Conditions: Helicobacter Pylori Infection
Keywords: Vonoprazan Lansoprazole
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1046
Healthy volunteers: no

Brief summary:
To compare the efficacy of Helicobacter pylori (HP) eradication with vonoprazan dual and triple therapy regimens versus lansoprazole triple therapy regimen in participants with HP infection, excluding participants who had a clarithromycin or amoxicillin resistant strain of HP at baseline.

Detailed description:

Arms:
arm 1: Participants will receive vonoprazan 20 mg twice daily (BID) in conjunction with amoxicillin 1 g, three times daily, for 14 days. arm 2: Participants will receive vonoprazan 20 mg twice daily (BID) in conjunction with amoxicillin 1 g BID and clarithromycin 500 mg, BID, for 14 days. arm 3: Participants will receive lansoprazole 30 mg twice daily (BID) in conjunction with amoxicillin 1 g BID and clarithromycin 500 mg BID, for 14 days.

Interventions: intervention 1: Vonoprazan intervention 2: Amoxicillin intervention 3: Clarithromycin intervention 4: Lansoprazole
Intervention descriptions: intervention 1: Over-encapsulated tablets administered orally. intervention 2: Capsules administered orally. intervention 3: Tablets administered orally. intervention 4: Over-encapsulated capsules administered orally.

Protocol document:
Prot_000.pdf: 
Protocol Number:  HP-301 
 
Official Title:  A Phase 3 Randomized Multicenter Study to Evaluate the Efficacy and 
Safety of Open-Label Dual Therapy with Oral Vonoprazan 20 mg or 
Double-Blind Triple Therapy with Oral Vonoprazan 20 mg Compared to 
Double-Blind Triple Therapy with Oral Lansoprazole 30 mg Daily in 
Patients with Helicobacter Pylori Infection  
 
NCT Number: NCT04167670 
 
Document Date:  11-May-2020 


CLINICAL STUDY PROTOCOL 
IND#143190/EUDRACT: 2019-002668-28 
A Phase 3 Randomized Multicenter Study to Evaluate the Efficacy and 
Safety of Open-Label Dual Therapy with Oral Vonoprazan 20 mg or 
Double-Blind Triple Therapy with Oral Vonoprazan 20 mg Compared to 
Double-Blind Triple Therapy with Oral Lansoprazole 30 mg Daily in 
Patients with Helicobacter Pylori Infection 
PROTOCOL NO.: HP-301 
Sponsor: 
Phathom Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, CA  94025 
Sponsor Contact: 
 
 
 
Medical Monitor: 
 
 
 
 
Version of Protocol:  
Version 3.0, Protocol Amendment 2 
Date of Protocol:  
11 May 2020 
Previous Date and Version: 
05 Nov 2019, Version 2.0 (Amendment 1) 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Phathom 
Pharmaceuticals, Inc. The concepts and information contained in this document or generated 
during the study are considered proprietary and may not be disclosed in whole or in part 
without the expressed, written consent of Phathom Pharmaceuticals, Inc. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6 R2: Good Clinical Practice.  
Page 1


Phathom Pharmaceuticals, Inc 
vonoprazan 
Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
Page 2
Protocol Approval – Sponsor Signatory 
Study Title 
A Phase 3 Randomized Multicenter Study to Evaluate the Efficacy 
and Safety of Open-Label Dual Therapy with Oral Vonoprazan 20 mg 
or Double-Blind Triple Therapy with Oral Vonoprazan 20 mg 
Compared to Double-Blind Triple Therapy with Oral Lansoprazole 
30 mg Daily in Patients with Helicobacter Pylori Infection 
Protocol Number HP-301 
Protocol Date 
11 May 2020 
Protocol accepted and approved by: 
Chief Operating Officer 






Phathom Pharmaceuticals, Inc 
vonoprazan 
Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
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Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 3 Randomized 
Multicenter Study to Evaluate the Efficacy and Safety of Open-Label Dual Therapy with 
Oral Vonoprazan 20 mg or Double-Blind Triple Therapy with Oral Vonoprazan 20 mg 
Compared to Double-Blind Triple Therapy with Oral Lansoprazole 30 mg Daily in Patients 
with Helicobacter Pylori Infection” and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 3.0, Protocol Amendment 2, dated 11 May 2020, 
the International Council for Harmonisation harmonised tripartite guideline E6 R2: Good 
Clinical Practice and all applicable government regulations. I will not make changes to the 
protocol before consulting with Phathom Pharmaceuticals, Inc. or implement protocol 
changes without Institutional Review Boards/Independent Ethics Committee approval except 
to eliminate an immediate risk to subjects. I agree to administer study drug only to subjects 
under my personal supervision or the supervision of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Phathom Pharmaceuticals, Inc. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 


Phathom Pharmaceuticals, Inc 
vonoprazan 
Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
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Summary of Changes 
Protocol Amendment History and Reasons for Amendment 
Version 
Date 
Reasons for Amendment 
Version 1.0 
19 Aug 2019 
Original Protocol 
Version 2.0 
(Protocol 
Amendment 1) 
05 Nov 2019 
•
To change the primary objective and primary
endpoint to exclude subjects who have a
clarithromycin or amoxicillin resistant strain
of Helicobacter pylori at baseline
•
To make CYP2C19 genotyping optional
•
To remove wording allowing a subject’s
legally acceptable representative as a party
capable of giving consent for the study
•
To clarify that contraception must be double
barrier and that adequate double barrier
contraception must be used from the signing
of informed consent until Day -2 and 2 forms
of adequate contraception must be used from
Day -1 until 4 weeks after the last dose of
study drug
•
To allow rescreening of subjects with
approval from the Medical Monitor
•
To clarify that subjects who discontinue study
drug or withdraw from the study prematurely
will undergo early termination assessments
•
To redefine noncompliance as taking either
less than 75% or more than 120% of study
drug during any evaluation period
•
To exclude the use of CYP3A4 substrates
with a narrow therapeutic index from 14 days
prior to Day 1 through the End of treatment
visit
•
To update the resistance breakpoint for
amoxicillin to > 0.125 µg/mL from
> 0.03 µg/mL
•
To add overall study stopping criteria in
Section 6.2.1.15


Phathom Pharmaceuticals, Inc 
vonoprazan 
Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 7 
 
Version 
Date 
Reasons for Amendment 
• To remove the requirement for at least one 
dose of study drug to be taken as a condition 
for inclusion in the modified intent-to-treat 
analysis set 
• To add smoking status and alcohol use in the 
Schedule of Events and to include smoking 
status, alcohol use, and clinical condition as 
variables for subgroup analyses 
• To redefine the 4-week post-treatment period 
in the Schedule of Events to be Days 42 to 70 
• To remove the requirement that the early 
termination visit be conducted within 14 days 
of the last dose being taken 
• To clarify that testing for 13C-UBT for HP 
infection status should be performed at least 
4 weeks after the last dose of study 
medication  
Version 3.0 
(Protocol 
Amendment 2) 
11 May 2020 
• Addition of pre-screen optional fingerstick 
test to evaluate for HP+ status 
• Clarify at screening negative urine drug test 
results for cannabinoids/tetrahydrocannabinol 
and non-prescribed medications. 
• Addition to Schedule of Events to include a 
Week 1 phone call visit to remind subjects 
about study drug compliance and other 
assessments. 
• Addition to Schedule of Events to include 
pharmacokinetic samples on Day 15 
• To clarify that PTE and AE collection and 
reporting time windows include PTEs/AEs 
that are considered SAEs. 
• To clarify that SAE eCRF forms must be 
completed and submitted within 24 hours of 
the investigator first becoming aware of the 
SAE (including SAEs that are PTEs). 
For details of Protocol Amendment 1 and Amendment 2, see Appendix 4 (Section 13.4). 


Phathom Pharmaceuticals, Inc 
vonoprazan 
Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
Page 8 
Table of Contents 
Summary of Changes .................................................................................................................6 
Table of Contents .......................................................................................................................8 
List of Tables ............................................................................................................................12 
List of Figures ..........................................................................................................................12 
Protocol Synopsis.....................................................................................................................13 
List of Abbreviations................................................................................................................17 
1 
Introduction ......................................................................................................................19 
1.1 
Study Rationale .......................................................................................................20 
1.2 
Background .............................................................................................................21 
1.3 
Justification for Dose ..............................................................................................24 
2 
Study Objectives and Endpoints.......................................................................................26 
3 
Investigational Plan ..........................................................................................................27 
3.1 
Study Design ...........................................................................................................27 
3.1.1 
Rationale of Study Design .......................................................................29 
4 
Subject Selection and Withdrawal Criteria ......................................................................30 
4.1 
Selection of Study Population .................................................................................30 
4.1.1 
Inclusion Criteria .....................................................................................30 
4.1.2 
Exclusion Criteria ....................................................................................31 
4.1.3 
Lifestyle Considerations ..........................................................................33 
4.1.4 
Screen Failures .........................................................................................33 
4.2 
Withdrawal of Subjects From Study Drug and/or the Study ..................................33 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................34 
4.2.2 
Handling of Withdrawals .........................................................................35 
4.2.3 
Lost to Follow-up ....................................................................................36 
4.2.4 
Replacements ...........................................................................................36 
5 
Study Drugs ......................................................................................................................37 
5.1 
Method of Assigning Subjects to Treatment Groups ..............................................37 
5.2 
Treatments Administered ........................................................................................37 
5.3 
Identity of Investigational Product..........................................................................38 


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5.4 
Management of Clinical Supplies ...........................................................................39 
5.4.1 
Study Drug Packaging and Storage .........................................................39 
5.4.2 
Study Drug Accountability ......................................................................39 
5.5 
Overdose Management ...........................................................................................40 
5.5.1 
Treatment of Overdose ............................................................................40 
5.6 
Blinding ..................................................................................................................40 
5.6.1 
Breaking the Blind ...................................................................................41 
5.7 
Treatment Compliance ............................................................................................41 
5.8 
Prior and Concomitant Therapy ..............................................................................42 
5.8.1 
Background Medications .........................................................................42 
5.8.2 
Excluded Medications .............................................................................43 
6 
Study Assessments and Procedures ..................................................................................45 
6.1 
Efficacy Assessments ..............................................................................................45 
6.1.1 
13C-Urea Breath Test ................................................................................45 
6.1.2 
Endoscopy/Gastric Biopsy for Histopathology and Antibiotic 
Susceptibility Test ....................................................................................46 
6.1.2.1 
Biopsy for Culture and Antibiotic Susceptibility Test .............................46 
6.1.2.2 
Biopsy for Histopathology .......................................................................47 
6.2 
Safety Assessments .................................................................................................47 
6.2.1 
Pre-treatment Adverse Events and Adverse Events .................................47 
6.2.1.1 
Definitions of Pre-treatment Adverse Events ..........................................47 
6.2.1.2 
Definitions of Adverse Events .................................................................47 
6.2.1.3 
Serious Adverse Events ...........................................................................48 
6.2.1.4 
Adverse Events of Special Interest ..........................................................50 
6.2.1.5 
Additional Points to Consider for PTEs and AEs ....................................50 
6.2.1.6 
Assessment of Severity ............................................................................53 
6.2.1.7 
Assessment of Causality ..........................................................................53 
6.2.1.8 
Relationship to Study Procedures ............................................................54 
6.2.1.9 
Start Date .................................................................................................54 
6.2.1.10 Stop Date .................................................................................................54 
6.2.1.11 Frequency ................................................................................................54 
6.2.1.12 Action Concerning Study Drug ...............................................................54 
6.2.1.13 Outcome ...................................................................................................55 
6.2.1.14 Time Period and Frequency for Collecting AE and SAE Information ....55 


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6.2.1.15 Regulatory Reporting Requirements for SAEs ........................................58 
6.3 
Safety Monitoring Committee ................................................................................59 
6.4 
Pregnancy ................................................................................................................59 
6.5 
Laboratory Analyses ...............................................................................................60 
6.6 
Physical Examinations ............................................................................................62 
6.7 
Vital Signs ...............................................................................................................62 
6.8 
Electrocardiograms .................................................................................................62 
6.9 
Pharmacogenetics ...................................................................................................63 
6.10 Pharmacogenomics .................................................................................................63 
6.11 Pharmacokinetics ....................................................................................................63 
7 
Statistical and Analytical Plan ..........................................................................................64 
7.1 
Primary Efficacy Endpoint .....................................................................................64 
7.2 
Secondary Efficacy Endpoint .................................................................................64 
7.3 
Sample Size Calculations ........................................................................................64 
7.4 
Analysis Sets ...........................................................................................................65 
7.5 
Description of Subgroups to be Analyzed ..............................................................67 
7.6 
Statistical Analysis Methodology ...........................................................................67 
7.6.1 
Efficacy Analyses ....................................................................................67 
7.6.2 
Safety Analyses ........................................................................................68 
7.6.3 
Other Analyses .........................................................................................68 
7.6.4 
Interim Analyses ......................................................................................68 
8 
Data Quality Assurance ....................................................................................................69 
8.1 
Data Management ...................................................................................................69 
9 
Ethics ................................................................................................................................70 
9.1 
Independent Ethics Committee or Institutional Review Board ..............................70 
9.2 
Ethical Conduct of the Study ..................................................................................70 
9.3 
Subject Information and Consent ...........................................................................70 
10 Investigator’s Obligations ................................................................................................72 
10.1 Confidentiality ........................................................................................................72 
10.2 Financial Disclosure and Obligations .....................................................................72 


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10.3 Investigator Documentation ....................................................................................73 
10.4 Study Conduct .........................................................................................................73 
10.5 Adherence to Protocol ............................................................................................73 
10.6 Adverse Events and Study Report Requirements ...................................................74 
10.7 Investigator’s Final Report .....................................................................................74 
10.8 Records Retention ...................................................................................................74 
10.9 Publications .............................................................................................................74 
11 Study Management ...........................................................................................................75 
11.1 Monitoring ..............................................................................................................75 
11.1.1 
External Data Monitoring Committee .....................................................75 
11.1.2 
Monitoring of the Study ...........................................................................75 
11.1.3 
Inspection of Records ..............................................................................75 
11.2 Management of Protocol Amendments and Deviations..........................................75 
11.2.1 
Modification of the Protocol ....................................................................75 
11.2.2 
Protocol Deviations .................................................................................76 
11.3 Study Termination ...................................................................................................76 
11.4 Final Report ............................................................................................................76 
12 Reference List...................................................................................................................78 
13 Appendices .......................................................................................................................82 
13.1 Appendix 1: Schedule of Events .............................................................................83 
13.2 Appendix 2: Contraceptive Guidance .....................................................................87 
13.3 Appendix 3: Liver Safety Monitoring and Withdrawal Criteria .............................89 
13.3.1 
Liver Function Test Monitoring ...............................................................89 
13.3.2 
Considerations for Temporary Discontinuation of Study Drug ...............89 
13.3.3 
Permanent Discontinuation of Study Drug ..............................................90 
13.3.4 
Re-initiation of Study Drug .....................................................................91 
13.4 Appendix 4: Protocol Amendments ........................................................................92 
13.4.1 
Protocol Amendment 1 ............................................................................92 
13.4.2 
Protocol Amendment 2 ..........................................................................102 
 
 
 


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Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 12 
List of Tables 
Table 1-1 
H. pylori MIC Values as a Function of pH ..................................................... 22 
Table 2-1 
Study Objectives and Endpoints ..................................................................... 26 
Table 5-1 
Study Drugs Timings ...................................................................................... 38 
Table 5-2 
Excluded Medications and Treatments ........................................................... 44 
Table 6-1 
Medically Significant Adverse Event List ...................................................... 49 
Table 6-2 
Adverse Events of Special Interest List .......................................................... 50 
Table 6-3 
Protocol-Required Safety Laboratory Assessments ........................................ 61 
Table 13-1 
Schedule of Events .......................................................................................... 83 
Table 13-2 
Abnormal Liver Function Criteria For Permanent Discontinuation of Study 
Drug ................................................................................................................ 90 
 
List of Figures 
Figure 3-1 
Study Design ................................................................................................... 27 
 


Phathom Pharmaceuticals, Inc 
vonoprazan 
Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 13 
Protocol Synopsis 
Protocol Number: 
HP-301 
Title: 
A Phase 3 Randomized Multicenter Study to Evaluate the Efficacy 
and Safety of Open-Label Dual Therapy with Oral Vonoprazan 
20 mg or Double-Blind Triple Therapy with Oral Vonoprazan 
20 mg Compared to Double-Blind Triple Therapy with Oral 
Lansoprazole 30 mg Daily in Patients with Helicobacter Pylori 
Infection 
Sponsor: 
Phathom Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, CA 94025 
Study Phase: 
3 
Study Sites: 
Approximately 150 sites in US and Europe 
Indication: 
Helicobacter pylori infection 
Rationale: 
The purpose of this study is to compare the efficacy and safety of 
vonoprazan open-label dual therapy (vonoprazan and amoxicillin) 
and vonoprazan double-blind triple therapy (vonoprazan, 
amoxicillin, and clarithromycin) administered for 14 days 
compared to lansoprazole double-blind triple therapy 
(lansoprazole, amoxicillin, clarithromycin) administered for 
14 days in subjects with Helicobacter pylori (HP) infection. 
Objectives: 
Primary Objective 
To compare the efficacy of HP eradication with vonoprazan dual 
and triple therapy regimens versus lansoprazole triple therapy 
regimen in HP+ subjects who do not have a clarithromycin or 
amoxicillin resistant strain of HP at baseline 
Secondary Objectives 
• To compare the efficacy of HP eradication with vonoprazan 
dual and triple therapy regimens versus lansoprazole triple 
therapy regimen in subjects infected with a clarithromycin 
resistant strain of HP 
• To compare the efficacy of HP eradication with vonoprazan 
dual and triple therapy regimens versus lansoprazole triple 
therapy regimen in all subjects 
Safety Objectives 
To compare the safety of vonoprazan dual and triple therapy 
regimens versus lansoprazole triple therapy regimen in HP+ 
subjects 


Phathom Pharmaceuticals, Inc 
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Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 14 
Study Population: 
Subjects aged ≥18 years of age with confirmed HP infection not 
previously treated with any regimen to attempt to eradicate HP. 
Study Design: 
This is a Phase 3 randomized study to compare the efficacy and 
safety of vonoprazan open-label dual therapy (vonoprazan and 
amoxicillin) and vonoprazan double-blind triple therapy 
(vonoprazan, amoxicillin, and clarithromycin) administered for 
14 days compared to lansoprazole double-blind triple therapy 
(lansoprazole, amoxicillin, clarithromycin) administered for 
14 days in HP+ subjects.  
Approximately 975 subjects will be randomized in a 1:1:1 ratio to 
receive: 
• Vonoprazan dual therapy arm: vonoprazan 20 mg twice daily 
(BID) in conjunction with amoxicillin 1 g three times daily 
(TID) for 14 days 
• Vonoprazan triple therapy arm: vonoprazan 20 mg BID in 
conjunction with amoxicillin 1 g BID and clarithromycin 
500 mg BID for 14 days 
• Lansoprazole triple therapy arm/control arm: lansoprazole 
30 mg BID in conjunction with amoxicillin 1 g BID and 
clarithromycin 500 mg BID for 14 days. 
HP+ subjects whose eligibility is confirmed by 13C-urea breath test 
(13C-UBT) during the Screening Period will have an endoscopy 
performed to collect gastric mucosal biopsy specimens to 
document HP infection by histology and for culture and 
susceptibility testing to determine resistance to bacteria to 
clarithromycin, amoxicillin and metronidazole antibiotics. At 
Week 6 (4 weeks after the last dose of study drug), HP eradication 
status will be assessed by 13C-UBT. Subjects who remain HP+ 
should have a follow-up endoscopy with repeat bacteriological 
testing for resistant bacteria to the antibiotics used in the study, 
and the subjects should be treated as per the standard clinical care. 
Estimated Study 
Duration: 
The study will consist of a ≤34-day Screening Period, a 14-day 
Treatment Period and a 4-week Follow-up Period. 
Efficacy Assessments: 
The study will evaluate HP infection status as determined by a 
13C-UBT. 
If the subject’s 13C-UBT test is positive at 4 weeks after the last 
dose of study drug, an endoscopy will be performed, and gastric 
mucosal biopsy specimens will be taken for antibiotic 
susceptibility testing. 


Phathom Pharmaceuticals, Inc 
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Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
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Pharmacokinetic or 
Pharmacodynamic 
Assessments: 
For pharmacokinetic analysis of drug concentrations, blood 
samples will be collected at the Week 2 Visit, unless prohibited by 
local regulations.  
In order to determine the subject’s metabolizer status, an optional 
blood sample will be obtained for CYP2C19 genotype testing, 
unless prohibited by local regulations.  
Safety Assessments: 
Safety assessments will include treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs), clinical laboratory 
assessments, physical examinations, electrocardiograms and vital 
signs. 
Study Drug, Dosage, 
and Route of 
Administration: 
The vonoprazan dual therapy arm will consist of vonoprazan 
20 mg BID in conjunction with amoxicillin 1 g TID for 14 days. 
The vonoprazan triple therapy arm will consist of vonoprazan 
20 mg BID in conjunction with amoxicillin 1 g BID and 
clarithromycin 500 mg BID for 14 days. 
The lansoprazole triple therapy arm/control arm will consist of 
lansoprazole 30 mg BID in conjunction with amoxicillin 1 g BID 
and clarithromycin 500 mg BID for 14 days. 
All study drugs will be administered orally starting on Day 1 (the 
day after randomization).  
Sample Size: 
325 subjects per arm. 
Statistical Methods: 
The primary endpoint (proportion of subjects with successful HP 
eradication after the Treatment Period, as determined by 13C-UBT, 
at 4 weeks after the last dose of study drug, in subjects who do not 
have a clarithromycin or amoxicillin resistant strain of HP at 
baseline) will be calculated as a percentage of subjects in each 
treatment group. 
Noninferiority of vonoprazan triple therapy to lansoprazole triple 
therapy, and vonoprazan dual therapy to lansoprazole triple 
therapy, will be evaluated with a Farrington and Manning test with 
a noninferiority margin of 10 percentage points for the difference 
in HP eradication rates between treatments. For each 
noninferiority comparison that yields statistical significance, 
superiority will then be assessed via the Farrington and Manning 
test of the null hypothesis difference ≤0 versus the alternative 
hypothesis difference >0. 
The secondary endpoints will be evaluated in a similar manner as 
the primary endpoint for superiority of vonoprazan triple therapy 
to lansoprazole triple therapy and of vonoprazan dual therapy to 
lansoprazole triple therapy. 


