours 
post–morning dose
15
10 - 20


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* Start Time of Bismuth, TAK-438, Lansoprazole at morning   
Concentrations below the lower limit of quantification will be treated as zero in the analysis of concentration-time 
data.
0.5 hours 
post–morning dose
30
25 - 35
0.75 hours 
post–morning dose
45
40 - 50
1.0 hour
post–morning dose
60
55 - 65
1.5 hours 
post–morning dose
90
85 - 95
2.0 hours 
post–morning dose
120
115 - 125
3.0 hours 
post–morning dose
180
175 - 185
4.0 hours 
post–morning dose
240
235 - 245
5.0 hours 
post–morning dose
300
295 - 305
6.0 hours 
post–morning dose
360
355 - 365
8.0 hours 
post–morning dose
480
470 - 490
10.0 hours 
post–morning dose
600
590 - 610
12.0 hours 
post–morning dose
720
710 - 730


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7.1.3
Handling of Plasma TAK-438F/ Lansoprazole Concentrations
For each visit, all evaluable observation (i.e., 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 time to the 
scheduled time will be used. If there are two observations equidistant to the scheduled time, the later observation 
will be used.
Visit
Time
Scheduled Time
From Dose*
(min) 
Time Interval
(min)
Sampling Time
From Dose*
Day 12
Pre-morning dose
Morning
0
-10 – 0 
Day 12
Pre-evening dose
Evening
0
-10 – 0 
Day 13
Pre-morning dose
Morning
0
-10 – 0 
Day 13
Pre-evening dose
Evening
0
-10 – 0 
Day 14
Pre-morning dose
Morning
0
-10 – 0 
Day 14
Pre-evening dose
Evening
0
-10 – 0 
* Start Time of Bismuth, TAK-438, Lansoprazole
Concentrations below the lower quantifiable concentration will be treated as zero in the analysis of concentration-
time data.
7.1.4
Handling of Laboratory Test
For each visit, all evaluable observation (i.e., 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.
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


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Visit
Scheduled Study Day
(days) 
Time Interval (days)
Study Day
Day 15
Study Day: 15
15
Values below the lower limit of quantification will be handled as zero.
7.1.5
Handling of Vital Signs
For each visit, all evaluable observation (i.e., 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 time to the 
scheduled time will be used. If there are two observations equidistant to the scheduled time, the later observation 
will be used.
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 1
Pre–evening 
dose
Study Day: 1
Evening
0
Time: -60 – 0
Day 2 to 14
Pre-morning 
dose
Study Day: 2 to 14
Morning
0
Time: -60 – 0
Pre-evening 
dose
Study Day: 2 to 14
Evening
0
Time: -60 – 0
Day 15
Study Day: 15
Study Day: 
Post-dose – 15
* Start Time of Bismuth, TAK-438, Lansoprazole
7.1.6
Handling of 12-Lead ECGs
For each visit, all evaluable observation (i.e., 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 time to the 
scheduled time will be used. If there are two observations equidistant to the scheduled time, the later observation 
will be used.
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


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Visit
Time
Scheduled Study Day
(days)
Scheduled Time
From Dose*
(min) 
Time Interval (min)
/ Study Day (days)
Assessment Time
From Dose*
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, Lansoprazole
7.1.7
Handling of HP Breath Test
For each visit, all evaluable observation (i.e., 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.
Visit
Scheduled Study Day
(days) 
Time Interval (days)
Study Day
Screening
-2
-28 – -2
Day 42
42
Post-dose – 48
7.2 ANALYSIS SETS
The safety analysis set used for primary analysis will consist of subjects who received at least 1 dose of the study 
drug.


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The PK analysis set will consist of subjects who received the study drug, who have sufficient plasma/urine 
concentration data to calculate at least 1 pharmacokinetic parameter, and completed the minimum protocol specified 
procedures with no significant protocol deviations listed below:
- Subjects who did not meet inclusion criteria #3, #4 or #5
- Subjects who met exclusion criteria #1, #4, #6, #7, #8, #10, #11, #13, #14, #15, #16, #17, #21, or #22
- Subjects who have violated the rules specified in section 7.3 (excluded medications and dietary products) of the 
protocol up to end of Day 14
- Subjects with study medication compliance of less than 100%  
7.3 DISPOSITION OF SUBJECTS
7.3.1
Study Information
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables:
Date First Subject Signed Informed Consent Form
Date of Last Subject’s Last Visit/Contact
MedDRA Version
WHO Drug Version
SAS Version Used for Creating the Datasets
Analytical Methods:
(1) Study Information
Study information shown in the analysis variables section will be provided.
7.3.2
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]
Analytical Methods:
(1) Screen Failures
Frequency distributions for categorical variables and descriptive statistics for continuous 
variables will be provided.
7.3.3
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, 
Significant Protocol Deviation, 
Lost to Follow-Up, 
Voluntary Withdrawal, 