Phathom Pharmaceuticals, Inc 
vonoprazan 
Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 16 
 
Version and Date of 
Protocol: 
Version 3.0 (Protocol Amendment 2); 11 May 2020 


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Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 17 
List of Abbreviations 
Abbreviation 
Definition 
13C-UBT 
carbon 13-urea breath test 
ACG 
American College of Gastroenterology 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice daily 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CYP 
cytochrome P450 isoenzymes 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
GGT 
gamma-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HP 
Helicobacter pylori 
HP+ 
Helicobacter pylori positive  
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response system 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Definition 
MIC 
minimum inhibitory concentration 
MITT 
modified intent-to-treat 
NSAID 
nonsteroidal anti-inflammatory drug 
PCAB 
potassium-competitive acid blocker 
PD 
pharmacodynamic 
PP 
per protocol 
PPI 
proton pump inhibitor 
PT 
Preferred Term 
PTE 
pretreatment adverse event 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
System Organ Class 
SoE 
schedule of events 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TID 
three times daily 
UEG 
United European Gastroenterology 
ULN 
upper limit of normal 
 


Phathom Pharmaceuticals, Inc 
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Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 19 
1 
Introduction 
Vonoprazan belongs to a new class of acid-inhibitory agents called “potassium-competitive 
acid blockers” (PCAB), and in combination with antibiotics, is being developed for the 
eradication of Helicobacter pylori (HP) infection which is an important cause of peptic ulcer 
disease and gastric cancer (see Section 1.2). 
The gastric hydrogen, potassium–adenosine triphosphatase (H+, K+-ATPase), also known as 
the proton pump, is responsible for acid secretion from parietal cells in the stomach. It is 
inactive in the cytosol but relocates from the cytosol to the secretory membrane of the 
parietal cells when food is present in the stomach, thereby becoming active and pumping H+ 
ions out of the cells and into the canaliculi in exchange for K+ ions. It represents an attractive 
pharmacological target, since it is the final step of the acid secretion process. Two classes of 
pharmaceuticals, with distinct mechanisms of action for inhibiting the gastric proton pump, 
have been developed for clinical application: proton pump inhibitors (PPIs) and PCABs. As a 
PCAB, vonoprazan has a unique mechanism of action and pharmacokinetics relative to PPIs: 
• Acid activation and stability: Conventional PPIs are prodrugs, which are activated by 
acid and covalently bind the H+, K+-ATPase; however, activated PPIs are not stable in 
acidic conditions. In contrast, vonoprazan does not require acid activation, is stable in 
acidic conditions, and does not require enteric-coated formulations, enabling a more 
durable effect. Further, vonoprazan is rapidly protonated in the parietal cell canaliculi, 
which concentrates the drug proximal to the H+, K+-ATPase.  
• Activity against active and inactive proton pumps: Vonoprazan inhibits acid secretion by 
competitively inhibiting the binding of potassium ions to the H+, K+-ATPase. 
Vonoprazan can bind to the pump while it is either active or inactive; in contrast, PPIs 
covalently bind H+, K+-ATPase only when the pump is active, as an acidic environment 
is required for the activation and accumulation of PPIs in the parietal cell. Pumps are 
constantly switching between the active and inactive state throughout the day, therefore 
multiple doses of PPIs are required to control acid compared with a single dose of 
vonoprazan. Vonoprazan can also be dosed in the presence or absence of food, while 
most PPIs require dosing before a meal to stimulate activation of the pumps.  
• Extended half-life: The plasma half-life of vonoprazan (20 mg) is 5.7 and 7 hours after 
the first dose and after the seventh day of once daily dosing in humans, respectively 


Phathom Pharmaceuticals, Inc 
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Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 20 
(Jenkins et al 2015). This is significantly longer than the half-life of conventional PPIs 
(<2 hours) (Shin and Kim 2013).  
• Metabolism: Vonoprazan is predominantly metabolized by cytochrome P450 (CYP)3A4, 
which lacks a high degree of genetic polymorphism compared with CYP2C19, which is 
the primary enzyme responsible for the metabolism of PPIs. 
These unique aspects of the vonoprazan mechanism relative to PPIs translate into greater 
magnitude and duration of gastric acid suppression, which are reflected in the 
pharmacodynamic (PD) profile. 
In Japan, the Phase 1 Study TAK-438/CPH-010 evaluated the anti-secretory effect of 
vonoprazan 20 mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult 
male Japanese subjects who were CYP2C19 extensive metabolizers. In this study, gastric pH 
was consistently higher after administration of vonoprazan than after administration of 
esomeprazole or rabeprazole. The difference was first notable 2 hours after the study drug 
administration and persisted until Day 7. Whereas the gastric pH level on Day 1 was 
consistently lower over 24 hours than that on Day 7 after administration of esomeprazole or 
rabeprazole, they were similar after administration of vonoprazan (Sakurai et al 2015).  
Furthermore, in a Phase 1 study conducted in the United Kingdom, vonoprazan at doses 
 ≥20 mg demonstrated a rapid onset of action after the first dose and near maximal PD effect 
within 24 hours of dosing, which was maintained with repeat dosing (TAK-438 107, 
Jenkins et al 2015). 
Vonoprazan was developed by Takeda Pharmaceutical Company Limited (Takeda). Phathom 
has licensed the exclusive rights from Takeda to develop and commercialize vonoprazan in 
the United States (US), Europe, and Canada. Phathom is developing vonoprazan for the 
eradication of Helicobacter pylori (HP) infection in combination with amoxicillin (dual 
therapy) or in combination with amoxicillin and clarithromycin (triple therapy).  
1.1 Study Rationale 
Vonoprazan has been studied in a number of acid-related diseases including eradication of 
HP infection, erosive esophagitis healing and maintenance, gastric ulcer/duodenal ulcer 
healing, and for the prevention of recurrence of a gastric or duodenal ulcer during 


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nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin administration. Vonoprazan has 
received regulatory approval in Japan and other countries in Asia and Latin America for these 
indications.  
For the eradication of HP, a Phase 3 study in Japan tested vonoprazan 20 mg twice daily 
(BID) in combination with clarithromycin and amoxicillin and demonstrated noninferiority 
(pre-specified) and superiority (post hoc) compared with lansoprazole in combination with 
clarithromycin and amoxicillin (TAK-438/CCT-401, Murakami et al 2016). The eradication 
rate for the vonoprazan triple regimen was 92.6% compared to 75.9% for the lansoprazole 
triple therapy regimen. 
Study HP-301 will compare the efficacy and safety of vonoprazan open-label dual therapy 
(vonoprazan and amoxicillin) and vonoprazan double-blind triple therapy (vonoprazan, 
amoxicillin, and clarithromycin) administered for 14 days compared to lansoprazole 
double-blind triple therapy (lansoprazole, amoxicillin, clarithromycin) administered for 
14 days in subjects with HP infection.  
1.2 Background 
Helicobacter pylori is a gram-negative, microaerophilic bacterium found on human gastric 
mucosa. Its causal relationship to gastrointestinal diseases has been extensively studied 
(O’Connor 1994) since it was isolated from the gastric mucosa of a patient with chronic 
gastritis in 1983 (Warren and Marshall 1983). The current prevalence of HP infection in the 
US is estimated at 30% (Crowe 2019) and is between 20% and 40% in Europe (O’Connor 
and O’Morain 2013). The incidence of HP is lower in Northern and Western Europe than in 
Eastern and Southern Europe. As a result of the chronic inflammation induced by HP 
infection (Brawner et al 2014), approximately 20% of infected patients will develop a range 
of pathologies including peptic ulcer disease and gastric cancer.  
According to the 2017 American College of Gastroenterology (ACG) guidelines, HP 
infection is a chronic bacterial infection and, if left untreated, it can ultimately lead to gastric 
cancer in a subset of infected patients (Chey et al 2017). Gastric cancer is the third most 
common cause of cancer-related death worldwide and over 80% of gastric cancers are 
attributed to HP infection (Plummer et al 2015). Globally there are more than one million 
new cases of gastric cancer and approximately 780,000 deaths each year (IARC).  


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In a study conducted in Japan with a mean follow-up of 7.8 years, gastric cancer developed 
in 29% of patients with peptic ulcer, dyspepsia, or gastric hyperplasia who also had HP 
infection, whereas no cases were detected in uninfected patients with these conditions (ie, 
those without HP infection) (Nomura et al 1991; Parsonnet et al 1991; Uemura et al 2001). 
Additionally, immigrants who grew up in regions of the world with a high incidence of HP 
infection (eg, Eastern Europe, Latin America, and East Asia) and who now reside in the US 
or Western Europe have a higher prevalence of the infection than people born in Western 
Europe or the US. These individuals are also at increased risk of gastric cancer 
(Crowe 2019). Recently, the World Health Organization included HP among the 
16 antibiotic-resistant bacteria that pose the greatest threat to human health, and previously 
designated it as a class 1 carcinogen (Graham and Dore 2018).  
Recently the ACG and the Maastricht IV/Florence Consensus Report updated treatment 
guidelines for HP infection (Chey et al 2017; Malfertheiner et al 2017) and recommended 
using anti-secretory agents, such as PPIs, in conjunction with antibiotics to improve their 
efficacy against HP infection. The use of an anti-secretory agent enhances the effect of 
antibiotics in 2 ways. First, anti-secretory agents increase gastric pH, which in turn increases 
the stability of the antibiotics. For example, amoxicillin and clarithromycin are chemically 
unstable at the low pH typically found in the human stomach. Clarithromycin, in particular, is 
rapidly degraded at pH 2 (Erah et al 1997). Second, several antibiotics, including amoxicillin 
and clarithromycin, are most potent against HP at the time of maximum bacterial replication, 
which occurs at pH 6 to 7 (Marcus et al 2012). In contrast, HP is in a dormant state at lower 
pH values, which reduces the effectiveness of the antibiotics (Hassan et al 1999; Scott et al 
2015). As a result, increasing the pH reduces the minimum inhibitory concentration (MIC) of 
antibiotics against HP (Table 1-1). 
Table 1-1 
H. pylori MIC Values as a Function of pH
Agent 
MIC90 (mg/L) 
pH 7.5 
pH 6.0 
pH 5.5 
Penicillin 
0.03 
0.5 
0.5 
Ampicillin 
0.06 
0.25 
0.5 
Cephalexin 
2 
16 
32 
Erythromycin 
0.06 
2 
8 
Clarithromycin 
0.03 
0.06 
0.25 
Ciprofloxacin 
0.12 
0.5 
2 
Tetracycline 
0.12 
0.25 
0.5 


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Abbreviations: MIC, minimum inhibitory concentration. 
Source: Erah et al 1997. 
 
PPIs have been the recommended anti-secretory agent in combination with antibiotics for the 
eradication of HP; combination regimens have been approved in various countries around the 
world. A triple therapy regimen (PPI, clarithromycin, and either amoxicillin or 
metronidazole) is most common. However, HP eradication rates with PPI triple therapy have 
fallen from >90% in the 1990s to current levels of <80%, which may be accounted for by the 
increased resistance of HP to clarithromycin and metronidazole (Shiota et al 2015). A recent 
meta-analysis suggests that in the US, the resistance rates measured from 2012 to 2016 for 
clarithromycin, metronidazole, and levofloxacin were 20%, 29%, and 19%, respectively 
(Savoldi et al 2018). These figures represent a marked increase from 2009 to 2011 for both 
clarithromycin and metronidazole, where resistance was 9% for clarithromycin, 21% for 
metronidazole, while at 11% for levofloxacin (Savoldi et al 2018). A similar trend was seen 
in Europe where resistance rates measured from 2012 to 2016 for clarithromycin, and 
metronidazole were 28% and 46%, respectively (Savoldi et al 2018) and also represent an 
increase from 2009 to 2011, where resistance was 23% for clarithromycin and 33% for 
metronidazole (Savoldi et al 2018). Helicobacter pylori resistance to amoxicillin remains low 
despite its extensive use in most triple therapy regimens of 7, 10, or 14 days duration, and a 
wide range of other clinical infections. Resistance levels to amoxicillin are generally <2% 
among isolates in the US (Meyer et al 2002) and Europe (Megraud 2012). Given the 
declining eradication rates for HP, quadruple therapy (eg, PPI, clarithromycin, amoxicillin, 
and metronidazole, or PPI, bismuth salt, tetracycline, and metronidazole) is recommended as 
first-line treatment in areas with high rates of clarithromycin or metronidazole resistance. 
However, regimens with multiple drugs dosed at multiple times throughout the day may pose 
compliance challenges for patients (Vakil 2005). Further, geographic patterns of resistance 
are poorly understood, and treatment is largely empiric, with susceptibility testing rarely 
conducted before first-line treatment. As such, there is a clear need for simpler, more 
effective first-line treatment options.  
In Japan, vonoprazan has shown the potential to restore the effectiveness of the most 
common triple therapy antibiotic combination regimen to historical cure rates of greater than 
90% and has also shown promising results as a dual therapy combined with high dose 
amoxicillin. The vonoprazan dual therapy regimen has the potential for improved 
convenience and compliance over triple or quadruple therapy regimens. Further, this regimen 


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spares the use of clarithromycin, metronidazole, and levofloxacin, representing an 
opportunity both for effective treatment and for sound antibiotic stewardship through the 
avoidance of antibiotics to which HP is known to acquire resistance. Less frequent use of 
these antibiotics, which have important uses aside from the treatment of HP infection, may 
help to limit the spread of resistance among other pathogenic bacteria within populations. 
1.3 Justification for Dose 
The current ACG guideline and the Maastricht IV/Florence Consensus Report recommend a 
number of treatment regimens including triple therapy consisting of a PPI, clarithromycin 
(500 mg BID), and amoxicillin (1 g BID) for 14 days (Chey et al 2017; Malfertheiner et al 
2017). The guidelines stress the importance of increasing clarithromycin resistance and 
suggests alternative regimens when local resistant rates are known to be high. Therefore, for 
the purposes of this study, PPI-based triple therapy is a reasonable comparator to use 
empirically because the clarithromycin resistance rate will vary across countries and 
investigative sites, and clarithromycin resistance in a particular subject is not known at the 
time of treatment initiation.  
Lansoprazole is the PPI in the active comparator arm of this study, as it is a well-established 
regimen used globally. The lansoprazole regimens proposed in this study are consistent with 
the approved dosing recommendation in the US and Europe (PREVACID 2018; eMC 2018).  
As described in Section 1, vonoprazan provides more rapid and potent acid suppression than 
PPIs. The combination regimen of vonoprazan, amoxicillin, and clarithromycin studied in 
Japan has been shown to be highly efficacious in the treatment of HP infection with an 
eradication rate of 92.6% (Murakami et al 2016). The vonoprazan triple therapy regimen will 
use the same doses and treatment duration of amoxicillin and clarithromycin being used in 
the lansoprazole triple therapy active control to allow a direct comparison of the 2 regimens. 
Although the doses of amoxicillin and clarithromycin are higher than those used in the Japan 
development program, they reflect the differences in standard of care between Japan and 
Western countries and are appropriate for use in the proposed Study HP-301 to be conducted 
in the US and Europe. 
Dual therapy with PPI and high dose amoxicillin is approved for the eradication of HP in 
many regions; however, the eradication rates are now unacceptably low (Graham et al 2017). 


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The use of vonoprazan and high dose amoxicillin as dual therapy is supported by the results 
of 2 Japanese investigator-initiated studies that demonstrated that vonoprazan dual therapy 
achieves eradication rates similar to those of triple therapy with a PPI, and triple therapy with 
vonoprazan.  
One study of 61 subjects assessed vonoprazan 20 mg BID in combination with amoxicillin 
500 mg three times daily (TID) for 7 days compared with vonoprazan 20 mg BID in 
combination with amoxicillin 750 mg BID and clarithromycin 200 mg BID for 7 days. In this 
study, vonoprazan dual therapy was as efficacious as vonoprazan triple therapy (93.3% 
versus 90.3%) (Furuta et al 2018).  
A second study enrolled 81 subjects, 41 of whom had failed standard first-line therapy. 
Subjects assigned to dual therapy were treated with vonoprazan 20 mg BID in combination 
with amoxicillin 500 mg TID for 7 days. Subjects assigned to triple therapy were treated 
first-line with esomeprazole 20 mg or rabeprazole 10 mg BID, amoxicillin 750 mg BID, and 
clarithromycin 200 mg BID, or second-line with esomeprazole 20 mg or rabeprazole 10 mg 
BID, amoxicillin 750 mg BID, and metronidazole 250 mg BID for 7 days. Dual therapy with 
vonoprazan was as efficacious as both first- and second-line therapy with eradication rates of 
95% (19 of 20) and 90% (18 of 20), respectively, versus 81% (17 of 21) and 85% (17 of 20) 
for PPI-based triple therapies (Furuta et al 2016). 


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2 
Study Objectives and Endpoints 
Table 2-1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• To compare the efficacy of HP eradication with 
vonoprazan dual and triple therapy regimens 
versus lansoprazole triple therapy regimen in 
HP+ subjects who do not have a clarithromycin 
or amoxicillin resistant strain of HP at baseline 
• Proportion of subjects with successful HP 
eradication after the Treatment Period, as 
determined by 13C-UBT, at 4 weeks after the last 
dose of study drug in subjects who do not have a 
clarithromycin or amoxicillin resistant strain of 
HP at baseline 
Secondary 
 
• To compare the efficacy of HP eradication with 
vonoprazan dual and triple therapy regimens 
versus lansoprazole triple therapy regimen in 
subjects infected with a clarithromycin resistant 
strain of HP 
• To compare the efficacy of HP eradication with 
vonoprazan dual and triple therapy regimens 
versus lansoprazole triple therapy regimen in all 
subjects 
• Proportion of subjects with successful HP 
eradication after the Treatment Period, as 
determined by 13C-UBT at 4 weeks after the last 
dose of study drug, among subjects who had a 
clarithromycin resistant strain of HP at baseline 
• Proportion of subjects with successful HP 
eradication after the Treatment Period, as 
determined by 13C-UBT, at 4 weeks after the last 
dose of study drug among all subjects 
Safety 
 
• To compare the safety of vonoprazan dual and 
triple therapy regimens versus lansoprazole triple 
therapy regimen in HP+ subjects 
• Adverse events (AEs) 
• 
Laboratory test values (hematology, serum 
chemistry, urinalysis)  
• 
Electrocardiogram (ECG) 
• 
Vital signs 
 


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3 
Investigational Plan 
3.1 Study Design 
This is a Phase 3, randomized, parallel group study to compare the efficacy and safety of 
vonoprazan open-label dual therapy (vonoprazan and amoxicillin) and vonoprazan 
double-blind triple therapy (vonoprazan, amoxicillin, and clarithromycin) administered for 
14 days compared to lansoprazole double-blind triple therapy (lansoprazole, amoxicillin, 
clarithromycin) administered for 14 days in HP+ subjects.  
A schematic diagram of the overall study design is presented in Figure 3-1. 
Figure 3-1 
Study Design 
 
 
The study will include 3 main periods: 
1. Screening Period (Day -35 to Day -2): Subjects will provide informed consent and the 
subject will undergo screening assessments to determine study eligibility, and baseline 
assessments will be performed. If all eligibility criteria are met, the subject will enter the 
study. 
 
Treatment Period 
(14 Days) 
Follow-up Period 
(4 weeks) 
 
 
 
 
 
Visit 1 
Visit 2 
 
Visit 3 
 
Visit 4 
 
 
 
 
 
 
Vonoprazan Dual 
Therapy 
(Open Label) 
 
 
Informed 
consent 
 
Vonoprazan 
Triple Therapy 
(Double Blind) 
 
 
 
Lansoprazole 
Triple Therapy 
(Double Blind) 
 
 
 
 
 
 
 
 
Screening Period 
(≤ 34 days) 
 
 
 
 
Randomization 
Day -1 
 
Eradication 
Assessment 


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Subjects may be pre-screened for HP infection using a fingerstick test performed not 
more than 30 days prior to screening. The subjects will sign a pre-screening ICF for 
optional fingerstick test of HP status.  
An endoscopy will be performed to collect gastric mucosal biopsy specimens (one each 
from the greater and lesser curve of the gastric body, and one each from the greater and 
lesser curve of the antrum) at the start of the study for histopathology (Section 6.1.2.2) to 
document HP infection. Two additional gastric mucosal biopsy specimens will be 
collected (one from the greater curve of the antrum and one from the lesser curve of the 
gastric body) for culture and susceptibility testing (Section 6.1.2.1) to determine 
resistance to bacteria to clarithromycin, amoxicillin and metronidazole antibiotics which 
are commonly used in the treatment of HP infection. After randomization, as part of the 
overall analysis, MICs of amoxicillin, clarithromycin, and metronidazole against HP will 
be determined using the strains isolated from these specimens by the 2-fold agar dilution 
method. Results from the gastric mucosal biopsy specimens (histology and culture) will 
be available post-randomization. Any remaining gastric mucosal biopsy samples may be 
used for future pharmacogenomic evaluation of HP (Section 6.10).   
2. Treatment Period (2-week treatment period): HP+ subjects whose eligibility is confirmed 
by 13C-urea breath test (13C-UBT) during the Screening Period will be randomly assigned 
in a 1:1:1 ratio to receive vonoprazan 20 mg BID in conjunction with amoxicillin 1 g TID 
(vonoprazan dual therapy arm) for 14 days, vonoprazan 20 mg BID in conjunction with 
amoxicillin 1 g BID and clarithromycin 500 mg BID (vonoprazan triple therapy arm) for 
14 days, or lansoprazole 30 mg BID in conjunction with amoxicillin 1 g BID and 
clarithromycin 500 mg BID (lansoprazole triple therapy arm/control arm) for 14 days. 
Subjects will receive a phone call from the site at Week 1 to remind subjects about 
compliance with study drug and other assessments described in the SoE (Section 13.1). 
Subjects will return at Week 2 for laboratory tests and other assessments described in the 
SoE (Section 13.1). 


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3. Follow-up Period: A phone call follow-up will be performed at Week 4 (2 weeks after last 
dose of study drug) to assess adverse events (AEs) and any concomitant medication 
usage. At Week 6 (4 weeks after the last dose of study drug), HP eradication status will be 
assessed by 13C-UBT. Subjects who remain HP+ at the Follow-up Period should have a 
follow-up endoscopy with repeat bacteriological test for resistant bacteria to the 
antibiotics used in the study, and the subjects can be treated as per the standard clinical 
care. 
End of study definition: A subject is considered to have completed the study if he/she has 
completed all phases of the study including Visit 4 performed 4 weeks after the last dose of 
study drug. 
3.1.1 
Rationale of Study Design 
This Phase 3 randomized, parallel group study, with open-label dual therapy and 
double-blind triple therapy, is designed to evaluate the efficacy and safety of vonoprazan in 
HP+ subjects. The parallel group design allows for direct assessment of efficacy and safety of 
the 2 vonoprazan arms of the study relative to the lansoprazole control arm and of the 
2 vonoprazan arms to each other. Further, the primary endpoint for this study is based on an 
objective measurement via the 13C-UBT, and the UBT testing facility will remain blinded to 
all 3 treatment assignments ensuring that the evaluation of the efficacy endpoint is not 
subject to bias. 
Diagnosis and eradication of HP by 13C-UBT is a well-accepted method by both the ACG 
and United European Gastroenterology (UEG). 
The antibiotics amoxicillin and clarithromycin are recommended first line use by both the 
ACG and the UEG guidelines, and the duration of dosing of 14 days is accepted in both 
regions. 
While PPIs require 3 to 5 days to exert their maximum acid-inhibitory effects, vonoprazan is 
known to exhibit its maximum acid-inhibitory effects in a much shorter time compared with 
PPIs, and to exert potent and sustained acid-inhibitory effects. The relatively higher pH in the 
stomach, due to faster and greater acid suppression by vonoprazan, is expected to confer 
greater efficacy in eradication by optimizing the conditions in the stomach for the antibiotics 
to work. This should lead to better treatment outcomes and a greater adjunctive effect to HP 
eradication therapy. 


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4 
Subject Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
This study will be conducted in approximately 150 sites in the US and Europe with an 
estimated total of 975 randomly assigned subjects (325 subjects per treatment group). 
Subjects will be assigned to study drug only if they meet all of the inclusion criteria and none 
of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or subject 
safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
4.1.1 
Inclusion Criteria 
Subjects are eligible for enrollment in the study if they meet all of the following inclusion 
criteria: 
1. The subject is ≥ 18 years of age at the time of informed consent signing. 
2. In the opinion of the investigator or sub-investigators, the subject is capable of 
understanding and complying with protocol requirements. 
3. The subject signs and dates a written, informed consent form (ICF) and any required 
privacy authorization prior to the initiation of any study procedures. The subject is 
informed of the full nature and purpose of the study, including possible risks and side-
effects. The subject has the ability to cooperate with the investigator. Ample time and 
opportunity should be given to read and understand verbal and/or written instructions. 
4. The subject has at least one of the following clinical conditions with confirmed HP 
infection demonstrated by a positive 13C-UBT during the Screening Period. 
• Dyspepsia (ie, pain or discomfort centered in the upper abdomen) lasting at least 
2 weeks 
• A confirmed diagnosis of functional dyspepsia 
• A recent / new diagnosis of (non-bleeding) peptic ulcer 
• A history of peptic ulcer not previously treated for HP infection 
• A requirement for long-term NSAID treatment at a stable dose of the NSAID 


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5. A female subject of childbearing potential who is or may be routinely sexually active 
with a nonsterilized male partner agrees to routinely use adequate double barrier 
contraception from the signing of informed consent until Day -2 and 2 forms of adequate 
contraception from Day -1 until 4 weeks after the last dose of study drug as detailed in 
Appendix 2 (Section 13.2) of this protocol. 
4.1.2 
Exclusion Criteria 
Subjects are not eligible for study participation if they meet any of the following exclusion 
criteria: 
1. The subject has previously been treated with any regimen to attempt to eradicate HP. 
2. The subject has gastric or duodenal ulcer with endoscopic evidence of current or recent 
bleeding. 
3. The subject has confirmed diagnosis of gastric cancer by biopsy. 
4. The subject is receiving colchicine. 
5. The subject has received any investigational compound (including those in 
post-marketing studies) within 30 days prior to the start of the Screening Period. A 
subject who has screen failed from another clinical study and who has not been dosed 
may be considered for enrollment in this study. 
6. The subject is a study site employee, an immediate family member, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, 
spouse, parent, child, sibling) or who may have consented under duress. 
7. The subject has cutaneous lupus erythematosus or systemic lupus erythematosus. 
8. The subject has had clinically significant upper or lower gastrointestinal bleeding within 
4 weeks prior to randomization. 
9. The subject has Zollinger-Ellison syndrome or other gastric acid hypersecretory 
conditions. 


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10. The subject has a history of hypersensitivity or allergies to vonoprazan (including the 
formulation excipients: D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose, 
fumaric acid, croscarmellose sodium, magnesium stearate, hypromellose, macrogol 8000, 
titanium oxide, red or yellow ferric oxide), PPIs, amoxicillin and/or clarithromycin, or any 
excipients used in the 13C-UBT: mannitol, citric acid or aspartame. Skin testing may be 
performed according to local standard practice to confirm hypersensitivity. 
11. The subject has a history of alcohol abuse, illegal drug use, or drug addiction within the 
12 months prior to screening, or who regularly consume >21 units of alcohol (1 unit = 12 
oz/300 mL beer, 1.5 oz/25 mL hard liquor/spirits, or 5 oz/100 mL wine) per week based 
on self-report. Subjects must have a negative urine drug screen for cannabinoids/ 
tetrahydrocannabinol and non-prescribed medications at screening. 
12. The subject is taking any excluded medications or treatments listed in the protocol 
(Section 5.8.2). 
13. If female, the subject is pregnant, lactating, or intending to become pregnant before, 
during, or within 4 weeks after participating in this study; or intending to donate ova 
during such time period.  
14. The subject has a history or clinical manifestations of significant central nervous system, 
cardiovascular, pulmonary, hepatic, renal, metabolic, other gastrointestinal, urological, 
endocrine or hematological disease that, in the opinion of the investigator, would confound 
the study results or compromise subject safety. 
15. The subject requires hospitalization or has surgery scheduled during the course of the 
study or has undergone major surgical procedures within 30 days prior to the Screening 
Visit. 
16. The subject has a history of malignancy (including MALToma) or has been treated for 
malignancy within 5 years prior to the start of the Screening Period (Visit 1) (the subject 
may be included in the study if he/she has cured cutaneous basal cell carcinoma or 
cervical carcinoma in situ). 
17. The subject has acquired immunodeficiency syndrome (AIDS) or human 
immunodeficiency virus (HIV) infection, or tests positive for the hepatitis B surface 
antigen (HBsAg), hepatitis C virus (HCV) antibody or HCV RNA. However, subjects 
who test positive for HCV antibody, but negative for HCV RNA are permitted to 
participate. 


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18. The subject has any of the following abnormal laboratory test values at the start of the 
Screening Period: 
a) Creatinine levels: >2 mg/dL (>177 μmol/L). 
b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the upper 
limit of normal (ULN) or total bilirubin >2 × ULN. 
4.1.3 
Lifestyle Considerations 
Subjects should be instructed as follows: 
• To refrain from excessive drinking and eating, an extreme diet change (eg, change to an 
extremely high-fat diet) or excessive exercise throughout the study. 
• Not to donate blood during the study, and to report on any such donation immediately. 
4.1.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomly assigned to study drug. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
If a suspected erroneous laboratory result is obtained at screening, retesting of that laboratory 
parameter will be allowed at investigator discretion with medical monitor approval. 
Rescreening of subjects is permitted if approved by the Medical Monitor. Results from 
assessments performed during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the inclusion/exclusion 
criteria is met.  
4.2 Withdrawal of Subjects From Study Drug and/or the Study 
The duration of the study is defined for each subject as the date signed written informed 
consent is provided through the last Follow-up Visit performed 4 weeks after the last dose of 
study drug. 


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4.2.1 
Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study site. Every effort should be made 
to keep subjects in the study. The primary reason for discontinuation or withdrawal of the 
subject from the study or study drug should be recorded in the electronic case report form 
(eCRF). For screen failure subjects, refer to Section 4.1.4. A subject may be withdrawn from 
the study for any of the following reasons: 
1. Adverse events or SAE: The subject has experienced a pretreatment adverse event (PTE), 
AE or SAE 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, AE or SAE. 
Note: If a subject is discontinued from study participation due to a PTE, AE, or SAE, the 
event will be followed until it is fully resolved. 
2. Liver Function Test (LFT) abnormalities: Appropriate clinical follow-up (including repeat 
laboratory tests) is to be done until a subject’s laboratory profile has returned to 
normal/baseline status. See Appendix 3 (Section 13.3) for the criteria of liver function 
abnormalities for temporary and permanent discontinuation of study drug. 
3. Significant protocol deviation: The discovery post-randomization that the subject failed 
to meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health. 
4. Lost to follow-up: The subject did not return to the clinic and attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented 
(3 documented telephone contact attempts and 1 certified letter, at a minimum) within 
6 weeks of the most recent planned visit. 
5. Voluntary withdrawal: The subject wishes to withdraw from the study. The reason for the 
withdrawal, if provided, should be recorded in the eCRF.  
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal 
due to an AE or lack of efficacy). 
6. Study termination: The sponsor, Institutional Review Boards (IRB), Independent Ethics 
Committees (IEC), or regulatory agency terminates the study. 


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7. Pregnancy: The subject is found to be pregnant. Note: If the subject is found to be 
pregnant, the subject must be withdrawn immediately. The procedure is described in 
Section 6.4. 
8. Lack of efficacy: The investigator has determined that the subject is not benefiting from 
investigational treatment and continued participation would pose an unacceptable risk to 
the subject.  
9. Other: The subject is discontinued from the study for any reason other than those listed 
above. The specific reason(s) for subject discontinuation should be recorded in the 
“specify” field of the eCRF. 
4.2.2 
Handling of Withdrawals 
Subjects are free to withdraw from the study or study drug at any time upon request. Subject 
participation in the study may be stopped at any time at the discretion of the investigator or at 
the request of the sponsor. 
Subjects who discontinue study drug or active participation in the study will no longer 
receive study drug. When a subject withdraws from the study drug or active participation in 
the study, the reason(s) for withdrawal shall be recorded by the investigator on the relevant 
page of the eCRF. Whenever possible, all subjects who discontinue study drug or withdraw 
from the study prematurely will undergo all early termination assessments. Subjects who fail 
to return for final assessments will be contacted by the site in an attempt to have them 
comply with the protocol. 
It is vital to obtain follow-up data on any subject withdrawn because of an AE or SAE. In 
every case, efforts must be made to undertake protocol-specified safety follow-up 
procedures. 
See the SoE (Section 13.1) for data to be collected at the time of discontinuation of study 
drug and follow-up and for any further evaluations that need to be completed. 
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 4.2.1. 


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4.2.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter (or local equivalent methods) to the subject’s last known 
mailing address). These contact attempts should be documented in the subject’s medical 
record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study due to being lost to follow-up.  
4.2.4 
Replacements 
Discontinued or withdrawn subjects will not be replaced. 


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5 
Study Drugs 
5.1 Method of Assigning Subjects to Treatment Groups 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomly assigned at the baseline/randomization visit (Visit 2/Day -1) to receive vonoprazan 
dual therapy, vonoprazan triple therapy, or lansoprazole triple therapy for 14 days using a 
1:1:1 allocation ratio.  
An interactive response system (IRT) will be used to administer the randomization schedule. 
Biostatistics will generate the randomization schedule using SAS software Version 9.4 or 
later (SAS Institute Inc, Cary, North Carolina) for IRT, which will link sequential subject 
randomization numbers to treatment codes. It will also use an appropriate block size, which 
will not be revealed. 
5.2 Treatments Administered 
Subjects randomly assigned to vonoprazan dual therapy will receive vonoprazan 20 mg BID 
in conjunction with amoxicillin 1 g TID for 14 days. 
Subjects randomly assigned to vonoprazan triple therapy will receive vonoprazan 20 mg BID 
in conjunction with amoxicillin 1 g BID and clarithromycin 500 mg BID for 14 days. 
Subjects randomly assigned to lansoprazole triple therapy will receive lansoprazole 30 mg 
BID in conjunction with amoxicillin 1 g BID and clarithromycin 500 mg BID for 14 days. 
All study drugs will be administered orally starting on Day 1 (the day after randomization, 
Table 13-1).  
Study drug administration will be as presented in Table 5-1. 


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Table 5-1 
Study Drugs Timings 
Study Drugs 
Vonoprazan Dual 
Therapy 
Vonoprazan Triple 
Therapy 
Lansoprazole Triple 
Therapy 
Mor 
Aft 
Eve 
Mor 
Aft 
Eve 
Mor 
Aft 
Eve 
Vonoprazan 20 mg 
X 
- 
X 
X 
- 
X 
- 
- 
- 
Lansoprazole 30 mg 
- 
- 
- 
- 
- 
- 
X 
- 
X 
Amoxicillin 1 g 
X 
X 
X 
X 
- 
X 
X 
- 
X 
Clarithromycin 500 mg 
- 
- 
- 
X 
- 
X 
X 
- 
X 
Abbreviations: Aft, afternoon; Eve, evening; Mor, morning. 
Subjects should be instructed as follows: 
• To take study drug(s) 30 minutes before breakfast, lunch and dinner (for subjects enrolled 
in the dual-therapy arm) or breakfast and dinner (for subjects enrolled in the 
triple-therapy arm) at about the same time as he/she usually does with approximately 240 
mL (8 oz) water. 
• To present to the clinic in a fasting state when he/she is scheduled for laboratory tests 
and/ or an endoscopy. On such study visit days, subjects will be instructed to take their 
dose of study drug(s) (if appropriate) after study procedures are completed. 
5.3 Identity of Investigational Product 
Vonoprazan 
Vonoprazan study medication will be supplied as 20 mg capsules. The tablet drug product 
will be over-encapsulated into Swedish Orange DB-AAel capsules containing 
microcrystalline cellulose at the contract manufacturing organization, PCI, Rockford, IL, 
USA. Takeda Pharmaceutical Company, Ltd, Hikari, Japan manufactures the vonoprazan 
drug substance and tablet drug product.  
The over-encapsulated vonoprazan 20 mg will be packaged in a blister card.  
Lansoprazole 
Commercially available lansoprazole 30 mg capsules will be supplied by Delpharm Novaro, 
Cerano, Italy in plain white capsules. The capsule product will be over-encapsulated into 
Swedish Orange DB-AAel capsules containing microcrystalline cellulose at the contract 
manufacturing organization, PCI, Rockford, IL, USA. 


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The over-encapsulated lansoprazole will be packaged in a blister card. 
Amoxicillin and Clarithromycin 
Commercially available amoxicillin and clarithromycin will be supplied in their commercial 
packaging. 
Each blister card/bottle will bear a label that includes the pertinent study information and 
local regulatory requirements. Labels will be in the appropriate language for the area in 
which the study medication is dispensed. 
5.4 Management of Clinical Supplies 
5.4.1 
Study Drug Packaging and Storage 
Over-encapsulated vonoprazan and over-encapsulated lansoprazole will be prepared in blister 
cards and shipped by PCI. Each blister card will contain a (randomized) dosage for 1 subject 
and will contain a sufficient quantity for dispensing during the Treatment Period. 
Commercially available amoxicillin and clarithromycin will be supplied in their commercial 
packaging. The commercial product may be packaged in study-specific secondary packaging, 
for patient convenience. 
Study supplies must be stored in a secure area (eg, a locked cabinet), protected from 
moisture, and kept at controlled room temperature 20° to 25°C (68° to 77°F); excursions 
allowed between 15°to 30°C (59° to 86°F) until they are used, or returned to the sponsor or 
designee for destruction. 
5.4.2 
Study Drug Accountability 
The investigator will maintain accurate records of receipt of all study drugs, including dates 
of receipt. In addition, accurate records will be kept regarding when and how much study 
drug is dispensed and used by each subject in the study. Reasons for departure from the 
expected dispensing regimen must also be recorded. At the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study drug will be reconciled and 
retained or destroyed according to applicable regulations. 


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5.5 Overdose Management 
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.  
Cases of overdose without manifested signs or symptoms are not considered AEs. Adverse 
events associated with an overdose will be documented on AE eCRF(s) according to 
Section 6.2.1.14.1. The SAEs associated with overdose should be reported according to the 
procedure outlined in Section 6.2.1.14.2. 
5.5.1 
Treatment of Overdose 
In the event of drug overdose, the subject should be treated symptomatically. 
5.6 Blinding 
The study treatment blind for the triple therapy groups will be maintained using the IRT. The 
dual therapy group will be open-label. 
The latest Good Manufacturing Practice Guidance for non-penicillin beta-lactam drugs, 
recommending segregated manufacturing facilities, has resulted in clinical supply 
manufacturers no longer able to handle drugs such as amoxicillin. Therefore, only 
commercially available amoxicillin can be used, and amoxicillin dosing will not be blinded. 
Given that the dual therapy arm uses a different amoxicillin regimen than the two triple 
therapy arms, the dual therapy arm will be considered open label for this study. 
A double-blind design is employed for the triple therapy regimens so that both the 
investigators and the subjects will be unaware of the treatment assignment during the whole 
study. Although the dual therapy regimen will be open-label, the primary endpoint for this 
study is based on an objective measurement via the 13C-UBT, and the UBT testing facility 
will remain blinded to all 3 treatment assignments ensuring that the evaluation of the efficacy 
endpoint is not subject to bias. Moreover, 
 personnel and the Phathom Pharmaceuticals, 
Inc. team including the study statistician will be blinded to the triple therapy treatment 
regimens. The dual therapy group will be open-label; therefore, the site, subjects, some 
 
personnel and potentially Phathom Pharmaceuticals, Inc. team will be unblinded to the dual 
therapy regimen. No summary of study data by the open-label dual therapy arm will be done 


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during the study and data management and clean-up will be done on blinded data sets as if 
the study were a completely blinded study. The final study report will include all data 
including all endpoints after all subjects have completed the study, database is locked, and 
the study is unblinded. 
5.6.1 
Breaking the Blind 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. In 
the event of a medical emergency, the investigator will be able to access the IRT to determine 
the subject’s treatment group assignment. The investigator will, whenever possible, discuss 
options with the medical monitor before unblinding. The sponsor must be notified as soon as 
possible if the investigational drug blind is broken. The date, time, and reason the blind is 
broken must be recorded in the source documents, and the same information (except the 
time) must be recorded on the eCRF. If any site personnel are unblinded, investigational drug 
must be stopped immediately, and the subject must be withdrawn from the study. 
5.7 Treatment Compliance 
As subjects will self-administer study drug(s) at home, compliance with study drug will be 
assessed at each visit. For on-site visits, compliance will be assessed by direct questioning 
and counting returned tablets/capsules during the site visits. For phone visits, a compliance 
reminder will be provided to the subjects; compliance will be assessed by direct questioning. 
Subject treatment compliance assessment results will be record in the source documents and 
eCRF.  
A record of the number of tablets/capsules dispensed to and taken by each subject must be 
maintained and reconciled with study drug and compliance records. Study drug start and stop 
dates, including dates for study drug delays and/or dose reductions will also be recorded in 
the eCRF. 
Noncompliance is defined as (taking less than 75% or more than 120% of study drug during 
any evaluation period [visit to visit]). Subjects exhibiting poor compliance as assessed by 
tablet/capsule counts should be counseled on the importance of good compliance to the study 
dosing regimen. 


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5.8 Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of enrollment (or has 
received within 30 days before the time of enrollment) or receives during the study must be 
recorded along with the following: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Subjects are to be instructed not to take any medications, including over-the-counter 
medications, without first consulting the investigator or sub-investigators. However, 
single-use medications for endoscopic examination and topical medications, including 
liniments, ophthalmic drops, nasal drops, ear drops, inhaled drugs, adhesive skin patches, and 
gargle (mouthwash), will be allowed, whether or not they are excluded or restricted. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
5.8.1 
Background Medications 
Subjects who are being treated with these medications before signing the informed consent, 
who have no endoscopic evidence of current or recent gastric or duodenal ulcer bleeding 
(see Section 4.1.2) during the Screening Period, and who are compliant with the dosage as 
instructed by the medication package insert, the following medications are permitted but the 
dose and administration method is not permitted to change however, switching between 
once-daily and weekly regimens is permitted for drugs containing the same active ingredient: 
• Corticosteroids 
• Bisphosphonates 
• Anti-platelets 
• Anticoagulants 


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• Psychotropics 
• Antidepressants 
• Methotrexate 
• NSAIDs 
Corticosteroids are permitted for the subjects that are using them before signing the ICF at 
start of the Screening Period, but the dose and administration will not be changed during the 
study. 
5.8.2 
Excluded Medications 
A list of excluded medications is provided in Table 5-2. 


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Table 5-2 
Excluded Medications and Treatments 
Excluded Medications and Treatments 
Beginning of 
Exclusion 
End of 
Exclusion 
Other investigational drugs or drugs administered due to 
participation in another clinical trial 
30 days prior to start of 
Screening Period 
4-week Post-
Treatment Visit 
Medications (excluding PPIs and antibiotics) that may interfere 
with 13C-UBT (ecabet, sodium hydrate)a 
14 days prior to 
Screening 13C-UBT  
4-week Post-
Treatment Visit 
Antibiotics, Bismuth 
30 days prior to 
screening 13C-UBT 
4-week Post-
Treatment Visit 
Antiprotozoals 
30 days prior to Day 1 
4-week Post-
Treatment Visit 
H2 receptor antagonists 
14 days prior to 
Screening 13C-UBT 
4-week Post-
Treatment Visit 
PPIs 
14 days prior to 
Screening 13C-UBT 
4-week Post-
Treatment Visit 
Medications contraindicated with clarithromycin: colchicine, 
pimozide, ergot derivatives, tadalafil, terfenadine, astemizole, 
cisapride, simvastatin, lovastatin, atorvastatin, etc.  
Note: other statins such as fluvastatin, pravastatin, and 
rosuvastatin may be allowed but used with caution 
30 days prior to Day 1 
End of treatment 
Strong inhibitors or inducers of CYP2C19 (eg, fluconazole, 
fluoxetine, fluvoxamine, ticlopidine, rifampicin, ritonavir) 
14 days prior to Day 1 
End of treatment  
Strong inhibitors or inducers of CYP3A4 (eg, itraconazole, 
ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
telithromycin) 
14 days prior to Day 1 
End of treatment 
CYP3A4 substrates with a narrow therapeutic index 
14 days prior to Day 1 
End of treatment 
Surgical procedures that could affect gastric acid secretion (eg, 
any form of partial gastrectomy, vagotomy) 
30 days prior to Day 1 
4-week Post-
Treatment Visit 
Other agents affecting digestive organs including muscarinic 
antagonists (eg, hyoscyamine), prokinetics, oral anticholinergic 
agents, prostaglandins, bismuth, sucralfate 
30 days prior to Day 1 
4-week Post-
Treatment Visit 
Atazanavir sulfates; rilpivirine hydrochloride (contraindicated 
with vonoprazan) 
5 days prior to Day 1 
4-week Post-
Treatment Visit 
Abbreviations: 13C-UBT, 13C-urea breath test; CYP, cytochrome P450 isoenzymes; H2, histamine-2 (receptor); 
HP, Helicobacter pylori; PPI, proton pump inhibitor. 
a Prohibited period is 14 days prior to any 13C-UBT or as otherwise stated in the package insert for the 13C-urea 
breath testing kit package to be used. The exclusion period is not applicable to proton pump inhibitors and 
antibiotics; they have a separate exclusion period. 


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6 
Study Assessments and Procedures 
• Before performing any study procedures, all potential subjects will sign and date an ICF. 
Subjects will have the opportunity to have any questions answered before signing the 
ICF. The investigator must address all questions raised by the subject. The investigator or 
designee will also sign and date the ICF. 
o An optional pre-screening ICF may be used to evaluate a subject for HP infection 
using a fingerstick test. 
• Study procedures and their timing are summarized in the SoE (Section 13.1).  
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue study 
drug. 
• Adherence to the study design requirements, including those specified in the SoE, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
6.1 Efficacy Assessments 
6.1.1 
13C-Urea Breath Test 
Helicobacter pylori infection status will be measured at Screening to establish HP infection 
and at Week 6 (4 weeks after the last dose of study drug) to assess HP eradication status. 
To establish HP infection status, a 13C-UBT will be performed.  
Exhaled air samples will be taken in accordance with instructions for use of centrally 
provided testing kits for HP infection status determination.  
Medications such as PPIs are to be stopped at least 14 days before taking the 13C-UBT in 
order to exclude false negative results. Antibiotics (particularly those with anti-helicobacter 


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action, and bismuth preparations) are to be stopped 30 days before taking the test. See 
Section 5.8.2, Table 5-2. 
6.1.2 
Endoscopy/Gastric Biopsy for Histopathology and Antibiotic 
Susceptibility Test 
During the Screening Period, an endoscopy will be performed on all subjects to collect 
biopsy specimens. The screening endoscopy can be performed any time during that period; 
however, it should be performed after the subject has fulfilled all other admission criteria. 
The gastric mucosal biopsy samples for antibiotic susceptibility testing are to be taken FIRST 
in order to avoid any contamination of the specimens with formalin. 
6.1.2.1 
Biopsy for Culture and Antibiotic Susceptibility Test 
Gastric mucosal biopsy specimens will be taken for culture and subsequent antimicrobial 
susceptibility testing. The testing is to determine if there are any resistant bacteria to the 
antibiotics used in the study.  
Two biopsy specimens will be obtained, one from the greater curve of the antrum and 
one from the lesser curve of the gastric body, at the start of study (Visit 1) and sent to a 
central laboratory. 
The subject can be randomized prior to receiving the antibiotic susceptibility test result. 
Minimum inhibitory concentrations of amoxicillin, clarithromycin, and metronidazole 
against HP will be determined using the strains isolated from these specimens by the 2-fold 
agar dilution method.  
Clarithromycin ≥ 1 µg/mL, amoxicillin > 0.125 µg/mL and metronidazole > 8 µg/mL are 
determined as resistance breakpoints. 
If subject’s 13C-UBT test is positive at 4 weeks after the last dose of study drug, an 
endoscopy will be performed and two gastric mucosal biopsy specimens (one from the 
greater curve of the antrum and one from the lesser curve of the gastric body) will be taken 
for antibiotic susceptibility testing, and the subjects can then be treated as per the standard of 
care. 