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Study Termination, 
Did Not Meet Entrance Criteria, 
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.
7.3.4
Disposition of Subjects
Analysis Set:
Randomized Set
Analysis Variables:
Study Drug Administration Status
[No]
Reason for Not Being Treated
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation,
Lost to Follow-Up, 
Voluntary Withdrawal, Study Termination, 
Pregnancy, Other]
Study Drug Completion Status
[Completed Study Drug, 
Prematurely Discontinued Study Drug]
Reason for Discontinuation of Study Drug
[Pretreatment Event/Adverse Event, 
Significant Protocol Deviation,
Lost to Follow-Up, 
Voluntary Withdrawal, Study Termination, 
Pregnancy, 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.
7.3.5
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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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.
7.4 DEMOGRAPHIC AND BASELINE CHARACTERISTICS
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
[The Subject Has Never Smoked, 
The Subject Is a Current Smoker, 
The Subject Is an Ex-smoker]
Consumption of Alcohol
[Drink Every day, 
Drink a Couple of Days Per Week,
Drink a Couple of Days Per Month, 
Never Drink]
Consumption of Caffeine
[Yes, No]
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.


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7.5 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 19.0 or higher) coding system.
There will be no analysis of medical history and concurrent medical conditions.
7.6 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 2016Q1 or higher.
There will be no analysis of medication history and concomitant medications.
7.7 STUDY DRUG EXPOSURE AND COMPLIANCE
TAK-438/ Lansoprazole 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.


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7.8 EFFICACY ANALYSIS
Not applicable. 
7.9 PHARMACOKINETIC ANALYSIS
Plasma Bismuth Concentration
Analysis Set:
PK Analysis Set
Analysis Variable:
Plasma Bismuth Concentrations
Time Point:
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 during Day 14
Analytical Methods:
Following analysis will be provided by treatment group.
(1) Summary of Plasma Concentrations by Time Point
Descriptive statistics for observed values will be provided for each time point. In 
addition, geometric mean, and %CV will be provided
(2) Concentration-time Profiles of Bismuth for Individual Subjects
Observed values will be plotted using individual case plot.
(3) Mean Concentration-time Profiles with Standard Deviations
Mean of plasma concentration  will be plotted by time point using linear scale and 
natural log scale.
Plasma TAK-438F/ Lansoprazole Concentration
Analysis Set:
PK Analysis Set
Analysis Variable:
Plasma TAK-438F Concentrations
Plasma Lansoprazole Concentrations
Visit and Time Point: Day 12 Pre–morning dose, Day 12 Pre–evening dose, Day 13 Pre–morning dose, Day 13
Pre–evening dose, Day 14 Pre–morning dose and Day 14 Pre–evening dose
Analytical Methods:
(1) Summary of Plasma Concentrations by Time Point
Descriptive statistics for observed values will be provided for each visit and time point.
In addition, geometric mean, and %CV will be provided.


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Plasma PK Parameters of Bismuth
Analysis Set:
PK Analysis Set
Analysis Variable:
Plasma PK Parameters of Bismuth
Cmax
AUCτ
CL/F
λz
t1/2z
tmax
Vz/F
Visit
Day 14
Analytical Methods:
For all variables, Summary (1) will be provided by treatment group.
For Cmax and AUCτ, Summary (2) will be provided.
(1) Summary of Plasma PK Parameters
Descriptive statistics for PK parameters will be provided. In addition, geometric mean 
and %CV will be computed for Cmax and AUCτ.
(2) Analysis of Variance with Natural log-transformed AUCτ and Cmax
Two-sided confidence intervals (90% and 95% confidence level) of the ratio between
administration conditions (bismuth with CAL and bismuth with CAT) will be calculated 
using an analysis of variance with natural log-transformed AUCτ and Cmax of bismuth. 
Urine PK parameters of Bismuth
Analysis Set:
PK Analysis Set
Analysis Variable:
Urine PK parameters of Bismuth
Aeτ
fe, τ
CLR
Visit
Day 14
Analytical Methods:
(1) Summary of Urine PK Parameters
Descriptive statistics for PK parameters will be provided.
7.10
OTHER OUTCOMES
HP Breath Test
Analysis Set:
Safety Analysis Set
Analysis Variable:
HP Breath Test
Visit
Screening and Day 42
Analytical Methods:
(1) Summary of HP Breath Test
Frequency distributions will be provided by treatment group and overall.