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Details on processes for collection and shipment of these samples can be found in the 
Laboratory Manual. 
6.1.2.2 
Biopsy for Histopathology 
Four gastric mucosal biopsy specimens will be obtained, one each from the greater and lesser 
curve of the gastric body, and one each from the greater and lesser curve of the antrum and 
sent to a central laboratory at the start of study to document HP infection.  
The biopsies will be placed in 10% buffered formalin and shipped to the central pathology 
laboratory for subsequent staining and analysis. All biopsies will be evaluated for the 
presence or absence of HP infection. 
Details on processes for collection and shipment of these samples can be found in the 
Laboratory Manual. 
6.2 Safety Assessments 
6.2.1 
Pre-treatment Adverse Events and Adverse Events 
6.2.1.1 
Definitions of Pre-treatment Adverse Events 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who 
has signed informed consent to participate in a study which has occurred prior to 
administration of any study drug; it does not necessarily have to have a causal relationship 
with study participation. 
6.2.1.2 
Definitions of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its to study drug. An AE can therefore be any unfavorable sign or symptom, or a 
disease temporally associated with the use of study drug.  
A treatment-emergent AE (TEAE) is defined as any event that occurs after the first dose of 
study drug or any event at baseline that worsens in either intensity or frequency after the first 
dose of study drug. 


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6.2.1.3 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence at any dose for which the following 
occurs:  
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 symptom described in the Medically Significant AE List 
(Table 6-1). 


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Table 6-1 
Medically Significant Adverse Event List 
Term 
Acute respiratory failure/acute respiratory distress syndrome 
Torsade de pointes / ventricular fibrillation / ventricular tachycardia 
Malignant hypertension 
Convulsive seizure agranulocytosis  
Aplastic anemia  
Toxic epidermal necrolysis/Stevens-Johnson syndrome  
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis 
Confirmed or suspected endotoxin shock 
Confirmed or suspected transmission of infectious agent by a medicinal product 
Neuroleptic malignant syndrome / malignant hyperthermia 
Spontaneous abortion / stillbirth and fetal death 
 
The PTEs that fulfill one 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 Section 6.2.1.14.2 and 
Section 6.2.1.14.3). 
If a subject is noted to have an ALT or AST value of >3 × ULN and a total bilirubin value of 
>2 × ULN, for which an alternative etiology has not been identified, the event should be 
recorded as an SAE and reported (see Section 6.2.1.14.2). The investigator must contact the 
medical monitor for discussion of the relevant subject details and possible alternative 
etiologies, such as acute viral hepatitis A or B or other acute liver disease or medical 
history/concurrent medical conditions. Follow-up laboratory tests as described in Section 6.5 
must also be performed. In addition, if the LFT increases are SAEs, a Liver Function Test 
Increase Form must be completed and transmitted (see Section 6.2.1.14.2). 


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6.2.1.4 
Adverse Events of Special Interest 
An AE of special interest (AESI) is defined as a noteworthy event for the particular product 
or class of products that a sponsor may wish to monitor carefully. It could be serious or 
non-serious (eg, hair loss, loss of taste, impotence), and could include events that might be 
potential precursors or prodromes for more serious medical conditions in susceptible 
individuals.  
AESI includes any event described in the AESI list (Table 6-2). 
Table 6-2 
Adverse Events of Special Interest List 
Term 
Hepatotoxicity  
Severe cutaneous adverse reactions 
Clostridioides difficile infections and Pseudomembranous colitis 
Hypergastrinemia 
Bone fracture 
For additional details on liver function monitoring see Section 13.3. 
6.2.1.5 
Additional Points to Consider for PTEs and AEs 
An untoward finding generally may involve the following:  
• Indicates a new diagnosis or unexpected worsening of a pre-existing condition. 
(intermittent events for pre-existing conditions or underlying disease should not be 
considered PTEs or AEs.)  
• Necessitates therapeutic intervention.  
• Requires an invasive diagnostic procedure.  
• Requires discontinuation or a change in dose of study drug or a concomitant medication.  
• Is considered unfavorable by the investigator for any reason.  
• Is caused by a study procedure (eg, a bruise after blood draw); those events should be 
recorded as a PTE/AE.  


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Diagnoses versus signs and symptoms:  
• Each event is required to be recorded to represent a single diagnosis, or disorder using 
standard medical terminology, rather than its individual symptoms. Accompanying signs 
(including abnormal laboratory values or electrocardiogram [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 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 a pathology for which 
there is an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only 
should be reported as a PTE or as an AE. 
Pre-existing conditions:  
• Pre-existing conditions (present at the time of signing informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, or X-rays) should NOT be recorded as PTEs 
unless related to study procedures. However, if the subject experiences a worsening or 
complication of a concurrent condition, the worsening or complication should be 
recorded appropriately as a PTE (worsening or complication occurs before start of study 
drug) or an AE (worsening or complication occurs after start of study drug). 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…”).  


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• 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 than 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 drug, 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 
drug, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, 
“worsening of…”). 
• At each required study visit, all AEs that have occurred since the previous visit or AEs 
that have changed in severity since the previous visit must be recorded in the AE record 
of the eCRF. 
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. 
Preplanned procedures:  
• Preplanned procedures 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 procedure should be reported as AEs. 
Elective surgeries or procedures:  


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• Elective procedures performed where there is no change in the subject’s medical 
condition should not be recorded as PTEs or AEs but should be documented in the 
subject’s source documents. Complications resulting from an elective surgery should be 
reported as AEs. 
Insufficient clinical response (lack of efficacy):  
• Insufficient clinical response, efficacy, or pharmacologic action should NOT be recorded 
as an AE. The investigator must make the distinction between exacerbation of pre-
existing illness and lack of therapeutic efficacy. 
Overdose:  
• Any manifested side effects will be considered AEs and will be recorded on the AE page 
of the eCRF. 
6.2.1.6 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s 
daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria: 
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. 
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of onset and duration of each episode. 
6.2.1.7 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to the study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 


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The relationship or association of each AE to study drug(s) will be assessed using the 
following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a 
study 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 study drug and/or that can reasonably be explained by other 
factors, such as underlying diseases, complications, concomitant drugs, and 
concurrent treatments. 
6.2.1.8 
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. 
6.2.1.9 
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. 
6.2.1.10 
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. 
6.2.1.11 
Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of 
consecutive days are considered intermittent. All other events are considered continuous. 
6.2.1.12 
Action Concerning Study Drug 
• Drug withdrawn – a study drug is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study drug.  


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• Unknown – only to be used if it has not been possible to determine what action has been 
taken.  
• Not Applicable – a study drug was stopped for a reason other than the particular AE eg, 
the study has been terminated, the subject died, or dosing with the study drug was already 
stopped before the onset of the AE.  
• Dose Interrupted – the dose was interrupted/held due to the particular AE. 
6.2.1.13 
Outcome 
• Recovered/Resolved –the subject returned to baseline status with respect to the AE/PTE.  
• Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved but has 
not returned to the normal range or to baseline; or 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 worsened from 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 the cause of death.  
• Unknown – the course of the AE/PTE cannot be followed up due to a hospital change or 
residence change at the end of the subject’s participation in the study. 
6.2.1.14 
Time Period and Frequency for Collecting AE and SAE 
Information 
6.2.1.14.1 
Collection and Reporting of Adverse Events 
Collection of PTEs (including PTEs that are SAEs) 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 drug or until screen failure. For subjects who discontinue prior to study 


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drug administration, PTEs are collected until the subject discontinues study participation. 
Collection of AEs (including AEs that are SAEs) will commence from the time that the 
subject is first administered study drug (Day 1). Routine collection will continue until the end 
of the Follow-Up Period or withdrawal from the study. 
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 drug or not, must be monitored until the 
symptoms subside and any clinically relevant changes in laboratory values have returned to 
baseline or until there is a satisfactory explanation for the changes observed.  
All PTEs and AEs will be documented in the PTE/AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event: 
1. Event term  
2. Start and stop date  
3. Severity 
4. Investigator’s opinion of the causal relationship between the event and administration of 
study drug(s) (related or not related) (not completed for PTEs)  
5. Investigator’s opinion of the causal relationship to study procedure(s), including the 
details of the suspected procedure  
6. Action concerning study drug (not applicable for PTEs)  
7. Outcome of event  
8. Seriousness  


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6.2.1.14.2 
Collection and Reporting of Serious Adverse Events 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:  
An SAE eCRF form must be completed and submitted via Medidata Rave immediately or 
within 24 hours of the investigator first becoming aware of the SAE occurrence, including 
for those SAEs that are PTEs. The information should be completed as fully as possible but 
contain, at a minimum:  
• A short description of the event and the reason why the event is categorized as serious  
• Subject identification number  
• Investigator’s name  
• Name of the study drug(s) 
• Causality assessment  
If the Medidata Rave system is not functioning for any reason, a paper SAE case report form 
must be completed (in English), signed by the investigator and faxed to the contact listed 
below. 
The SAE eCRF form should be transmitted within 24 hours to 
:  
 
 
 
 
 
 
 
 
Any SAE spontaneously reported to the investigator following the AE collection period 
should be reported to the sponsor if considered related to study participation.  
Investigators are not obligated to actively seek information regarding new AEs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a subject has been discharged from the study, and he/she 


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considers the event to be reasonably related to the study drug or study participation, the 
investigator must promptly notify the sponsor. Reporting of serious PTEs will follow the 
procedure described for SAEs. 
6.2.1.14.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator should update the SAE eCRF form 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 provided 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. 
6.2.1.14.4 
Safety Reporting to Investigators, IRBs or IECs, and 
Regulatory Authorities 
The sponsor designee (contract research organization) will be delegated the responsibility for 
reporting all suspected unexpected serious adverse reactions (SUSARs) and any other 
applicable SAEs to regulatory authorities, including the European Medicines Agency, 
investigators and the Institutional Review Boards (IRBs) or Independent Ethics Committees 
(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 an 
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 designee 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. 
6.2.1.15 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor /sponsor designee of an SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of subjects 
and the safety of a study drug under clinical investigation are met. 


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The sponsor/sponsor designee has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study drug under clinical 
investigation. The sponsor/sponsor designee will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IEC, and 
investigators. 
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for SUSARs according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it and will notify the IRB/IEC, if appropriate according to local requirements. 
If there is an increase in unexpected SAEs or if there is a change in the frequency and 
character of expected SAEs based on the known safety profile of vonoprazan, further 
evaluation will be conducted to characterize these events and any impact on benefit/risk. 
Health Authorities will be consulted to agree upon the appropriate action to be taken 
regarding the conduct of the study including no change to the protocol, revision of the safety 
monitoring plan, suspension of enrollment, or discontinuation of the study. 
6.3 Safety Monitoring Committee 
Not applicable. 
6.4 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn, and any 
sponsor-supplied drug (vonoprazan active, lansoprazole active, amoxicillin active, 
clarithromycin active) should be immediately discontinued. If the pregnancy occurs during 
administration of active study drug, eg, after Visit 2 (Randomization) or within 4 weeks of 
the last dose of active study drug, the pregnancy should be reported immediately, using a 
pregnancy notification form, to the contact listed in Section 6.2.1.14.2. 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 


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the primary care physician that the subject was participating in a clinical study at the time she 
became pregnant and provide details of the treatment the subject received (blinded or 
unblinded, as applicable). All pregnancies in subjects on active study drug including 
comparator will be followed up to final outcome, using the pregnancy form. The outcome, 
including any premature termination, must be reported to the sponsor. An evaluation after the 
birth of the child will also be conducted. 
6.5 Laboratory Analyses 
• See Table 6-3 for the list of clinical laboratory tests to be performed and to the SoE 
(Section 13.1) for the timing and frequency. 
• The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Abnormal laboratory findings 
that are expected with the underlying disease should not be considered clinically 
significant unless judged by the investigator to be more severe than expected for the 
subject's condition.  
• All laboratory tests with abnormal values considered clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor 
notified. 
• All protocol-required laboratory assessments, as defined in Table 6-3, must be conducted 
in accordance with the Laboratory Manual and the SoE. 
• If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in subject management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the Unscheduled Labs eCRF. 
All samples will be collected in accordance with acceptable laboratory procedures. Details of 
these procedures and required safety monitoring will be provided in the Laboratory Manual. 


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All study-required laboratory assessments will be performed by a central laboratory. 
Table 6-3 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
• 
Platelet count 
• 
RBC count 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC indices: MCV, MCH 
• 
%Reticulocytes 
• 
WBC count with differential: neutrophils, lymphocytes, monocytes, eosinophils, 
basophils 
Clinical chemistrya 
• 
Blood urea nitrogen  
• 
Creatinine 
• 
Total and direct bilirubin 
• 
ALT/ SGPT 
• 
AST/ SGOT 
• 
Alkaline phosphatase 
• 
Total protein 
• 
Potassium 
• 
Sodium 
• 
Calcium 
• 
Glucose, fasting 
• 
GGT  
Routine urinalysis 
• 
Specific gravity, appearance, color 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase  
• 
Microscopic examination (if blood or protein is abnormal) 
Other screening 
tests 
• 
FSH if menopause is suspectedb 
• 
Urine drug screen including amphetamines (including methamphetamine), 
barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, methadone and 
phencyclidinec 
• 
Serum human chorionic gonadotropin (hCG) pregnancy testd at Screening Visit 1 
• 
Urine human chorionic gonadotropin (hCG) pregnancy testd at randomization 
and all other study visits 
• 
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C 
virus antibody; hepatitis C viral load RNAe [Qualitative]) 


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Laboratory 
Assessments 
Parameters 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; eCRF, electronic case report 
form; FSH, follicle-stimulating hormone; GGT, gamma-glutamyl transferase; HIV, human 
immunodeficiency virus; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; RBC, 
red blood cells, RNA, ribonucleic acid; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum 
glutamic-pyruvic transaminase; ULN, upper limits of normal; WBC, white blood cell. 
a 
For liver test monitoring see Section 13.3.1. For temporary and permanent discontinuation of study 
drugs due to abnormal liver function tests see Section 13.3.2 and Section 13.3.3, respectively.  
b 
Follicle-stimulating hormone will be conducted at the investigator’s discretion to determine the 
postmenopausal status of women whose duration of (consecutive) amenorrhea is borderline or open to 
doubt and where the investigator believes the subject to be menopausal by history. 
c 
The central laboratory will confirm any positive drug screen results.  
d 
As needed for women of childbearing potential. Serum pregnancy test will be performed if the urine 
pregnancy test is positive at randomization and all other visits. 
e 
Reflex- if Hepatitis C positive 
Investigators must document their review of each laboratory safety report. 
6.6 Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight will 
also be measured and recorded. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
6.7 Vital Signs 
Vital signs will include body temperature (oral, tympanic or temporal measurement), sitting 
blood pressure (resting more than 5 minutes), and pulse (beats per minute). 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.  
6.8 Electrocardiograms 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using one of the following categories: within 
normal limits, abnormal but not clinically significant, or abnormal and clinically significant. 
The following parameters will be recorded on the eCRF from the subject’s ECG trace: heart 


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rate, RR interval, PR interval, QT interval and QRS interval. A copy of the ECG trace should 
be kept with the subject’s notes. For ECG results printed on thermal paper, nonthermal paper 
copies should be made to avoid degradation of trace over time. 
6.9 Pharmacogenetics 
Collection for genotyping is optional. Subjects willing to participate must sign the informed 
consent form. During the study, a blood sample will be collected for CYP2C19 genotype 
testing to determine the subject’s metabolizer status, unless prohibited by local regulations. 
The DNA sample collected from each subject will be used for CYP2C19 genotyping 
analysis. Genetic variation in the CYP2C19 gene may lead to changes in metabolic activity 
of the CYP2C19 enzyme that may contribute to the variability in the clinical efficacy of 
lansoprazole. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the subject. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent.  
Details on processes for collection and shipment and destruction of these samples can be 
found in the Laboratory Manual. 
6.10 Pharmacogenomics 
Gastric mucosal biopsy specimens that were not used for culture (and subsequent 
antimicrobial susceptibility testing; Section 6.1.2.1) or histopathology evaluation 
(Section 6.1.2.2) may be available from the central laboratory and may be used for possible 
future genomic analysis of HP in the specimens.  
6.11 Pharmacokinetics 
During the study, blood samples will be collected for pharmacokinetic analysis of drug 
concentrations, unless prohibited by local regulations. The sample collection day will be per 
the SoE (Section 13.1). Details for collection, sample processing, shipment, and destruction 
of these samples can be found in the Laboratory Manual. 
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7 
Statistical and Analytical Plan 
This section briefly describes the statistical and analytical methods to be used for the study. A 
statistical analysis plan (SAP) will provide details of the statistical methods and definitions 
for the analysis of efficacy and safety data. To preserve the integrity of the statistical analysis 
and study conclusions, the SAP will be finalized before database lock. 
7.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with successful HP eradication 
after the Treatment Period, as determined by 13C-UBT, at 4 weeks after the last dose of study 
drug, in subjects who do not have a clarithromycin or amoxicillin resistant strain of HP at 
baseline. 
7.2 Secondary Efficacy Endpoint 
The secondary efficacy endpoints are the proportion of subjects with successful HP 
eradication after the Treatment Period, as determined by 13C-UBT, at 4 weeks after the last 
dose of study drug, among subjects who had a clarithromycin resistant strain of HP at 
baseline and the proportion of subjects with successful HP eradication after the Treatment 
Period, as determined by 13C-UBT, at 4 weeks after the last dose of study drug among all 
subjects. 
7.3 Sample Size Calculations 
Assuming a true eradication rate for the primary endpoint of 90% for lansoprazole triple 
therapy and 90% for both vonoprazan triple therapy and vonoprazan dual therapy, a sample 
size of 260 subjects per treatment group provides >90% power to achieve noninferiority with 
a noninferiority margin of 10% using the Farrington Manning test (Farrington and Manning 
1990). Assuming 20% of subjects will have a clarithromycin resistant strain of HP at 
baseline, 325 subjects per treatment group (975 total) will be enrolled. 
A fixed noninferiority margin of -10% is justified based on the following historical 
eradication rates. These historical eradication rates are from studies in which the 
clarithromycin resistance rate was low (approximately 5%) and are therefore relevant to 
establishing the noninferiority margin for the primary endpoint in this study.  


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• A pooled estimate of the eradication rate for lansoprazole triple therapy of 83%, based on 
the eradication rates with lansoprazole triple therapy from three studies (M93-131, M95-
392, and M95-399) as reported in the US full prescribing information for Prevacid 
(PREVACID 2018). 
• A pooled estimate of the eradication rate for a regimen of amoxicillin 2 g and 
clarithromycin 1 g of 42%, based on eradication rates with amoxicillin and 
clarithromycin reported in Study M95-392 and in three studies included in the US full 
prescribing information for Prilosec (PRILOSEC 2016). 
• An eradication rate for amoxicillin 3 g of 0% from a double-blind, multicenter study 
evaluating lansoprazole and amoxicillin dual therapy (Harford et al 1996). 
For the comparison of the two triple therapies, the difference in the HP eradication rate for 
triple therapy with lansoprazole (83%) versus treatment with a combination of amoxicillin 
and clarithromycin (42%) is 41%; the lower limit of the 2-sided 95% CI for the difference is 
34%. Using the conservative assumption of the lower bound as the true treatment effect of 
lansoprazole triple therapy, a -10% noninferiority margin assures that the vonoprazan triple 
therapy regimen retains at least 70% of the treatment effect of lansoprazole triple therapy. 
For the comparison of vonoprazan dual therapy to lansoprazole triple therapy, the difference 
in the HP eradication rate for triple therapy with lansoprazole (83%) versus treatment with 
amoxicillin alone (0%) is 83%; the lower limit of the 2-sided 95% CI for the difference is 
75%. Using the conservative assumption of the lower bound as the true treatment effect of 
lansoprazole triple therapy, a -10% noninferiority margin assures that the vonoprazan dual 
therapy regimen retains at least 87% of the treatment effect of the active control 
(lansoprazole triple therapy). 
7.4 Analysis Sets 
In this study, 3 analysis sets are defined: modified intent-to-treat (MITT) analysis set, the per 
protocol (PP) analysis set, and the safety analysis set. The primary and secondary endpoints 
will be summarized using the MITT and PP sets, respectively. The MITT set will be 
considered the primary population for efficacy analysis. 


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The MITT analysis set includes the randomized subjects with HP infection documented by 
13C-UBT and biopsy at baseline. The MITT analysis set will be analyzed according to the 
treatment group into which each subject was randomized. Subjects who do not have a post-
baseline 13C-UBT will be considered treatment failures, ie, “not eradicated.” 
The PP analysis set includes the randomized subjects with all of the following: 
• The subject is included in the MITT analysis set 
• Visit 4 occurs between 28 and 56 days after the end of treatment with documented 
diagnostic testing by 13C-UBT, unless the subject has documented persistence of HP 
infection at any time after the end of treatment 
• At least 75% of each study drug was taken, unless caused by treatment failure  
• An antimicrobial known to be effective against HP was not taken within 7 days of Day 1, 
during treatment, or between completion of treatment and the test-of-cure visit, unless 
given for treatment failure 
• A proton pump inhibitor or high dose (as per below) H2-receptor antagonist was not taken 
within 14 days of Day 1, during treatment, or between completion of treatment and the 
test-of-cure visit, unless given for treatment failure 
Subjects can use no more than standard doses of H2-receptor antagonists, as indicated below, 
and still be included in the per-protocol population: 
• Ranitidine less than or equal to 300 mg/day 
• Cimetidine less than or equal to 800 mg/day 
• Famotidine less than or equal to 40 mg/day  
• Nizatidine less than or equal to 300 mg/day  
The PP analysis set will be analyzed with each subject included in the treatment group 
according to the treatment group into which each subject was randomized. 
The safety analysis set will include all subjects who received at least one dose of study drug 
and will be summarized by treatment group according to the test treatment each subject 
received in the trial. 


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7.5 Description of Subgroups to be Analyzed 
Subgroup analyses for the primary endpoint will be conducted for demographic and other 
relevant clinical variables, including age, sex, body mass index, smoking status, alcohol use, 
clinical condition, study drug compliance, CYP2C19 status, region, and baseline 
susceptibility to amoxicillin, clarithromycin, and metronidazole. 
7.6 Statistical Analysis Methodology 
Statistical analysis will be performed using SAS software Version 9.4 or later. Continuous 
variables will be summarized using the mean, the standard deviation, median, minimum 
value, and maximum value. Categorical variables will be summarized using frequency counts 
and percentages.  
7.6.1 
Efficacy Analyses 
The primary endpoint (proportion of subjects with successful HP eradication after the 
Treatment Period, as determined by 13C-UBT, at 4 weeks after the last dose of study drug in 
subjects who do not have a clarithromycin or amoxicillin resistant strain of HP at baseline) 
will be calculated as a percentage of subjects in each treatment group.  
The noninferiority of vonoprazan triple therapy to lansoprazole triple therapy, and 
vonoprazan dual therapy to lansoprazole triple therapy, will be evaluated with a Farrington 
and Manning test with a noninferiority margin of 10 percentage points for the difference in 
HP eradication rates between treatments. The point estimate and 2-sided 95% CI of the 
difference in HP eradication rates between each of the pairs of treatments will be calculated 
via the Miettinen and Nurminen method. For each noninferiority comparison that yields 
statistical significance, superiority will then be assessed via the Farrington and Manning test 
of the null hypothesis difference ≤ 0 versus the alternative hypothesis difference > 0. 
The secondary endpoints will be evaluated in a similar manner as the primary endpoint for 
superiority of vonoprazan triple therapy to lansoprazole triple therapy and of vonoprazan 
dual therapy to lansoprazole triple therapy.  
In these analyses, subjects who do not have a post-baseline 13C-UBT will be considered 
treatment failures, ie, “not eradicated.” 


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Methodology for control of Type I error among the among multiple comparisons will be 
addressed in the statistical analysis plan. 
7.6.2 
Safety Analyses 
Safety analysis will be performed using the safety analysis set.  
Adverse Events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). A treatment-emergent adverse event (TEAE) will be defined as an AE occurring 
after receiving the first dose of study medication. 
The number and proportion of subjects with TEAEs will be summarized by MedDRA 
System Organ Class (SOC) and Preferred Term (PT) overall, by severity, and by relationship 
to study drug for each treatment group. Separate summaries will also be generated for 
treatment-related AEs overall and by severity.  
For tabulations of TEAE frequency, if a subject has more than 1 episode of the same event, 
the subject will be counted only once for that event. If a subject has more than 1 TEAE that is 
coded to the same PT, the subject will be counted only once for that PT. If a subject has more 
than 1 TEAE within a SOC, the subject will be counted only once for that SOC. In the 
tabulation of TEAE frequency by intensity, a subject will be counted only once using the 
highest severity for each PT and SOC. 
Change from baseline in laboratory test values and in vital signs will be summarized by 
treatment group. The number and proportion of subjects with markedly abnormal values for 
laboratory tests and vital signs will be summarized. No statistical testing or inferential 
statistics will be generated. 
7.6.3 
Other Analyses 
Demographics and other baseline characteristics will be summarized overall and by treatment 
group using the MITT, per protocol, and safety analysis sets. 
7.6.4 
Interim Analyses 
No interim analysis is planned. 


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8 
Data Quality Assurance 
This study will be conducted according to the International Council for Harmonisation (ICH) 
E6 R2 risk and quality processes described in the applicable procedural documents. The 
quality management approach to be implemented in this study will be documented and will 
comply with the current ICH guidance on quality and risk management. 
8.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include diary cards, laboratory 
reports, ECG strips, etc. 
Investigative site personnel will enter subject data into electronic data capture system. The 
analysis data sets will be a combination of these data and data from other sources (eg, 
laboratory data). 
Clinical data management will be performed in accordance with applicable sponsor’s 
standards and data cleaning procedures to ensure the integrity of the data, eg, removing errors 
and inconsistencies in the data. Adverse event terms will be coded using MedDRA, and 
concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHODRUG). 
After database lock, each study site will receive a CDROM containing all of their site 
specific eCRF data as entered into Medidata Rave for the study, including full discrepancy 
and audit history. Additionally, a CDROM copy of all of the study site’s data from the study 
will be created and sent to the sponsor for storage. 
 will maintain a duplicate CDROM 
copy for their records. In all cases, subject initials will not be collected or transmitted to the 
sponsor. 


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9 
Ethics 
9.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations, national regulations, and the ICH guidelines require that approval be 
obtained from an IRB/IEC before participation of human subjects in research studies. Before 
study onset, the protocol, informed consent, advertisements to be used for the recruitment of 
study subjects, and any other written information regarding this study to be provided to the 
subject must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and of 
the IRB/IEC compliance with ICH harmonised tripartite guideline E6: Good Clinical Practice 
(GCP) will be maintained by the site and will be available for review by the sponsor or its 
designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
9.3 Subject Information and Consent 
A written informed consent in compliance with the respective applicable regulatory authority 
regulations shall be obtained from each subject before entering the study or performing any 
unusual or nonroutine procedure that involves risk to the subject. An informed consent 
template may be provided by the sponsor to investigative sites. If any institution-specific 
modifications to study-related procedures are proposed or made by the site, the consent 
should be reviewed by the sponsor or its designee or both before IRB/IEC submission. Once 
reviewed, the consent will be submitted by the investigator to his or her IRB/IEC for review 


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and approval before the start of the study. If the ICF is revised during the course of the study, 
all active participating subjects must sign the revised form. 
Before recruitment and enrollment, each prospective subject will be given a full explanation 
of the study and be allowed to read the approved ICF. Once the investigator is assured that 
the subject understands the implications of participating in the study, the subject will be 
asked to give consent to participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the subject. 


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10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject, except as necessary for monitoring and auditing by the sponsor, its 
designee, the US Food and Drug Administration (FDA), or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 Code of Federal Regulations (CFR) 54. In addition, the investigator must provide to the 
sponsor a commitment to promptly update this information if any relevant changes occur 
during the course of the investigation and for 1 year following the completion of the study. 
Neither the sponsor nor 
 is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor 
 is financially responsible for 
further treatment of the subject’s disease. 


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10.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6 8.2 and 
Title 21 of the CFR by providing the following essential documents, including but not limited 
to the following: 
• IRB/IEC approval. 
• Original investigator-signed investigator agreement page of the protocol. 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 for US sites and equivalent form for non-US sites. 
• Curriculum vitae for the investigator and each sub-investigator listed on Form FDA 1572 
or equivalent form for non-US sites. 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, the 
investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
• IRB/IEC-approved informed consent, samples of site advertisements for recruitment for 
this study, and any other written information regarding this study that is to be provided to 
the subject. 
• Laboratory certifications and normal ranges for any local laboratories used by the site, in 
accordance with 42 CFR 493. 
10.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6. The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of subjects begins. 
10.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6 and all applicable guidelines and regulations. 


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10.6 Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs to the 
sponsor and/or IRB/IEC according to the timeline and method outlined in the protocol. In 
addition, the investigator agrees to submit annual reports to the study site IRB/IEC as 
appropriate. 
10.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
10.8 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
10.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The sponsor has final approval authority over all 
such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 


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11 Study Management 
11.1 Monitoring 
11.1.1 
External Data Monitoring Committee 
Not applicable. 
11.1.2 
Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals, 
in addition to maintaining necessary telephone and letter contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the investigator and 
personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.3 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, representatives 
of the sponsor, or a regulatory agency access to all study records. 
The investigator should promptly notify the sponsor and 
 of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or its 


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designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB/IEC for approval before subjects can be enrolled into an amended protocol. 
11.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to the sponsor for agreement, 
and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
subject or investigator that results in a significant, additional risk to the subject. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, or nonadherence to 
FDA regulations or ICH GCP guidelines, and will lead to the subject being withdrawn from 
the study (Section 4.2). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal investigators will be notified in writing by the monitor of 
deviations. The IRB/IEC should be notified of all protocol deviations in a timely manner. 
11.3 Study Termination 
Although the sponsor has every intention of completing the study, the sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes Follow-up Visit). 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 


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reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the clinical study report, the sponsor will provide the investigator with 
the full summary of the study results. The investigator is encouraged to share the summary 
results with the study subjects, as appropriate. The study results will be posted on publicly 
available clinical trial registers. 


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12 Reference List 
Brawner KM, Morrow CD, Smith PD. Gastric microbiome and gastric cancer. Cancer J 
2014;20(3):211-6. 
Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: Treatment of 
Helicobacter pylori Infection. Am J Gastroenterol 2017;112(2):212-39. 
Crowe SE. Helicobacter pylori infection. N Engl J Med 2019;380(12):1158-65. 
Electronic Medicines Compendium (eMC). Zentiva. Lansoprazole 30mg Gastro-resistant 
Capsules. Summary of Product Characteristics (SmPC). 2018. Available at: 
https://www.medicines.org.uk/emc/product/4010/smpc. Accessed 28 June 2019. 
Erah PO, Goddard AF, Barrett DA, et al. The stability of amoxycillin, clarithromycin and 
metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection. 
J Antimicrob Chemother. 1997;39(1):5-12. 
Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial 
trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med 
1990;9:1447–54. 
Furuta T, Sahara S, Ichikawa I, et al. Dual therapy with vonoprazan and amoxicillin is as 
effective as standard PPI-based triple therapy with amoxicillin and clarithromycin or 
metronidazole in Japan. Gastroenterol 2016;150(4 Suppl 1):S877. Digestive Disease Week 
2016, Abstract No. Tu1333. 
Furuta T, Sugimoto M, Sahara S, et al. Comparison of vonoprazan and high doses of PPI as 
the acid inhibitor in the rescue therapy for eradication of H. Pylori. 2018:S1165. Abstract No. 
Tul 300. 
Graham DY, Lu H, Shiotani A. Failure of optimized dual proton pump inhibitor amoxicillin 
therapy: What now? Saudi J Gastroenterol 2017;23(5):265-7. 
Graham DY, Dore MP. Update on the use of vonoprazan: A competitive acid blocker. 
Gastroenterology 2018;154(3):462-6. 


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Harford W, Lanza F, Arora A, et al. Double-blind, multicenter evaluation of lansoprazole and 
amoxicillin dual therapy for the cure of Helicobacter pylori infection. Helicobacter 
1996;1(4):243-50. 
Hassan IJ, Stark RM, Greenman J, Millar MR. Activities of beta-lactams and macrolides 
against Helicobacter pylori. Antimicrob Agents Chemother 1999;43(6):1387-92. 
International Agency for Research on Cancer (IARC). Global Cancer Observatory. Available 
at: http://globocan.iarc.fr/Pages/online.aspx. Accessed 23 May 2019. 
Jenkins H, Sakurai Y, Nishimura A, et al. Randomised clinical trial: safety, tolerability, 
pharmacokinetics and pharmacodynamics of repeated doses of TAK-438 (vonoprazan), a 
novel potassium-competitive acid blocker, in healthy male subjects. Aliment Pharmacol Ther 
2015;41(7):636-48. 
Malfertheiner P, Megraud F, O'Morain CA, et al. Management of Helicobacter pylori 
infection-the Maastricht V/Florence Consensus Report. Gut 2017;66(1):6-30. 
Marcus EA, Inatomi N, Nagami GT, et al. The effects of varying acidity on Helicobacter 
pylori growth and the bactericidal efficacy of ampicillin. Aliment Pharmacol 
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Megraud F. The challenge of Helicobacter pylori resistance to antibiotics: the comeback of 
bismuth-based quadruple therapy. Therap Adv Gastroenterol 2012;5(2):103-9. 
Meyer JM, Silliman NP, Wang W, et al. Risk factors for Helicobacter pylori resistance in the 
United States: the surveillance of H. pylori antimicrobial resistance partnership (SHARP) 
study, 1993-1999. Ann Intern Med 2002;136(1):13-24. 
Murakami K, Sakurai Y, Shiino M, et al. Vonoprazan, a novel potassium-competitive acid 
blocker, as a component of first-line and second-line triple therapy for Helicobacter pylori 
eradication: a phase III, randomised, double-blind study. Gut. 2016 Sep;65(9):1439-46.  
Nomura A, Stemmermann GN, Chyou PH, et al. Helicobacter pylori infection and gastric 
carcinoma among Japanese Americans in Hawaii. N Engl J Med 1991;325(16):1132-6. 


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O’Connor HJ. The role of Helicobacter pylori in peptic ulcer disease. Scand J Gastroenterol 
Suppl 1994;201:11-5. 
O’Connor A, O’Morain C. Helicobacter pylori infection in Europe: current perspectives. 
Expert Rev Gastroenterol Hepatol 2013;7(6):541-8. 
Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk 
of gastric carcinoma. N Engl J Med 1991;325(16):1127-31. 
Plummer M, Franceschi S, Vignat J, Forman D, de Martel C. Global burden of gastric cancer 
attributable to Helicobacter pylori. Int J Cancer 2015;136(2):487-90. 
PREVACID (lansoprazole) delayed-release capsules, for oral use PREVACID SOLTAB 
(lansoprazole) delayed-release orally disintegrating tablets [package insert]. Takeda 
Pharmaceuticals America, Inc., Deerfield (IL); 2018. 
PRILOSEC® (omeprazole) delayed-release capsules PRILOSEC® (omeprazole magnesium) 
for delayed-release oral suspension [package insert]. AstraZeneca Pharmaceuticals LP 
Wilmington (DE); 2016. 
Sakurai Y, Mori Y, Okamoto H, et al. Acid-inhibitory effects of vonoprazan 20 mg compared 
with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects-a randomised 
open-label cross-over study. Aliment Pharmacol Ther 2015;42(6):719-30. 
Savoldi A, Carrara E, Graham DY, Conti M, Tacconelli E. Prevalence of antibiotic resistance 
in Helicobacter pylori: A systematic review and meta-analysis in World Health Organization 
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Scott DR, Munson KB, Marcus EA, Lambrecht NW, Sachs G. The binding selectivity of 
vonoprazan (TAK-438) to the gastric H+, K+ -ATPase. Aliment Pharmacol Ther 
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Shiota S, Reddy R, Alsarraj A, El-Serag HB, Graham DY. Antibiotic resistance of 
Helicobacter pylori among male United States veterans. Clin Gastroenterol Hepatol 
2015;13(9):1616-24. 
Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the 
development of gastric cancer. N Engl J Med 2001;345(11):784-9. 
Vakil N. Primary and secondary treatment for Helicobacter pylori in the United States. Rev 
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13 Appendices 
 


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13.1 Appendix 1: Schedule of Events 
Table 13-1 
Schedule of Events 
  
Screening 
Period 
 
Treatment Period 
Follow-Up Period 
Early 
Termination 
Timing 
 
Day -1 a 
Week 0 
Day 1 
Week 1 
Day 8  
Week 2 
Day 15  
Week 4 
Day 29 
4-Week  
Post-
Treatment 
Visit Windows (Days): 
-35 to -2 
- 
- 
6 to 10 
15 to 18 
26 to 32  
42 to 70 
 
Visit Number: 
1 
2 
NA 
Phone call b 
3 
Phone call c 
4 
- 
Informed consent 
Xd 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
Smoking status and alcohol use 
X 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
Physical examination e 
X 
X 
 
 
X 
X 
X 
Vital signs  
X 
X 
 
 
X 
X 
X 
Weight and height 
X 
 
 
 
Concomitant medications 
X 
X 
 
X b  
X 
X c 
X 
X 
Concurrent medical conditions 
X 
 
 
 
13C-UBT for HP infection status 
X f 
 
 
X g 
X h 
Hepatitis B & C + HIV 
X 
 
 
 
Urine drug screen 
X 
 
 
 
Clinical laboratory test including 
hematology, serum chemistry, 
urinalysis 
X 
 
 
X 
X 
FSH i 
X 
 
 
 


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Screening 
Period 
 
Treatment Period 
Follow-Up Period 
Early 
Termination 
Timing 
 
Day -1 a 
Week 0 
Day 1 
Week 1 
Day 8  
Week 2 
Day 15  
Week 4 
Day 29 
4-Week  
Post-
Treatment 
Visit Windows (Days): 
-35 to -2 
- 
- 
6 to 10 
15 to 18 
26 to 32  
42 to 70 
 
Visit Number: 
1 
2 
NA 
Phone call b 
3 
Phone call c 
4 
- 
Pregnancy test (serum hCG) j,  
X 
 
 
 
Pregnancy test (urine hCG) j 
X k 
 
 
X k 
X k 
X k 
Guidance on avoidance of pregnancy 
X 
X 
 
 
X 
X 
CYP2C19 genotyping test  
 
 
 
 
X l 
 
 
 
ECG 
X 
 
 
 
X 
 
 
X 
Endoscopy 
X 
 
 
 
 
 
X g 
 
Gastric mucosa biopsy for antibiotic 
susceptibility test m, n 
X o 
 
 
 
 
 
X g 
 
Gastric mucosa biopsy for presence of 
HP n, p 
X 
 
 
 
 
 
 
 
Randomization  
 
X a 
 
 
 
 
 
 
Dispense study drug 
 
X 
 
 
 
 
 
 
First day of study drug administration  
 
 
X 
 
 
 
 
 
Study drug return/ 
accountability/review treatment 
compliance q 
 
 
 
X b  
X 
 
 
X 
Pharmacokinetics r 
 
 
 
 
X 
 
 
  
AE/pre-treatment event assessment 
X 
X 
 
X b 
X 
X c 
X 
X 


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Screening 
Period 
 
Treatment Period 
Follow-Up Period 
Early 
Termination 
Timing 
 
Day -1 a 
Week 0 
Day 1 
Week 1 
Day 8  
Week 2 
Day 15  
Week 4 
Day 29 
4-Week  
Post-
Treatment 
Visit Windows (Days): 
-35 to -2 
- 
- 
6 to 10 
15 to 18 
26 to 32  
42 to 70 
 
Visit Number: 
1 
2 
NA 
Phone call b 
3 
Phone call c 
4 
- 
Abbreviations: AE, adverse events; CYP2C19, cytochrome P450 2C19; ECG, electrocardiogram; FSH, follicle-stimulating hormone; hCG, human 
chorionic gonadotropin; HIV, human immunodeficiency virus; HP, Helicobacter pylori; NA, not applicable; PPI, proton pump inhibitor; UBT, 
urea breath test. 
a 
The date of randomization is defined as Day -1. 
b 
Subjects will receive a phone call for Week 1, Day 8 that will include a compliance reminder, and an assessment of concomitant medications 
and any AEs. 
c 
Subjects will receive a phone call for Week 4, Day 29 that will include an assessment of concomitant medications and any AEs. 
d 
Subjects may be pre-screened for HP infection using a fingerstick test performed not more than 30 days prior to screening. The subjects will 
sign a pre-screening ICF for optional fingerstick test of HP status. 
e 
Full physical examination is performed at baseline; a brief physical examination is performed at all other visits. 
f 
If the subject takes PPI prior to 13C-UBT test, it may show false negative, for those cases retest can be allowed 2 weeks after the PPI 
discontinuation when appropriate in investigator’s judgment. 
g 
If subject’s 13C-UBT test is positive at 4 weeks post-treatment, an endoscopy and antibiotic susceptibility testing should be performed within 
4 weeks of a positive 13C-UBT test result. The subject can then be treated as per standard of care.  
h 
Should be performed between 4-weeks and 8-weeks after last dose of study medication. 
i 
If menopause is suspected. 
j 
Only female subjects of childbearing potential. 
k 
If the urine hCG is positive, serum hCG to be performed. 
l 
Collection for genotyping is optional. Subjects willing to participate must sign the informed consent form. 
m Gastric mucosa is to be sampled: one from the greater curve of the antrum and one from the lesser curve of the gastric body. This sample to be 
taken prior to the histopathology sample for HP. 
n 
Gastric mucosal biopsy specimens that were not used for culture (and subsequent antimicrobial susceptibility testing) or histopathology 
evaluation may be available from the central laboratory and may be used for possible future genomic analysis of HP in the specimens. 
o 
If the subject fails screening, susceptibility test is not to be performed with the collected sample. 


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Screening 
Period 
 
Treatment Period 
Follow-Up Period 
Early 
Termination 
Timing 
 
Day -1 a 
Week 0 
Day 1 
Week 1 
Day 8  
Week 2 
Day 15  
Week 4 
Day 29 
4-Week  
Post-
Treatment 
Visit Windows (Days): 
-35 to -2 
- 
- 
6 to 10 
15 to 18 
26 to 32  
42 to 70 
 
Visit Number: 
1 
2 
NA 
Phone call b 
3 
Phone call c 
4 
- 
p 
Gastric mucosa is to be sampled: one each from the greater and lesser curve of the gastric body, and one each from the greater and lesser curve 
of the antrum and sent to a central laboratory at the start of study to document HP infection. 
q 
As subjects will self-administer study drug(s) at home, compliance with study drug will be assessed at each visit. For on-site visits, compliance 
will be assessed by direct questioning and counting returned tablets/capsules during the site visits. For phone visits, a compliance reminder will 
be provided to the subjects; compliance will be assessed by direct questioning. Subject treatment compliance assessment results will be 
documented in the source documents and eCRF. 
r 
For pharmacokinetic analysis of drug concentrations, blood samples will be collected at the Week 2 Visit, unless prohibited by local 
regulations. Date and time of blood sample, as well as date and time of last study drug(s) dose will be collected in source documents and eCRF.  
 
 


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13.2 Appendix 2: Contraceptive Guidance 
Contraception Guidance: 
From signing of informed consent through Day -2, female subjects of childbearing potential* 
who are sexually active with a non-sterilized male partner** must use adequate contraception. 
Starting on Day -1, throughout the duration of the study, and for 4 weeks after the last dose of 
study drug, female subjects of childbearing potential who are sexually active with a non-
sterilized male partner must use 2 forms of adequate contraception. In addition, they must be 
advised not to donate ova during this period. 
*Females NOT of childbearing potential are defined as those who have been
surgically sterilized (hysterectomy, bilateral oophorectomy, or tubal ligation) or who
are postmenopausal (eg, defined as at least 1 year since last regular menses with an
FSH >40 IU/L or at least 5 years since last regular menses, confirmed before any
study drug is implemented).
**Sterilized males should be at least 1-year post vasectomy and should have 
confirmed that they have obtained documentation of the absence of sperm in the 
ejaculate. 
Birth Control: Birth control methods considered acceptable for this study include: 
Barrier methods (each time the subject has intercourse)1: 
•
Male condom PLUS spermicide
•
Cap (plus spermicidal cream or jelly) PLUS male condom and spermicide
•
Diaphragm (plus spermicidal cream or jelly) PLUS male condom and spermicide
1 Barrier methods are only applicable in countries where spermicide is available 
Intrauterine devices (IUDs): 
•
Copper T
•
Progesterone T PLUS condom or spermicide


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Hormonal Contraceptives: 
• Implants 
• Hormone shot/injection 
• Combined pill 
• Minipill 
• Patch 
• Vaginal ring PLUS male condom and spermicide 
During the course of the study, regular urine human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for women of childbearing potential and subjects will receive 
continued guidance with respect to the avoidance of pregnancy as part of the study 
procedures (see Section 13.1, Schedule of Events). Female subjects must have a negative 
urine hCG pregnancy test on Day 1 prior to study drug dispensation. 
 
 


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13.3 Appendix 3: Liver Safety Monitoring and Withdrawal Criteria 
13.3.1 
Liver Function Test Monitoring 
Liver function will be carefully monitored throughout the study. Additional monitoring may 
be necessary and is recommended for subjects with abnormal LFTs. 
If subjects with normal baseline ALT or AST levels experience ALT or AST >3 × ULN, and a 
2-fold increase above baseline, follow-up laboratory tests (at a minimum, serum alkaline 
phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase (GGT), and international 
normalized ratio (INR) should be repeated within a maximum of 7 days and preferably 
within 48 to 72 hours after the abnormality was found. 
If subjects with elevated baseline ALT or AST levels experience ALT or AST >5 × ULN, 
follow-up laboratory tests (at a minimum, serum alkaline phosphatase, ALT, AST, total 
bilirubin, GGT, and INR) should be repeated within a maximum of 7 days and preferably 
within 48 to 72 hours after the abnormality was found. 
If subjects with either a normal or elevated baseline ALT or AST levels experience ALT or 
AST >8 × ULN, follow-up laboratory tests (at a minimum, serum alkaline phosphatase, ALT, 
AST, total bilirubin, GGT, and INR) should be repeated within a maximum of 48 hours after 
the abnormality was found. 
13.3.2 
Considerations for Temporary Discontinuation of Study Drug 
If the ALT or AST levels remain elevated >3 × ULN in subjects with normal baseline ALT or 
AST levels and a 2-fold increase above baseline OR if the ALT or AST levels remain 
elevated >5 × ULN in subjects with elevated baseline ALT or AST levels on 2 consecutive 
occasions, the investigator must contact the medical monitor to discuss additional testing, 
recommended monitoring, possible temporary discontinuation of study medication, and 
possible alternative etiologies. 