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7.11
SAFETY ANALYSIS
7.11.1
Adverse Events
7.11.1.1
Overview of Treatment-Emergent Adverse Events
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Relationship to Study Drug
Relationship to TAK-438/
Lansoprazole
[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 (number of events, 
number and percentage of subjects) 
3) Intensity of Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects) 
4) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation (number 
of events, number and percentage of subjects) 
5) Serious Treatment-Emergent Adverse Events (number of events, number and percentage 
of subjects) 
6) Relationship of Serious Treatment-Emergent Adverse Events to Study Drug (number of 
events, number and percentage of subjects) 
7) Serious Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
(number of events, number and percentage of subjects) 
8) Treatment-Emergent Adverse Events Resulting in Death (number of events, number and 
percentage of subjects) 
9) Significant Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)
10) Relationship of Significant Treatment-Emergent Adverse Events to Study Drug
(number of events, number and percentage of subjects)
TEAEs will be counted according to the rules below.
Number of subjects
・
Summaries for 2), 6) and 10)
A subject with occurrences of TEAE in both categories (i.e., Related and Not Related) 
will be counted once in the Related category.
・
Summary for 3)


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A subject with multiple occurrences of TEAE will be counted once for the TEAE with 
the maximum intensity.
・
Summaries other than 2),  3), 6) and 10)
A subject with multiple occurrences of TEAE will be counted only once.
Number of events
For each summary, the total number of events will be calculated.
7.11.1.2
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/ Lansoprazole, 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
(5) Intensity of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class, and Preferred Term
(7) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term
(8) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term
(9) Significant Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
(10) Drug-Related Significant Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term
The frequency distribution will be provided according to the rules below.
Number of subjects


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・
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.
7.11.1.3
Displays of Pretreatment Events
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables: PTE
Analytical Methods: The following summaries will be provided using frequency distribution.
PTEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC will 
be sorted alphabetically and PT will be sorted in decreasing frequency.
(1) Pretreatment Events by System Organ Class and Preferred Term
(2) Serious Pretreatment Events by System Organ Class and Preferred Term
The frequency distribution will be provided according to the rules below.
Number of subjects
A subject with multiple occurrences of PTE within a SOC will be counted only once in that 
SOC. A subject with multiple occurrences of PTE within a PT will be counted only once in 
that PT.
7.11.2
Clinical Laboratory Evaluations
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 ( ×109/L)
Serum Chemistry
ALT (U/L)
Alkaline phosphatase (U/L)
AST (U/L)
GGT (U/L)
Total Bilirubin (μmol/L)
LDH (U/L)
Creatine kinase (U/L)
Creatine kinase MB (μg/L)
Albumin (g/L)


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Total Protein (g/L)
Serum creatinine (umol/L)
Blood urea nitrogen (mmol/L)
Uric Acid (mmol/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)
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.
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


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Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided.
7.11.3
Vital Signs
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 1at Pre–evening dose, Day 2 to 14 at Pre–morning dose, Day 2 to 14 Pre–
evening dose, , Day 15
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.
7.11.4
12-Lead ECGs
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"]
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.


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(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.
7.11.5
Other Observations Related to Safety
Not applicable
7.12 INTERIM ANALYSIS
Not applicable
7.13 CHANGES IN THE STATISTICAL ANALYSIS PLAN 
Time intervals in 7.1.5 and 7.1.6 were modified from SAP version 1.0 to include all records for pre-
morning dose, pre-evening dose, and Day 15 as well as to correct misspecification for post-morning dose.


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8.0
REFERENCES
Not applicable


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9.0
APPENDIX
9.1CRITERIA FOR MARKEDLY ABNORMAL VALUES
9.1.1
Hematology, Serum Chemistry, Vital Signs, and 12-lead ECG (except Upper 
MAV Criteria of QTcF Interval)
For each parameter, all evaluable data (i.e., 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
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
-


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Parameter
MAV Criteria
Lower Criteria
Upper Criteria
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
Vital Signs
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Body Temperature (°C)
<35.6
>37.7
Systolic Blood Pressure (mmHg)
<85
>180
Diastolic Blood Pressure (mmHg)
<50
>110
Pulse (bpm)
<50
>120
12-lead ECG
Parameter
MAV Criteria
Lower Criteria
Upper Criteria
Heart Rate (bpm)
<50
>120
QT Interval (msec)
<=50
>=460
QTcF Interval (msec)
<=50
-
9.1.2
12-lead ECG (Upper MAV Criteria of QTcF Interval)
All evaluable data (i.e., 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.


CROSS-REGIONAL TEMPLATE
Template Number:
C-TMPL-DO-801
Page:
31 of 31
Version Number:
1.2
Effective Date:
14 Sep 2015
This version replaces:
1.1
Parent Document:
C-SOP-DO-800
Template Title:
Statistical Analysis Plan (Legacy Takeda)
Printed or downloaded documents must be verified against the effective version.
CONFIDENTIAL INFORMATION
Do not distribute outside of Takeda without a confidentiality agreement.
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


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