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13.3.3 
Permanent Discontinuation of Study Drug 
If any of the following circumstances occur as mentioned in Table 13-2 at any time during 
treatment, the study medication should be permanently discontinued: 
Table 13-2 
Abnormal Liver Function Criteria For Permanent 
Discontinuation of Study Drug 
Subject Baseline Aminotransferases 
Criteria for Discontinuation of Study Medication 
Normal or Elevated ALT or AST (all subjects) 
ALT or AST >8 × ULN  
Normal ALT and AST 
ALT or AST >5 × ULN and persists for more than 
2 weeks 
ALT or AST >3 × ULN AND a 2-fold increase 
above baseline value in conjunction with elevated 
total bilirubin >2 × ULN or INR >1.5 
ALT or AST >3 × ULN AND a 2-fold increase 
above baseline value with appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash and/or eosinophilia (>5%) 
Elevated ALT or AST 
ALT or AST >5 × ULN AND persists for more than 
2 weeks 
ALT or AST >5× ULN AND elevated total bilirubin 
>2 ULN or INR >1.5 
ALT or AST >5 × ULN AND appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash and/or eosinophilia (>5%) 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international 
normalized ratio ULN, upper limit of normal 
In each of these instances, appropriate clinical follow-up should be instituted (including 
repeat laboratory tests) until a satisfactory conclusion (ie, until the AE resolves, the 
laboratory value returns to baseline, or the condition becomes stable). 
If a subject meets the liver safety criteria and must be discontinued from study medication, 
the subject will continue to be followed per the protocol schedule until the study is 
completed. If the subject refuses to return for the study visits, telephone visits may be 
conducted; however, this is not preferred nor recommended. The reason for discontinuation 
of study medication should be listed as an LFT abnormality. 


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If any of the above circumstances occur at any time during the study, the abnormality should 
be documented as an SAE, and a Liver Function Test Increase Form completed and sent to: 
 
 
 
 
 
 
 
 
The Investigator must complete the AE/SAE eCRF page. If the event meets serious criteria, 
the SAE eCRF page must be completed and an SAE Fax Notification form must be sent to 
the sponsor or sponsor’s designee within 1 working day of the repeat laboratory test. 
13.3.4 
Re-initiation of Study Drug 
If the study medication is discontinued due to any of the scenarios provided above, the study 
medication must not be re-initiated without consultation with the medical monitor. 
 
 


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13.4 Appendix 4: Protocol Amendments 
Changes to the protocol text 
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. Additions to the study protocol are shown in bold and 
deletions are shown in strike-through text. Corrections of obvious typing errors or omissions 
are not highlighted. 
13.4.1 Protocol Amendment 1 
Protocol Synopsis 
Objectives (Primary Objective): 
To compare the efficacy of HP eradication with vonoprazan dual and triple therapy regimens 
versus lansoprazole triple therapy regimen in HP+ subjects excluding subjects who had do 
not have a clarithromycin or amoxicillin resistant strain of HP at baseline 
Pharmacokinetic or Pharmacodynamic Assessments: 
In order to determine the subject’s metabolizer status, a an optional blood sample will be 
obtained for CYP2C19 genotype testing, unless prohibited by local regulations.  
Study Drug, Dosage, and Route of Administration 
All study drugs will be administered orally starting on Day 1 (the day after 
randomization).  
Statistical Methods: 
The primary endpoint (proportion of subjects with successful HP eradication after the 
Treatment Period, as determined by 13C-UBT, at 4 weeks after the last dose of study drug, 
excluding in subjects who had do not have a clarithromycin or amoxicillin resistant strain of 
HP at baseline) will be calculated as a percentage of subjects in each treatment group.  


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Table 2-1 Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• To compare the efficacy of HP eradication with 
vonoprazan dual and triple therapy regimens 
versus lansoprazole triple therapy regimen in 
HP+ subjects excluding subjects who had do not 
have a clarithromycin or amoxicillin resistant 
strain of HP at baseline 
• Proportion of subjects with successful HP 
eradication after the Treatment Period, as 
determined by 13C-UBT, at 4 weeks after the last 
dose of study drug excluding in subjects who had 
do not have a clarithromycin or amoxicillin 
resistant strain of HP at baseline 
Secondary 
 
• To compare the efficacy of HP eradication with 
vonoprazan dual and triple therapy regimens 
versus lansoprazole triple therapy regimen in 
subjects infected with a clarithromycin resistant 
strain of HP 
• To compare the efficacy of HP eradication with 
vonoprazan dual and triple therapy regimens 
versus lansoprazole triple therapy regimen in all 
subjects 
• Proportion of subjects with successful HP 
eradication after the Treatment Period, as 
determined by 13C-UBT at 4 weeks after the last 
dose of study drug, among subjects who had a 
clarithromycin resistant strain of HP at baseline 
• Proportion of subjects with successful HP 
eradication after the Treatment Period, as 
determined by 13C-UBT, at 4 weeks after the last 
dose of study drug among all subjects 
Safety 
 
• To compare the safety of vonoprazan dual and 
triple therapy regimens versus lansoprazole triple 
therapy regimen in HP+ subjects 
• Adverse events (AEs) 
• 
Laboratory test values (hematology, serum 
chemistry, urinalysis)  
• 
Electrocardiogram (ECG) 
• 
Vital signs 
 
Study Design (Section 3.1) 
The study will include 3 main periods: 
Screening Period (Day -35 to Day -2): Subjects and/or subject’s legally acceptable 
representative(s) will provide informed consent and the subject will undergo screening 
assessments to determine study eligibility, and baseline assessments will be performed. If all 
eligibility criteria are met, the subject will enter the study. 


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Inclusion Criteria (Section 4.1.1) 
2. 
In the opinion of the investigator or sub-investigators, the subject is capable of 
understanding and complying with protocol requirements. 
3. 
The subject or, when applicable, the subject’s legally acceptable representative The 
subject signs and dates a written, informed consent form (ICF) and any required 
privacy authorization prior to the initiation of any study procedures. The subject (or 
legally acceptable representative, if applicable) is informed of the full nature and 
purpose of the study, including possible risks and side-effects. The subject has the 
ability to cooperate with the investigator. Ample time and opportunity should be 
given to read and understand verbal and/or written instructions. 
 
5. 
A female subject of childbearing potential who is or may be routinely sexually active 
with a nonsterilized male partner agrees to routinely use adequate double barrier 
contraception from the signing of informed consent until Day -2 and 2 forms of 
adequate contraception from Day -1 until 4 weeks after the last dose of study drug 
as detailed in Appendix 2 (Section 13.2) of this protocol. 
 
Screen Failures (Section 4.1.4) 
If a suspected erroneous laboratory result is obtained at screening, retesting of that laboratory 
parameter will be allowed at investigator discretion with medical monitor approval. 
Rescreening of subjects is permitted if approved by the Medical Monitor. Results from 
assessments performed during the initial screening period are acceptable in lieu of a 
repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. 
 
Reasons for Withdrawal/Discontinuation (Section 4.2.1) 
5. 
Voluntary withdrawal: The subject (or subject’s legally acceptable representative) 
wishes to withdraw from the study. The reason for the withdrawal, if provided, should 
be recorded in the eCRF.  


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Handling of Withdrawals (Section 4.2.2) 
Subjects who discontinue study drug or active participation in the study will no longer 
receive study drug. When a subject withdraws from the study drug or active participation in 
the study, the reason(s) for withdrawal shall be recorded by the investigator on the relevant 
page of the eCRF. Whenever possible, all subjects who discontinue study drug or withdraw 
from the study prematurely will undergo all end of study early termination assessments. 
Subjects who fail to return for final assessments will be contacted by the site in an attempt to 
have them comply with the protocol. 
 
Treatments Administered (Section 5.2) 
Subjects randomly assigned to lansoprazole triple therapy will receive lansoprazole 30 mg 
BID in conjunction with amoxicillin 1 g BID and clarithromycin 500 mg BID for 14 days. 
All study drugs will be administered orally starting on Day 1 (the day after randomization, 
Table 13-1).  
Study drug administration will be as presented in Table 5-1.  
 
Subjects should instructed as follows: 
• Starting on Day 1, Tto take study drug(s) 30 minutes before breakfast, lunch and dinner 
(for subjects enrolled in the dual-therapy arm) or breakfast and dinner (for subjects 
enrolled in the triple-therapy arm) at about the same time as he/she usually does with 
approximately 240 mL (8 oz) water. 
 
Treatment Compliance (Section 5.7) 
Noncompliance is defined as (taking less than 80 75% or more than 120% of study drug 
during any evaluation period [visit to visit]). Subjects exhibiting poor compliance as assessed 
by tablet/capsule counts should be counseled on the importance of good compliance to the 
study dosing regimen. 


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Table 5-2 Excluded Medications and Treatments 
Excluded Medications and Treatments 
Beginning of 
Exclusion 
End of 
Exclusion 
Other investigational drugs or drugs administered due to 
participation in another clinical trial 
30 days prior to start of 
Screening Period 
4-week Post-
Treatment Visit 
Medications (excluding PPIs and antibiotics) that may interfere 
with 13C-UBT (ecabet, sodium hydrate)a 
14 days prior to 
Screening 13C-UBT  
4-week Post-
Treatment Visit 
Antibiotics, Bismuth 
30 days prior to 
screening 13C-UBT 
4-week Post-
Treatment Visit 
Antiprotozoals 
30 days prior to Day 1 
4-week Post-
Treatment Visit 
H2 receptor antagonists 
14 days prior to 
Screening 13C-UBT 
4-week Post-
Treatment Visit 
PPIs 
14 days prior to 
Screening 13C-UBT 
4-week Post-
Treatment Visit 
Medications contraindicated with clarithromycin: colchicine, 
pimozide, ergot derivatives, tadalafil, terfenadine, astemizole, 
cisapride, simvastatin, lovastatin, atorvastatin, etc.  
Note: other statins such as fluvastatin, pravastatin, and 
rosuvastatin may be allowed but used with caution 
30 days prior to Day 1 
End of treatment 
Strong inhibitors or inducers of CYP2C19 (eg, fluconazole, 
fluoxetine, fluvoxamine, ticlopidine, rifampicin, ritonavir) 
14 days prior to Day 1 
End of treatment  
Strong inhibitors or inducers of CYP3A4 (eg, itraconazole, 
ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
telithromycin) 
14 days prior to Day 1 
End of treatment 
CYP3A4 substrates with a narrow therapeutic index 
14 days prior to Day 1 
End of 
treatment 
Surgical procedures that could affect gastric acid secretion (eg, 
any form of partial gastrectomy, vagotomy) 
30 days prior to Day 1 
4-week Post-
Treatment Visit 
Other agents affecting digestive organs including muscarinic 
antagonists (eg, hyoscyamine), prokinetics, oral anticholinergic 
agents, prostaglandins, bismuth, sucralfate 
30 days prior to Day 1 
4-week Post-
Treatment Visit 
Atazanavir sulfates; rilpivirine hydrochloride (contraindicated 
with vonoprazan) 
5 days prior to Day 1 
4-week Post-
Treatment Visit 
a Prohibited period is 14 days prior to any 13C-UBT or as otherwise stated in the package insert for the 13C-urea 
breath testing kit package to be used. The exclusion period is not applicable to proton pump inhibitors 
and antibiotics; they have a separate exclusion period. 
 


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Biopsy for Culture and Antibiotic Susceptibility Test (Section 6.1.2.1) 
Minimum inhibitory concentrations of amoxicillin, clarithromycin, and metronidazole 
against HP will be determined using the strains isolated from these specimens by the 2-fold 
agar dilution method.  
Clarithromycin ≥ 1 µg/mL, amoxicillin > 0.03 125 µg/mL and metronidazole ≥ > 8 µg/mL 
are determined as resistance breakpoints. 
Regulatory Reporting Requirements for SAEs (Section 6.2.1.15) 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it and will notify the IRB/IEC, if appropriate according to local requirements. 
If there is an increase in unexpected SAEs or if there is a change in the frequency and 
character of expected SAEs based on the known safety profile of vonoprazan, further 
evaluation will be conducted to characterize these events and any impact on 
benefit/risk. Health Authorities will be consulted to agree upon the appropriate action 
to be taken regarding the conduct of the study including no change to the protocol, 
revision of the safety monitoring plan, suspension of enrollment, or discontinuation of 
the study. 
 
Pharmacogenetics (Section 6.9) 
Collection for genotyping: every subject is optional. Subjects willing to participate must 
sign the informed consent in order to participate in this study form. During the study, a blood 
sample will be collected for CYP2C19 genotype testing to determine the subject’s 
metabolizer status, unless prohibited by local regulations. The DNA sample collected from 
each subject will be used for CYP2C19 genotyping analysis. Genetic variation in the 
CYP2C19 gene may lead to changes in metabolic activity of the CYP2C19 enzyme that may 
contribute to the variability in the clinical efficacy of lansoprazole. 
 


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Primary Efficacy Endpoint (Section 7.1) 
The primary efficacy endpoint is the proportion of subjects with successful HP eradication 
after the Treatment Period, as determined by 13C-UBT, at 4 weeks after the last dose of study 
drug, excluding in subjects who had do not have a clarithromycin or amoxicillin resistant 
strain of HP at baseline. 
Analysis Sets (Section 7.4) 
The MITT analysis set includes the randomized subjects with all of the following: 
• HP infection is documented by 13C-UBT and biopsy at baseline 
• At least one dose of study drug is taken  
 
The PP analysis set includes the randomized subjects with all of the following: 
• The subject is included in the MITT analysis set 
• Visit 4 occurs between 28 and 56 days after the end of treatment with documented 
diagnostic testing by 13C-UBT, unless the subject has documented persistence of HP 
infection at any time after the end of treatment 
• At least 75% of each study drug was taken and/or less than 20% of consecutive doses of 
each study drug were missed, unless caused by treatment failure  
• An antimicrobial known to be effective against HP was not taken within 7 days of Day 1, 
during treatment, or between completion of treatment and the test-of-cure visit, unless 
given for treatment failure 
• A proton pump inhibitor or high dose (as per below) H2-receptor antagonist was not taken 
within 14 days of Day 1, during treatment, or between completion of treatment and the 
test-of-cure visit, unless given for treatment failure 
 


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Description of Subgroups to be Analyzed (Section 7.5) 
Subgroup analyses for the primary endpoint will be conducted for demographic and other 
relevant clinical variables, including age, sex, body mass index, smoking status, alcohol 
use, clinical condition, study drug compliance, CYP2C19 status, region, and baseline 
susceptibility to amoxicillin, clarithromycin, and metronidazole. 
 
Efficacy Analyses (Section 7.6.1) 
The primary endpoint (proportion of subjects with successful HP eradication after the 
Treatment Period, as determined by 13C-UBT, at 4 weeks after the last dose of study drug 
excluding in subjects who had do not have a clarithromycin or amoxicillin resistant strain of 
HP at baseline) will be calculated as a percentage of subjects in each treatment group.  
 
The secondary endpoints will be evaluated in a similar manner as the primary endpoint for 
superiority of vonoprazan triple therapy to lansoprazole triple therapy and of vonoprazan 
dual therapy to lansoprazole triple therapy.  
In these analyses, subjects who do not have a post-baseline 13C-UBT will be considered 
treatment failures, ie, “not eradicated.” 
Methodology for control of Type I error among the among multiple comparisons will be 
addressed in the statistical analysis plan. 
 
Independent Ethics Committee or Institutional Review Board (Section 9.1) 
Federal regulations, national regulations, and the ICH guidelines require that approval be 
obtained from an IRB/IEC before participation of human subjects in research studies. Before 
study onset, the protocol, informed consent, advertisements to be used for the recruitment of 
study subjects, and any other written information regarding this study to be provided to the 
subject or the subject’s legally acceptable representative(s) must be approved by the 
IRB/IEC. Documentation of all IRB/IEC approvals and of the IRB/IEC compliance with ICH 


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harmonised tripartite guideline E6: Good Clinical Practice (GCP) will be maintained by the 
site and will be available for review by the sponsor or its designee. 
 
Subject Information and Consent (Section 9.3) 
Before recruitment and enrollment, each prospective subject or his or her legally acceptable 
representative(s) will be given a full explanation of the study and be allowed to read the 
approved ICF. Once the investigator is assured that the subject or legally acceptable 
representative(s) understands the implications of participating in the study, the subject or 
legally acceptable representative(s) will be asked to give consent to participate in the study 
by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the subject or legally acceptable representative(s). 
 
Confidentiality (Section 10.1) 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject (or the subject’s legally acceptable representative(s)), except as 
necessary for monitoring and auditing by the sponsor, its designee, the US Food and Drug 
Administration (FDA), or the IRB/IEC. 
 
Investigator Documentation (Section 10.3) 
• IRB/IEC-approved informed consent, samples of site advertisements for recruitment for 
this study, and any other written information regarding this study that is to be provided to 
the subject or legally acceptable representative(s). 
• Laboratory certifications and normal ranges for any local laboratories used by the site, in 
accordance with 42 CFR 493. 


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Table 13-1 Schedule of Events 
• The days for the 4-week post-treatment period were changed from 43 to 71 to 42 to 70 
• Smoking status and alcohol use were added as screening assessments 
• Assessments of weight and height are removed from Visit 4 and the Early Termination 
visit 
• ‘x’ is removed for first day of study drug administration at Visit 3 
• Footnote (j) is added for the 13C-UBT test: Should be performed between 4 weeks and 
8 weeks after last dose of study medication. 
• Footnote (k) is added for the CYP2C19 genotyping test: Collection for genotyping is 
optional. Subjects willing to participate must sign the informed consent form. 
 
Appendix 2: Contraceptive Guidance (Section 13.2) 
From signing of informed consent through Day -2, throughout the duration of the study, and 
for 4 weeks after the last dose of study drug, female subjects of childbearing potential* who 
are sexually active with a non-sterilized male partner** must use adequate contraception. 
Starting on Day -1, throughout the duration of the study, and for 4 weeks after the last 
dose of study drug, female subjects of childbearing potential who are sexually active 
with a non-sterilized male partner must use 2 forms of adequate contraception. In 
addition, they must be advised not to donate ova during this period. 
 
Appendix 3: Liver Safety Monitoring and Withdrawal Criteria (Section 13.3) 
If a subject meets the liver safety criteria and must be discontinued from study medication, 
the subject will continue to be followed per the protocol schedule until the study is 
completed. If the subject refuses to return for the study visits, telephone visits may be 


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conducted; however, this is not preferred nor recommended. The reason for discontinuation 
of study medication should be listed as an AE LFT abnormality. 
13.4.2 Protocol Amendment 2 
Pharmacokinetic or Pharmacodynamic Assessment (Synopsis) 
For pharmacokinetic analysis of drug concentration, blood samples will be collected at 
the Week 2 Visit, unless prohibited by local regulations. 
In order to determine the subject’s metabolizer status, an optional blood sample will be 
obtained for CYP2C19 genotype testing, unless prohibited by local regulations. 
Study Design (Section 3.1) 
1. Screening Period (Day -35 to Day -2): Subjects will provide informed consent and the 
subject will undergo screening assessments to determine study eligibility, and baseline 
assessments will be performed. If all eligibility criteria are met, the subject will enter the 
study. 
Subjects may have already been pre-screened for HP using a fingerstick test 
performed not more than 30 days prior to screening. The subjects will sign a 
pre-screening ICF for optional fingerstick test of HP status.  
An endoscopy will be performed to collect gastric mucosal biopsy specimens (one each 
from the greater and lesser curve of the gastric body, and one each from the greater and 
lesser curve of the antrum) at the start of the study for histopathology (Section 6.1.2.2) to 
document HP infection. Two additional gastric mucosal biopsy specimens will be 
collected (one from the greater curve of the antrum and one from the lesser curve of the 
gastric body) for culture and susceptibility testing (Section 6.1.2.1) to determine 
resistance to bacteria to clarithromycin, amoxicillin and metronidazole antibiotics which 
are commonly used in the treatment of HP infection. After randomization, as part of the 
overall analysis, MICs of amoxicillin, clarithromycin, and metronidazole against HP will 
be determined using the strains isolated from these specimens by the 2-fold agar dilution 
method. Results from the gastric mucosal biopsy specimens (histology and culture) will 
be available post-randomization. Any remaining gastric mucosal biopsy samples may 
be used for future pharmacogenomic evaluation of HP (Section 6.10).  


Phathom Pharmaceuticals, Inc 
vonoprazan 
Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 103 
2. Treatment Period (2-week treatment period): HP+ subjects whose eligibility is confirmed 
by 13C-urea breath test (13C-UBT) during the Screening Period will be randomly assigned 
in a 1:1:1 ratio to receive vonoprazan 20 mg BID in conjunction with amoxicillin 1 g TID 
(vonoprazan dual therapy arm) for 14 days, vonoprazan 20 mg BID in conjunction with 
amoxicillin 1 g BID and clarithromycin 500 mg BID (vonoprazan triple therapy arm) for 
14 days, or lansoprazole 30 mg BID in conjunction with amoxicillin 1 g BID and 
clarithromycin 500 mg BID (lansoprazole triple therapy arm/control arm) for 14 days. 
Subjects will receive a phone call at Week 1 to remind subjects about compliance 
and other assessments described in the SoE (Section 13.1). 
Subjects will return at Week 2 for laboratory tests and other assessments described in the 
schedule of activities (SoA) SoE (Section 13.1). 
Exclusion Criteria (Section 4.1.2) 
11. 
The subject has a history of alcohol abuse, illegal drug use, or drug addiction within 
the 12 months prior to screening, or who regularly consume >21 units of alcohol (1 
unit = 12 oz/300 mL beer, 1.5 oz/25 mL hard liquor/spirits, or 5 oz/100 mL wine) per 
week based on self-report. Subjects must have a negative urine drug screen for 
cannabinoids/tetrahydrocannabinol and non-prescribed medications at 
screening.  
Treatment Compliance (Section 5.7) 
As subjects will self-administer study drug(s) at home, compliance with study drug will be 
assessed at each visit. For on-site visits, Ccompliance will be assessed by direct questioning 
and counting returned tablets/capsules during the site visits. which For phone visits, a 
compliance reminder will be documented in the source documents and eCRF.provided to 
the subjects; compliance will be assessed by direct questioning. Subject treatment 
compliance assessment results shouldwill be recorded in the source documents and eCRF.  
Study Assessments and Procedures (Section 6) 
• Before performing any study procedures, all potential subjects will sign and date an ICF. 
Subjects will have the opportunity to have any questions answered before signing the 
ICF. The investigator must address all questions raised by the subject. The investigator or 
designee will also sign and date the ICF. 


Phathom Pharmaceuticals, Inc 
vonoprazan 
Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 104 
o An optional pre-screening ICF may be used to evaluate a subject for HP 
infection using a fingerstick assessment. 
Collection and Reporting of Adverse Events (Section 6.2.1.14.1) 
Collection of PTEs (including PTEs that are SAEs) 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 drug or until screen failure. For subjects who discontinue prior to 
study drug administration, PTEs are collected until the subject discontinues study 
participation. Collection of AEs (including AEs that are SAEs) will commence from the 
time that the subject is first administered study drug (Day 1). Routine collection will continue 
until the follow-up visit or withdrawal from the study. 
Collection and Reporting of Serious Adverse Events (Section 6.2.1.14.2) 
An SAE eCRF form must be completed and submitted via Medidata Rave immediately or 
within 24 hours of the investigator first onset or notification becoming aware of the event 
SAE occurrence, including for those SAEs that are PTEs. 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 
Electrocardiograms (Section 6.8) 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using one of the following categories: within 
normal limits, abnormal but not clinically significant, or abnormal and clinically significant. 
The following parameters will be recorded on the eCRF from the subject’s ECG trace: heart 
rate, RR interval, PR interval, QT interval and QRS interval. A copy of the ECG trace 
should be kept with the subject’s notes. For ECG results printed on thermal paper, 
nonthermal paper copies should be made to avoid degradation of trace over time. 
Pharmacogenomics (Section 6.10) 
Gastric mucosal biopsy specimens that were not used for culture (and subsequent 
antimicrobial susceptibility testing; Section 6.1.2.1) or histopathology evaluation 
(Section 6.1.2.2) may be available from the central laboratory and may be used for 
possible future genomic analysis of HP in the specimens. 


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vonoprazan 
Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 105 
Pharmacokinetics (Section 6.11) 
During the study, blood sample will be collected for pharmacokinetic analysis of drug 
concentrations, unless prohibited by local regulations. The sample collection day will be 
per the SoE (Section 13.1). Details for collection, sample processing, shipment, and 
destruction of these samples can be found in the Laboratory Manual. 
Table 13-1 Schedule of Events 
• New footnote added for informed consent criteria during screening period: Subjects may 
be pre-screened for HP infection using a fingerstick test performed not more than 30 
days prior to screening. The subjects will sign a pre-screening ICF for optional 
fingerstick test of HP status. 
• 
New phone call visit added on Week 1, Day 8. New footnote added for Day 8 
assessments: Subjects will receive a phone call for Week 1, Day 8 that will include a 
compliance reminder, and an assessment of concomitant medications and any AEs.  
• 
New footnote added for phone call visit on Day 29 assessments: Subjects will receive a 
phone call for Week 4, Day 29 that will include an assessment of concomitant 
medications and any AEs.  
• 
New footnote for physical examination: Full physical examination is performed at 
baseline; a brief physical examination is performed at all other visits. 
• Adjusted footnote for 13C-UBT: If subject’s 13C-UBT test is positive at 4 weeks 
post-treatment, an endoscopy and antibiotic susceptibility testing willshould be 
performed within 4 weeks of a positive 13C-UBT test result. The subject can then be 
treated as per standard of care. 
• New footnote added to gastric mucosa biopsy assessments: Gastric mucosal biopsy 
specimens that were not used for culture (and subsequent antimicrobial 
susceptibility testing) or histopathology evaluation may be available from the 
central laboratory and may be used for possible future genomic analysis of HP. 


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vonoprazan 
Protocol: HP-301 Version 3.0 (Protocol Amendment 2) 
11 May 2020 
 
Page 106 
• New footnote added to study drug return/ accountability/review treatment compliance 
assessment: As subjects will self-administer study drug(s) at home, compliance with 
study drug will be assessed at each visit. For on-site visits, compliance will be 
assessed by direct questioning and counting returned tablets/capsules during the site 
visits. For phone visits, a compliance reminder will be provided to the subjects; 
compliance will be assessed by direct questioning. Subject treatment compliance 
assessment results will be documented in the source documents and eCRF. 
• Added assessment of 1 PK sample collected at Day 15 and new footnote: For 
pharmacokinetic analysis of drug concentrations, blood samples will be collected at 
the Week 2 Visit, unless prohibited by local regulations. Date and time of blood 
sample, as well as date and time of last study drug(s) dose will be collected in source 
documents and eCRF. 
 

SAP_001.pdf: 
Protocol Number:  HP-301 
 
Official Title:  A Phase 3 Randomized Multicenter Study to Evaluate the Efficacy and 
Safety of Open-Label Dual Therapy with Oral Vonoprazan 20 mg or 
Double-Blind Triple Therapy with Oral Vonoprazan 20 mg Compared to 
Double-Blind Triple Therapy with Oral Lansoprazole 30 mg Daily in 
Patients with Helicobacter Pylori Infection  
 
NCT Number: NCT04167670 
 
Document Date:  09-Apr-2021 


 
Confidential 
 
 
 
 
 
 
 
 
 
Phathom Pharmaceuticals, Inc. 
 
HP-301 
 
A Phase 3 Randomized Multicenter Study to Evaluate the Efficacy and Safety 
of Open-Label Dual Therapy with Oral Vonoprazan 20 mg or Double-Blind 
Triple Therapy with Oral Vonoprazan 20 mg Compared to Double-Blind 
Triple Therapy with Oral Lansoprazole 30 mg Daily in Patients with 
Helicobacter Pylori Infection 
 
09Apr2021 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Prepared by: 
 
 
 
 
 
 


Phathom Pharmaceuticals, Inc. 
 
Statistical Analysis Plan, Version 3.0 
 
HP-301 
 
Date Issued: 09Apr2021 
 
  
 
 
 II
Signature Page  
 
 
Study Title 
 
A Phase 3 Randomized Multicenter Study to Evaluate the Efficacy and 
Safety of Open-Label Dual Therapy with Oral Vonoprazan 20 mg or 
Double-Blind Triple Therapy with Oral Vonoprazan 20 mg Compared 
to Double-Blind Triple Therapy with Oral Lansoprazole 30 mg Daily in 
Patients with Helicobacter Pylori Infection 
 
Protocol Number 
HP-301 
 
 
 
 
Approved by: 
 
 
Senior Director, Biostats & Programming 
 
 
DocuSign Envelope ID: 1ADFD4C8-CD38-49FD-9F23-EEDFB111E011


Phathom Pharmaceuticals, Inc. 
 
Statistical Analysis Plan, Version 3.0 
 
HP-301 
 
Date Issued: 09Apr2021 
 
  
 
  III
TABLE OF CONTENTS 
DOCUMENT HISTORY – CHANGES COMPARED TO FINAL VERSION 1.0 ............... V 
LIST OF ABBREVIATIONS .................................................................................................. VII 
1. 
INTRODUCTION ............................................................................................................ 1 
2. 
OBJECTIVES ................................................................................................................... 1 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 1 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 1 
3.2. STUDY ENDPOINTS ............................................................................................................. 2 
3.3. TREATMENTS ...................................................................................................................... 3 
3.4. DOSE ADJUSTMENT/MODIFICATIONS ................................................................................. 3 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 3 
4.1. SAMPLE SIZE ...................................................................................................................... 4 
4.2. RANDOMIZATION AND BLINDING ....................................................................................... 6 
4.3. ASSESSMENT WINDOWS ..................................................................................................... 6 
4.3.1. 
Study Day .................................................................................................................... 6 
4.3.2. 
Visit Window for Analysis ........................................................................................... 6 
4.4. ANALYSIS SET .................................................................................................................... 7 
4.4.1. 
Screened Set ................................................................................................................ 7 
4.4.2. 
Randomized Set ........................................................................................................... 7 
4.4.3. 
Modified Intent-to-Treat (MITT) Set ........................................................................... 8 
4.4.4. 
Modified Intent-to-Treat primary (MITTp) Set ........................................................... 8 
4.4.5. 
Per Protocol (PP) Set and Per Protocol primary (PPp) Set ...................................... 8 
4.4.6. 
Safety Set ..................................................................................................................... 9 
4.4.7. 
Pharmacokinetic (PK) Set ........................................................................................... 9 
4.5 MISSING DATA HANDLING FOR 13C-UBT ASSESSMENTS ........................................................ 9 
5. 
SUBJECT DISPOSITION ............................................................................................... 9 
5.1. DISPOSITION ....................................................................................................................... 9 
5.1.1. 
Screened and Screen Failure Subjects ........................................................................ 9 
5.1.2. 
Randomized Subjects .................................................................................................. 9 
5.2. PROTOCOL DEVIATIONS ................................................................................................... 10 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 10 
6.1. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ......................................................... 10 
6.2. MEDICAL HISTORY ........................................................................................................... 12 
6.2.1. 
General Medical History .......................................................................................... 12 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 12 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................... 12 
7.2. STUDY TREATMENTS ........................................................................................................ 13 
7.2.1. 
Treatment Compliance .............................................................................................. 13 
7.2.2. 
Extent of Exposure .................................................................................................... 14 
8. 
EFFICACY ANALYSIS ................................................................................................. 14 


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  IV
8.1. PRIMARY EFFICACY ENDPOINT ............................................................................................ 15 
8.1.1. 
Primary Analysis ....................................................................................................... 15 
8.1.2. 
Assumption Testing ................................................................................................... 16 
8.1.3. 
Sensitivity and Supportive Analyses .......................................................................... 16 
8.1.3.1. 
Sensitivity Analysis to Assess the Impact of Early and Late Test-of-Cure  
 
Visits................................................................................................................... 16 
8.1.3.2. 
Sensitivity Analysis on Use of Prohibited Medications ..................................... 16 
8.1.3.3. 
Tipping Point Analysis ....................................................................................... 17 
8.1.3.4. 
Multiple Imputation Analysis............................................................................. 17 
8.1.3.5. 
Supportive Analysis Using PPp Set ................................................................... 17 
8.1.3.6. 
Supportive Analysis with Different Amoxicillin Resistance Breakpoint .......... 18 
8.1.3.7. 
Shift Summary on Antibiotics Assessment ........................................................ 18 
8.1.4. 
Subgroup Analysis .................................................................................................... 18 
8.2. SECONDARY EFFICACY ENDPOINT .................................................................................... 19 
9. 
SAFETY ANALYSIS ..................................................................................................... 20 
9.1. ADVERSE EVENTS ............................................................................................................. 20 
9.1.2. 
Adverse Events of Special Interests (AESI) .............................................................. 22 
9.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 24 
9.3. VITAL SIGN ...................................................................................................................... 25 
9.4. PHYSICAL EXAMINATION ................................................................................................. 25 
9.5. ELECTROCARDIOGRAM ..................................................................................................... 25 
11. 
INTERIM ANALYSIS/OTHER ANALYSES ............................................................. 26 
11.1. 
INTERIM ANALYSIS ....................................................................................................... 26 
11.2. 
CORONAVIRUS PANDEMIC ............................................................................................. 26 
12. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 27 
13. 
REFERENCES ................................................................................................................ 27 
14. 
APPENDICES ................................................................................................................. 28 
14.1. SCHEDULE OF EVENTS ....................................................................................................... 29 
14.2.  IMPUTATION RULES FOR MISSING DATE INFORMATION .................................................... 32 
14.2.1.  Rules for Concomitant Medication Start Date Imputation ....................................... 32 
14.2.2.  Rules for Concomitant Medication End Date Imputation ......................................... 32 
14.2.3. Rules for AE Start Date Imputation ........................................................................... 33 
 
 
 


Phathom Pharmaceuticals, Inc. 
 
Statistical Analysis Plan, Version 3.0 
 
HP-301 
 
Date Issued: 09Apr2021 
 
  
 
 
 V
Document History – Changes compared to Final version 1.0 
Version 
Date 
Changes 
Final version 1.0 
09-Dec-2019 
Final version 
Final version 2.0 
21-Dec-2020 
1. Updated protocol version to Amendment 2, dated 11May2020, and 
included revised Schedule of Events in Table 5. 
 
2. Changed the method for type 1 error control in Section 4 and 
Section 8. Type 1 error will be controlled using a hierarchical testing 
of endpoints and weighted Bonferroni for regimen comparisons. 
Figure 2 and Section 8.1.1 were updated to reflect the new method. 
 
3. In Section 4.1, added references for the sample size assumptions 
and updated the justification for the non-inferiority margins for the 
comparisons of vonoprazan triple therapy and vonoprazan dual 
therapy to lansoprazole triple therapy. 
 
4. In Section 5 Subject Disposition, subsections were re-organized 
and the summary of protocol deviations was clarified. 
 
5. Added Race, Ethnicity, Clinical Conditions, and Subregion as 
baseline characteristics parameters in Section 6.1 and added subgroup 
analyses by these parameters in Section 8.1.4. 
 
6. Section 7 Treatments and Medications was updated to clarify the 
summarization of medications, including that ATC level 4 instead of 
level 2 coding will be used. 
 
7. Changed the compliance calculation algorithm in Section 7.2.1. 
 
8. Updated the α level in the tipping point analysis in Section 8.1.3.2 
based on the method for type 1 error control.  
 
9. Updated the method for multiple imputation in Section 8.1.3.3. 
 
10. Section 8.1.3 was updated to categorize analysis using the PPp Set 
as a supportive analysis. Moved this analysis to Section 8.1.3.4. 
Added new supportive analyses in Section 8.1.3.5 and 8.1.3.6. 
 
11. Added the details of SMQs and CQs for Adverse Events of 
Special Interest in Section 9.1.2. 
 
12. Updated that clinical laboratory results will be summarized for 
both SI and US conventional units, clarified the criteria for total 
bilirubin as 2xULN, and added additional criteria for abnormal liver 
function tests in Section 9.2. 
 
13. Added criteria for abnormal vital signs and for abnormal ECG 
values in Section 9.3 and 9.5, respectively. 
 
14. Added Section 10 Pharmacokinetics and definition of PK Set in 
Section 4.4. 
 
15. Added Section 11.2 to describe the handling of impacts from 
COVID-19 pandemic. Changed the visit analysis window to include 
out-of-window 13C-UBT due to COVID-19 in Section 4.3.2. 


Phathom Pharmaceuticals, Inc. 
 
Statistical Analysis Plan, Version 3.0 
 
HP-301 
 
Date Issued: 09Apr2021 
 
  
 
  VI
Version 
Date 
Changes 
 
16. Added Section 12 to describe changes in the planned analysis 
 
17. Throughout the document, additional edits were made for clarity 
and formatting with no change to content. 
Final Version 3.0 
09Apr2021 
Modified visit window in Table 3 to allow 13C-UBT results obtained 
on day 27 post treatment or greater than 56 days post treatment to be 
included in the MITT analyses for the primary and secondary 
endpoints. Sensitivity analyses were added in Sections 8.1.3.1 and 8.2 
to assess the impact of this change. 
 
In Section 5.2, clarified that protocol deviations will be summarized 
by CTMS activity type and subtype in the summary table. 
 
In Section 7.2.2, imputation of missing last dose date will be based on 
date of first dose instead of date of randomization. 
 
In Section 8.1.3.7, the summary of shifts in antibiotic susceptibility 
will be done for both the MITTp and MITT sets. 
 
In Section 8.1.4, clarified that the subgroup analysis for study drug 
compliance will be based on compliance with the complete regimen. 
 
In Section 10, removed PK summary table. 
 
 
 


Phathom Pharmaceuticals, Inc. 
 
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HP-301 
 
Date Issued: 09Apr2021 
 
  
 
  VII
List of Abbreviations 
 
13C-UBT 
carbon 13-urea breath test 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
twice daily 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019 
CQ 
customized queries 
CRF 
case report form 
CYP 
cytochrome P450 isoenzymes 
ECG 
electrocardiogram 
FSH 
follicle-stimulating hormone 
hCG 
human chorionic gonadotropin 
HIV 
human immunodeficiency virus 
HP 
Helicobacter pylori 
HP+ 
Helicobacter pylori positive 
ICF 
informed consent form 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
MITT 
modified intent-to-treat 
MITTp 
modified intent-to-treat primary 
PK 
pharmacokinetic 
PPI 
proton pump inhibitor 
PP 
per protocol 
PPp 
per protocol primary 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMQ 
standardized MedDRA queries 
SOC 
system organ class 
TEAE 
treatment-emergent adverse events 
TID 
three times daily 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
 
 


Phathom Pharmaceuticals, Inc. 
 
Statistical Analysis Plan, Version 3.0 
 
HP-301 
 
Date Issued: 09Apr2021 
 
  
 
 
 1
1. Introduction 
 
Study HP-301 will compare the efficacy and safety of vonoprazan open-label dual therapy 
(vonoprazan and amoxicillin) and vonoprazan double-blind triple therapy (vonoprazan, 
amoxicillin, and clarithromycin) administered for 14 days compared to lansoprazole 
double-blind triple therapy (lansoprazole, amoxicillin, clarithromycin) administered for 14 days 
in subjects with HP infection.  
 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of efficacy and safety data as described in the Protocol Amendment 2, dated 
11May2020. 
 
2. Objectives 
 
The primary objective of this study is as follows: 
 
• To compare the efficacy of HP eradication with vonoprazan dual and triple therapy 
regimens versus lansoprazole triple therapy regimen in HP+ subjects who do not have a 
clarithromycin or amoxicillin resistant strain of HP at baseline 
 
The secondary objectives of this study are as follows: 
 
• To compare the efficacy of HP eradication with vonoprazan dual and triple therapy 
regimens versus lansoprazole triple therapy regimen in subjects infected with a 
clarithromycin resistant strain of HP 
 
• To compare the efficacy of HP eradication with vonoprazan dual and triple therapy 
regimens versus lansoprazole triple therapy regimen in all subjects 
 
The safety objective of this study is as follows: 
 
To compare the safety of vonoprazan dual and triple therapy regimens versus lansoprazole triple 
therapy regimen in HP+ subjects 
 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
 
This is a Phase 3, randomized, parallel group study to compare the efficacy and safety of 
vonoprazan open-label dual therapy (vonoprazan and amoxicillin) and vonoprazan double-blind 
triple therapy (vonoprazan, amoxicillin, and clarithromycin) administered for 14 days compared 


Phathom Pharmaceuticals, Inc. 
 
Statistical Analysis Plan, Version 3.0 
 
HP-301 
 
Date Issued: 09Apr2021 
 
  
 
 
 2
to lansoprazole double-blind triple therapy (lansoprazole, amoxicillin, clarithromycin) 
administered for 14 days in HP+ subjects.  
A schematic diagram of the overall study design is presented in Figure 1. 
Figure 1 
Study Design 
 
 
3.2. Study Endpoints 
 
The primary efficacy endpoint of this study is as follows: 
 
• Proportion of subjects with successful HP eradication after the Treatment Period, as 
determined by 13C-UBT, at 4 weeks after the last dose of study drug in subjects who do 
not have a clarithromycin or amoxicillin resistant strain of HP at baseline  
 
The secondary efficacy endpoints of this study are as follows: 
 
• Proportion of subjects with successful HP eradication after the Treatment Period, as 
determined by 13C-UBT at 4 weeks after the last dose of study drug, among subjects who 
had a clarithromycin resistant strain of HP at baseline 
 
• Proportion of subjects with successful HP eradication after the Treatment Period, as 
determined by 13C-UBT, at 4 weeks after the last dose of study drug among all subjects 
 
 
 
Treatment Period 
(14 Days) 
Follow-up Period 
(4 weeks) 
 
 
 
 
 
Visit 1 
Visit 2 
 
Visit 3 
 
Visit 4 
 
 
 
 
 
 
Vonoprazan Dual 
Therapy 
(Open Label) 
 
 
Informed 
consent 
 
Vonoprazan 
Triple Therapy 
(Double Blind) 
 
 
 
Lansoprazole 
Triple Therapy 
(Double Blind) 
 
 
 
 
 
 
 
 
Screening Period 
(≤ 34 days) 
 
 
 
 
Randomization 
Day -1 
 
Eradication 
Assessment 


Phathom Pharmaceuticals, Inc. 
 
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 3
The safety endpoints of this study are as follows: 
 
• Adverse events (AEs) 
 
• Laboratory test values (hematology, serum chemistry, urinalysis)  
 
• Electrocardiogram (ECG) 
 
• Vital signs 
 
 
3.3. Treatments   
 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomly assigned at the baseline/randomization visit (Visit 2/Day -1) to receive vonoprazan 
dual therapy, vonoprazan triple therapy, or lansoprazole triple therapy for 14 days using a 1:1:1 
allocation ratio.  
 
 The open-label treatment of this study is: 
 
• Vonoprazan dual therapy: vonoprazan 20 mg BID in conjunction with amoxicillin 1 g 
TID for 14 days 
 
The double-blinded treatments of this study are: 
 
• Vonoprazan triple therapy: vonoprazan 20 mg BID in conjunction with amoxicillin 1 g 
BID and clarithromycin 500 mg BID for 14 days 
 
• Lansoprazole triple therapy: lansoprazole 30 mg BID in conjunction with amoxicillin 1 g 
BID and clarithromycin 500 mg BID for 14 days 
 
 
3.4. Dose Adjustment/Modifications 
 
No dose adjustments or modifications are allowed for this study.  
 
 
4. General Statistical Considerations 
 
In general, descriptive statistics will be presented by treatment group and by visit, as applicable. 
For continuous variables, summary statistics for the raw value and change from baseline at each 
time-point will include the number of subjects (n), arithmetic mean, standard deviation (SD), 
median, minimum and maximum.  


Phathom Pharmaceuticals, Inc. 
 
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Date Issued: 09Apr2021 
 
  
 
 
 4
 
Categorical variables will be summarized using subject counts and percentages. Percentages will 
be calculated using the total subjects per treatment unless otherwise specified.  
 
The efficacy analyses will be conducted on the Modified Intent-to-Treat Set and Per Protocol Set 
using the planned treatment. See Section 4.4 for the Modified Intent-to-Treat Set and Per 
Protocol Set definitions. 
 
The safety analyses will be conducted on the Safety Set using the actual treatment the subject 
received. See Section 4.4 for the Safety Set definition. 
 
The type 1 error will be controlled at a level of α = 0.05 using a hierarchical testing of endpoints 
and weighted Bonferroni for regimen comparisons (Bretz 2011). An initial assigned significance 
level of α = 0.04 will be used for analysis of vonoprazan triple therapy and an initial assigned 
significance level of α = 0.01 will be used for analysis of vonoprazan dual therapy. More details 
are addressed in Section 8. Statistical tests for noninferiority and superiority will be one-sided 
and will be conducted at the assigned α/2 significance level. P-values will be reported to 4 
decimal places, with p-values less than 0.0001 reported as “<0.0001”. 
 
SAS® version 9.4 or higher will be used to perform all statistical analyses or procedures. 
 
4.1. Sample Size 
 
Assuming a true eradication rate for the primary endpoint of 90% for lansoprazole triple therapy 
and 90% for both vonoprazan triple therapy and vonoprazan dual therapy, a sample size of 260 
subjects per treatment group provides >90% power to achieve noninferiority with a 
noninferiority margin of 10% using the Farrington Manning test (Farrington and Manning 1990). 
Assuming 20% of subjects will have a clarithromycin resistant strain of HP at baseline (Savoldi 
et al 2018), 325 subjects per treatment group (975 total) will be enrolled.  H pylori resistance to 
amoxicillin is expected to be low with rates less than 2% reported among isolates in the US (Meyer 
et al 2002) and Europe (Megraud 2012). Thus, the amoxicillin resistance rate has not be considered 
in the sample size estimates for the primary endpoint. 
 
Based on historical eradication rates, a fixed noninferiority margin of -10% is justified for the 
comparisons of vonoprazan triple therapy and vonoprazan dual therapy to lansoprazole triple 
therapy. These historical eradication rates are from studies in which the clarithromycin and 
amoxicillin resistance rate was low (approximately 5% or less) and are therefore relevant to 
establishing the noninferiority margins for the primary endpoint in this study.  
 
A fixed noninferiority margin of -10% for the comparison of the two triple therapy regimens is 
justified based on historical eradication rates from the original lansoprazole 14-day therapy 
development (Table 1; PREVACID 2018) and the original omeprazole 10-day therapy 
development (Table 2; PRILOSEC 2016) where the respective triple therapy regimens were 
compared to the clarithromycin/amoxicillin regimen. Due to the limited data for the 


Phathom Pharmaceuticals, Inc. 
 
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 5
clarithromycin/amoxicillin eradication rate from the lansoprazole 14-day therapy studies, the 
justification has been supplemented with data from the omeprazole 10-day therapy studies. 
 
 
Table 1 Historical 14-day H pylori Eradication Rates  
Amoxicillin/Clarithromycin 
Lansoprazole Triple Therapy 
Study M95-392 
64% (51/80) 
Study M95-392 
83% (58/70) 
 
 
Study M93-131 
85% (47/55) 
 
 
Study M95-399 
82% (103/126) 
Pooled 
64% (51/80) 
Pooled 
83% (208/251) 
Difference (95% CI) 
19% (7.6%, 30.6%) 
 
 
 
Table 2 Historical 10-day H pylori Eradication Rates  
Amoxicillin/Clarithromycin 
Omeprazole Triple Therapy 
Prilosec Study 1 
37% (31/84) 
Prilosec Study 1 
69% (55/80) 
Prilosec Study 2 
36% (30/83) 
Prilosec Study 2 
73% (56/77) 
Prilosec Study 3 
32% (32/99) 
Prilosec Study 3 
83% (70/84) 
Pooled 
35% (93/266) 
Pooled 
75% (181/241) 
Difference (95% CI) 
40% (32.2%, 48.1%) 
 
 
From Table 1, the difference in eradication rates between lansoprazole triple therapy and 
amoxicillin/clarithromycin was 19%.  In Table 2, the difference in eradication rates between 
omeprazole triple therapy and amoxicillin/clarithromycin was 40%. Considering only the 14-day 
regimen data, a -10% noninferiority margin maintains approximately 50% of the treatment effect 
of the PPI triple therapy, when using the observed difference between the two treatments.  When 
also considering the more robust amoxicillin/clarithromycin data set from the 10-day regimen, a 
-10% noninferiority margin maintains 67% of the treatment effect of the PPI triple therapy, when 
using the more conservative lower bound of the 2-sided 95% confidence interval as the true 
difference between the two treatments. 
 
A fixed noninferiority margin of -10% is also justified for the comparison of vonoprazan dual 
therapy to lansoprazole triple therapy.  An eradication rate for amoxicillin 3 g of 0% was 
observed in a double-blind, multicenter study evaluating lansoprazole and amoxicillin dual 
therapy for 14 days (Harford et al 1996).  The difference in the HP eradication rate for triple 
therapy with lansoprazole (83%) versus treatment with amoxicillin alone (0%) is 83%; the lower 
limit of the 2-sided 95% CI for the difference is 75%. Using the conservative assumption of the 
lower bound as the true treatment effect of lansoprazole triple therapy, a -10% noninferiority 
margin assures that the vonoprazan dual therapy regimen retains at least 87% of the treatment 
effect of the active control (lansoprazole triple therapy). 
 
 
 


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4.2. Randomization and Blinding 
 
Subjects will be randomized to receive vonoprazan dual therapy, vonoprazan triple therapy, or 
lansoprazole triple therapy for 14 days using a 1:1:1 allocation ratio.  
 
The vonoprazan dual therapy is open-label, and the other two treatment groups are double-
blinded to both investigators and subjects. Biostatistics and Programming will treat this study as 
a double-blinded study. 
 Biostatistics and Programming will remain blinded to the actual 
randomization and material schedules until database lock. However, due to the dose regimen of 
the vonoprazan open-label dual therapy, subjects who enter this arm can be identified from the 
data collected on the eCRF. To maintain study blind, including vonoprazan open-label dual 
therapy, for the Sponsor throughout the study, data or summaries that contain potentially 
unblinded information (i.e. Drug and Antibiotic Accountability CRF page) will not be delivered 
to the Sponsor until final database lock after the study blind has been broken.  
 
4.3. Assessment Windows 
4.3.1. Study Day 
 
The date of first dosing day is defined as Day 1 for this study. When study day is used for 
display or in comparisons the following algorithm will be used: 
• study day = date of assessment - Day 1 +1,  
if date of assessment ≥ Day 1. 
• study day = date of assessment - Day 1, 
 if date of assessment < Day 1. 
 
Note that the date of randomization is defined as Day -1. There is no Day 0 for study day. 
 
4.3.2. Visit Window for Analysis 
 
Visit windows will be defined for by-visit summary and analysis purposes. Summary data (such 
as AEs and concomitant medications) that are not reported by visit will not use visit windows. 
Both scheduled and unscheduled assessments will be considered as valid assessments for 
analysis. Visit labels will be assigned to each post-baseline record based on the windows for 
study day relative to the date of first dose. If an assessment on Day -1 is missing, the closest visit 
with non-missing assessment on or before the date of first dose will be used as baseline. All by-
visit summary and analysis will be based on the analysis visit windows in Table 3. 
 
 
 


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Table 3 Analysis Visit Windows 
 
Nominal Visit 
(recorded on 
eCRF) 
Analysis Visit 
Target Study 
Day of Visit 
Analysis Visit Window 
Visit 1 
Screening 
-35 to -2 
NA 
Visit 2 
Baseline 
-1 
NA 
Visit 3 
Week 2 
15 
12 to 22 days 
Visit 4 
4-Week Post-
Treatment 
56 
 ≥ 41 days for efficacy 
(≥ 27 days post treatment);         
23 to 70 days for safety 
 
 
Unscheduled and early termination assessments will also be assigned to analysis visits based on 
the analysis visit window. When data is summarized by assigned analysis visit based on study 
day, visits will be referenced in summary tables by analysis visits only. Listings will present both 
nominal visits as recorded on the eCRF, and the analysis visits. After all the records have been 
assigned to an analysis visit window based on study day, if there are multiple valid records for an 
assessment within an assigned analysis visit, only one of their records will be used for summary 
statistics and analyses. The record to be used is determined using the following hierarchy (in 
descending order): 
 
Safety assessments, including laboratory tests, ECG and vital signs: 
• the record closest to the target visit day 
• The latest visit in the analysis visit window 
 
13C-UBT assessments: 
• The latest visit in the analysis visit window 
 
4.4. Analysis Set 
4.4.1. Screened Set 
 
All subjects who signed the informed consent form (ICF) before entering the study. Screen 
failures are defined as subjects who were not randomized into the study. 
 
4.4.2. Randomized Set 
 
All subjects randomly assigned to receive study drug regardless of whether or not they received a 
dose of study drug during the study.  
 
 


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4.4.3. Modified Intent-to-Treat (MITT) Set 
 
The MITT Set will be defined as all subjects randomized into the study who have HP infection 
documented by 13C-UBT and biopsy (i.e. culture or histology) at baseline. All analyses using the 
MITT set will group subjects according to the randomized treatment. 
 
4.4.4. Modified Intent-to-Treat primary (MITTp) Set 
 
The MITTp Set will be defined as the subset of subjects in the MITT Set who did not have a 
clarithromycin or amoxicillin resistant strain of HP at baseline.  
 
This analysis set will be used for the primary analysis. All analyses using the MITTp set will 
group subjects according to the randomized treatment. 
 
4.4.5. Per Protocol (PP) Set and Per Protocol primary (PPp) Set 
 
The PP Set and PPp Set will consist of all MITT and MITTp subjects, respectively, with all of 
the following: 
• Test-of-cure visit (4-Week Post-Treatment) occurs between 28 and 56 days after the end of 
treatment with documented diagnostic testing by 13C-UBT, unless the subject has 
documented persistence of HP infection at any time after the end of treatment (i.e. treatment 
failure) 
• At least 75% of each study drug was taken, unless caused by treatment failure  
• An antimicrobial known to be effective against HP was not taken during the 7 days prior to 
Day 1, during treatment, or between completion of treatment and the test-of-cure visit, unless 
given for treatment failure 
• A proton pump inhibitor or high dose (as per below) H2-receptor antagonist was not taken 
during the 14 days prior to Day 1, during treatment, or between completion of treatment and 
the test-of-cure visit, unless given for treatment failure 
Subjects can use standard doses of H2-receptor antagonists, as indicated below, and still be 
included in the per-protocol population: 
o Ranitidine less than or equal to 300 mg/day 
o Cimetidine less than or equal to 800 mg/day 
o Famotidine less than or equal to 40 mg/day  
o Nizatidine less than or equal to 300 mg/day 


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4.4.6. Safety Set 
 
The safety set will be defined as all subjects who received at least 1 dose of study drug. All 
analyses using the safety set will group subjects according to the treatment actually received. 
 
4.4.7. Pharmacokinetic (PK) Set  
 
The PK Set will consist of all subjects who have received at least one dose of study drug and 
who have at least 1 evaluable post-dose PK concentration value. 
 
4.5 Missing Data Handling for 13C-UBT Assessments 
 
For the analyses of endpoints assessed by 13C-UBT, subjects who do not have post-baseline 
13C-UBT will be considered treatment failures, i.e., “not eradicated” for the primary analysis. 
 
5. Subject Disposition 
5.1. Disposition 
5.1.1. Screened and Screen Failure Subjects 
 
The number of screened and screen failure subjects will be presented for overall subjects 
included in the Screened Set.  
 
The following will be summarized for the Screened Set: 
 
• The total number of screened subjects. 
• The number and percentage of screen failures. 
• The number and percentage of each primary reason for screen failures. 
 
Subjects who fail to fulfill all inclusion/exclusion criteria will be listed for the Screened Set.  
 
5.1.2. Randomized Subjects 
 
The number of subjects included in each analysis set will be presented by treatment group and 
overall for all randomized subjects. 
 
 
 
 


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The following will be summarized for the Randomized Set: 
• The number of randomized subjects. 
• The number and percentage of subjects in the MITT Sets (MITT and MITTp), PP Sets 
(PP and PPp) and Safety Set. 
• The number and percentage with each reason for exclusion from the MITT Set and the 
PP Set. 
• The number and percentage of subjects who completed the treatment period. 
• The number and percentage of subjects who discontinued from the treatment period.  
• The number and percentage of subjects who completed the participation of the entire 
study. 
• The number and percentage of subjects who completed or discontinued from the follow-
up period. 
 
Reasons for discontinuation from the study drug will be summarized. Reasons for 
discontinuation from the study participation will also be summarized. Percentages will be based 
on the number of Randomized Set. 
 
The screening disposition for screen failures will be listed using the Screened Set. Subject 
disposition data for the treatment period will be listed for the Randomized Set.  Disposition data 
for the treatment period will be listed separately for subjects who discontinued from the study for 
the Randomized Set.  
 
5.2. Protocol Deviations 
 
Protocol deviations will be recorded within the 
 Clinical Trial Management System (CTMS) 
and will undergo a blinded review prior to database lock and unblinding. Significant protocol 
deviations are defined as the subset of deviations which are considered to affect primary efficacy 
and safety assessments, the safety or mental integrity of a subject, or the scientific value of the 
trial.  
 
The number and percentage of subjects with subject-specific significant protocol deviations will 
be summarized by CTMS activity type, subtype, treatment group and overall for the Randomized 
Set. Individual subject protocol deviations, both significant and non-significant, will be presented 
in a by-treatment, by-subject data listing using the Randomized Set. 
 
 
6. Demographics and Baseline Characteristics 
6.1. Demographics and Baseline Characteristics 
 
Demographic variables collected at Screening, such as age, sex, race, ethnicity, height (cm), 
weight (kg), and body mass index (BMI) will be summarized. Continuous variables, including 
age (years), BMI, weight, height, will be summarized using descriptive statistics for each 
treatment group and overall. The following categorical variables will be summarized by 


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reporting the number and percentage of subjects in each category for each treatment group and 
overall using the MITT Set, MITTp Set, PP Set, PPp Set, and Safety Set.  
 
• Age group at Screening (<45, ≥45 - <65, ≥65 - <75, ≥75) 
• Age group 2 at Screening (≥18 - ≤64, ≥65 - ≤84, ≥85) 
• Sex (Male, Female) 
• Race 
• Ethnicity 
• BMI category (<25, ≥25 - <30, ≥30) 
• 
Minimum Inhibitory Concentration (MIC) Against H pylori (μg/mL) value (<=0.03, 0.06, 
0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, >=128, Not Applicable) 
o Amoxicillin  
o Clarithromycin  
o Metronidazole  
• 
MIC Against H pylori (μg/mL) category 
o Amoxicillin (≤0.125, >0.125, Not Applicable) 
o Clarithromycin (<1, ≥1, Not Applicable) 
o Metronidazole (≤8, >8, Not Applicable) 
• Region (United States, Europe) 
• Subregion (US-West, US-Southwest, US-Southeast, US-North, Europe-Bulgaria, Europe-
Czech Republic, Europe-United Kingdom, Europe-Hungary, Europe-Poland) 
Classification of the US study sites to subregion will be done according to the following: 
o West: California, Colorado, Nevada, Utah, Washington 
o Southwest: Arizona, Oklahoma, Texas  
o Southeast: Alabama, Arkansas, Florida, Georgia, Louisiana, North Carolina, 
South Carolina, Tennessee, Virginia 
o North: Connecticut, Illinois, Indiana, Iowa, Maryland, Michigan, Missouri, 
Nebraska, New York, Ohio, Pennsylvania, South Dakota, Wisconsin 
• MIC Against H pylori (μg/mL) category by region 
• MIC Against H pylori (μg/mL) category by subregion 
• CYP2C19 status (extensive metabolizer, poor metabolizer) 
• Smoking status (never smoked, current smoker, ex-smoker) 
• Alcohol use (drink every day, drink a couple of days per week, drink a couple of days per 
month, never drink) 
• Clinical conditions (Dyspepsia lasting at least 2 weeks, a confirmed diagnosis of 
functional dyspepsia, a recent / new diagnosis of (non-bleeding) peptic ulcer, a history of 
peptic ulcer not previously treated for HP infection, a requirement for long-term NSAID 
treatment at a stable dose of the NSAID) 
 
The concordance of the tests for HP infection at baseline (13C-UBT, culture, and histology) will 
be summarized for the Randomized Set. The following categories will be summarized by 
reporting the number and percentage of subjects with positive results for HP infection in each 
category for each treatment group and overall. 
• 
13C-UBT only 
• 
13C-UBT and culture 


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• 
13C-UBT and histology 
• 
13C-UBT, either culture or histology 
• 
13C-UBT, culture and histology 
 
Demographic and baseline characteristics data will be listed by treatment and subject using the 
Randomized Set. 
 
 
6.2. Medical History 
6.2.1. General Medical History 
 
Medical history will be coded using Version 22 of the Medical Dictionary for Regulatory 
Activities (MedDRA). The number and percentage of subjects with medical history coded to 
each MedDRA SOC and PT will be summarized by treatment group and overall using the Safety 
Set.  
 
Medical history will be listed by treatment and subject using the Safety Set. 
 
7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
 
Any prior and concomitant medication used during the study will be recorded and coded using 
WHODRUG Version B3-March 2019. Summaries of all medications by drug class (ATC Level 
4 coding) and preferred term will be provided separately for prior medications and concomitant 
medications for each treatment group and overall. All summaries will be performed using the 
Safety Set. 
 
Prior medications are those with the start and stop dates prior to the first dose of the study drug. 
Concomitant medications are those with start dates prior to the first dose and continuing after the 
first dose of the study drug, or with start dates on or after the first dose of the study drug. 
 
The prior medications will be summarized by treatment group and overall. Concomitant 
medications with start dates on or before the last dose of study drug will be summarized by 
treatment group and overall. Concomitant medications with start dates after the last dose of study 
drug will be summarized separately by treatment group and overall.  
 
All prior medications and concomitant medications will be listed. 
 
In instances where a medication start date is incomplete, it will be conservatively imputed to 
determine whether or not the medication was prior or concomitant. If the start date is missing, 
then it will be assumed to be concomitant. Imputation details for missing concomitant 
medication start and end date are presented in Appendix section 12.2.  


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All prior and concomitant medications will be listed by treatment and subject for the Safety Set. 
 
7.2. Study Treatments 
7.2.1. Treatment Compliance 
 
Treatment compliance will be calculated separately for each study drug. For vonoprazan 20 mg, 
lansoprazole 30 mg, and clarithromycin, compliance will be calculated as: 
 
Compliance (%) = (total actual capsules taken / total expected capsules) × 100, where 
 
total expected capsules = 14 × 2 and  
 
total actual capsules taken = total number of capsules dispensed – total number of capsules 
returned 
 
 
For amoxicillin, compliance will be calculated as: 
 
Compliance (%) = (total actual capsules taken / total expected capsules) × 100, where 
 
total expected capsules = 14 × 2 × n(*) and  
 
total actual capsules taken = total number of capsules dispensed – total number of capsules 
returned 
 
(*) n = 2 if regimen is BID, n = 3 if regimen is TID.  
 
 
In addition, an overall compliance of the complete regimen will be calculated as: 
 
Compliance (%) = (total actual capsules taken / total expected capsules) × 100, where 
 
total expected capsules is the sum of all expected capsules from all study drug and  
 
total actual capsules taken is the sum of all actual capsules taken from all study drug   
 
 
If a kit is not returned, the compliance of the lost kit will be imputed as 100%. Compliance rate 
will be summarized for each treatment group and overall.  
 
Overall compliance information will be used to categorize subjects as being either compliant or 
not. A subject is considered compliant if the overall study drug compliance is greater than or 
equal to 75% and less than or equal to 120%. 
 


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Treatment compliance for the treatment period will be summarized for the Safety Set. Summary 
statistics for treatment compliance percentages will be summarized for each treatment group and 
overall. Individual subject compliance information will be listed by treatment and subject using 
the Safety Set. 
 
7.2.2. Extent of Exposure 
 
Descriptive summary statistics including the number of subjects, mean, standard deviation, 
median, minimum, and maximum for the duration of study drug exposure (days) will be 
presented by treatment group and overall.  
 
Treatment duration of exposure will be categorized and summarized as follows: ≥1 to ≤10 days, 
>10 to ≤14 days, >14 days. 
 
Treatment exposure will be calculated as the number of days from first to last dose date: 
 
Exposure = Date of last dose – Date of first dose + 1 
 
The date of last dose is recorded on the End of Treatment (EOT) page on the eCRF. The date of 
first dose is recorded on the Drug and Antibiotic Accountability page on the eCRF. If the date of 
first dose is missing, it will be imputed using the date of randomization + 1. If the date of last 
dose is missing, it will be imputed as the date of first dose + 13. All summaries for the treatment 
period will be performed using the Safety Set.  
 
All data for treatment exposure during the treatment period will be listed by treatment and 
subject using the Safety Set.  
 
8. Efficacy Analysis 
 
The type 1 error will be controlled at an overall level of α = 0.05 using hierarchical testing of the 
primary and secondary endpoints and weighted Bonferroni for the regimen comparisons (Bretz 
2011), as shown in the testing hierarchy in Figure 2. An α level of 0.04 will be initially assigned 
to the vonoprazan triple therapy, and an α level of 0.01 will be initially assigned to the 
vonoprazan dual therapy. For each therapy, the 1-sided p-value must be less than the assigned 
α/2 to be significant. If non-inferiority is declared from the primary efficacy analysis of a 
therapy, testing for that therapy will continue to the next endpoint following the testing 
hierarchy. If all endpoints are significant for a therapy, the α can be passed to the other therapy, 
if needed. Therefore, endpoints for the other therapy can be retested at the 0.05 level in 
hierarchical order until a 1-sided p-value is > 0.025. 
 
Only p-values that are significant according to this sequential order are inferential and 
statistically significant. All other p-values are descriptive.   
 


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Additional comparisons will be made between the two vonoprazan therapies (dual therapy vs. 
triple therapy) for each primary and secondary efficacy endpoint as a reference with no 
adjustment for multiple comparisons. 
 
 
Figure 2 Testing Hierarchy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1. Primary Efficacy Endpoint 
 
 
The primary efficacy endpoint is the proportion of subjects with successful HP eradication after 
the Treatment Period, as determined by 13C-UBT, at 4 weeks after the last dose of study drug, in 
subjects who do not have a clarithromycin or amoxicillin resistant strain of HP at baseline, i.e., 
the MITTp Set. 
 
8.1.1. Primary Analysis 
 
 
The frequency and the percentage of subjects with successful HP eradication will be summarized 
for each treatment group. The noninferiority of vonoprazan triple therapy to lansoprazole triple 
Primary Endpoint 
Noninferiority: HP eradication rate 
in subjects who do not have a 
clarithromycin or amoxicillin 
resistant strain  
Superiority: HP eradication rate in 
subjects with clarithromycin 
resistant strain  
 
Superiority: HP eradication rate in 
all subjects 
Vonoprazan triple therapy α=0.04 
Primary Endpoint 
Noninferiority: HP eradication rate 
in subjects who do not have a 
clarithromycin or amoxicillin 
resistant strain  
Superiority: HP eradication rate in 
subjects with clarithromycin 
resistant strain  
 
Superiority: HP eradication rate in 
all subjects 
Vonoprazan dual therapy α=0.01 
If all tests are significant at the assigned α level for one therapy, α can be passed to 
the other therapy for retesting at α=0.05 (if needed) 


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therapy, and vonoprazan dual therapy to lansoprazole triple therapy, will be evaluated with a 
Farrington and Manning test with a noninferiority margin of 10% for the difference in HP 
eradication rates between treatments. The noninferiority test will be 1-sided with an overall 
significance level of α/2 for each pair of treatments. The point estimate and 2-sided (1- α)% CI of 
the difference in HP eradication rates between each of the pairs of treatments will be calculated 
via the Miettinen and Nurminen method. For each noninferiority comparison that yields 
statistical significance, superiority will then be assessed via the Farrington and Manning test of 
the null hypothesis difference ≤ 0 versus the alternative hypothesis difference > 0 as an 
exploratory analysis. 
 
If a subject’s 13C-UBT test is positive at 4-Week Post-Treatment, an endoscopy and antibiotic 
susceptibility testing will be performed. HP culture and antibiotic susceptibility results at post-
treatment assessments will be listed. 
 
8.1.2. Assumption Testing 
 
Given the large sample sizes for each treatment group, the test statistic for the Farrington and 
Manning test is expected to be normally distributed. Testing for normality with Farrington and 
Manning test might be added as an ad hoc analysis at the end of the study. 
 
8.1.3. Sensitivity and Supportive Analyses 
 
The following sensitivity and supportive analyses will be performed on the primary efficacy 
endpoint to evaluate the robustness of the results. Data summaries will parallel those described 
for the primary analysis of the primary efficacy endpoint. 
 
 
 
8.1.3.1. Sensitivity Analysis to Assess the Impact of Early and Late Test-of-Cure 
Visits 
 
To assess the impact of early and late test-of-cure visits on the robustness of the primary 
analysis, a sensitivity analysis will be performed for non-inferiority in which subjects with test-
of-cure visits outside the window of 28 to 56 days post treatment will be considered treatment 
failures, i.e. “not eradicated”.   
  
8.1.3.2. Sensitivity Analysis on Use of Prohibited Medications 
 
To explore how use of the prohibited medications of antimicrobials known to be effective against 
HP, proton pump inhibitors or high dose H2-receptor antagonists affects the robustness of the 
primary analysis, a sensitivity analysis will be performed for non-inferiority considering subjects 
as non-responders after use of these prohibited medications.  Use of these prohibited medications 
will be defined consistent with the definition of the PP Set in Section 4.4.5. This sensitivity 
analysis will be performed using the MITTp Set. 


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8.1.3.3. Tipping Point Analysis  
 
A tipping point analysis will also be performed as a sensitivity analysis. The tipping point 
analysis begins with most conservative imputation for missing data (e.g., most heavily slanted 
against the active treatment non-inferior to active control).  
 
Implementation of the tipping point approach will involve the following steps for each 
vonoprazan therapy vs. lansoprazole therapy: 
 
1. The missing data for lansoprazole subjects is assumed to be responders. Missing data 
for vonoprazan subjects is assumed to be non-responders. 
2. The data set is analyzed using the Farrington and Manning method to see if the 
p-value is ≤ the assigned α/2 level of this regimen; and if so, the tipping point analysis 
will be stopped at this point.  
3. Repeat step #1 switching an imputed responder for one lansoprazole subject to an 
imputed non-responder.  
4. Repeat step #2 to obtain the p-value to see if the p-value is ≤ the assigned α/2 level of 
this regimen. 
 
Repeat steps #3 and #4 increasing the number of imputed lansoprazole non-responders one at a 
time until the p-value is ≤ the assigned α/2 level of this regimen or all missing data has been 
switched from an imputed responder to a non-responder for all lansoprazole subjects with an 
imputed result. The number of non-responders that achieves this p-value will be considered the 
“tipping point.” 
 
8.1.3.4. Multiple Imputation Analysis 
 
A multiple imputation analysis under missing at random (MAR) followed by calculation of 
difference in HP eradication with 95% CI will also be performed as a sensitivity analysis for the 
primary endpoint. The missing pattern of this endpoint will be monotone as it is being collected 
only once post-baseline. Considering that the endpoint being imputed is binary, the logistic 
regression method will be used. The following steps will be followed: 
 
1. Impute missing primary endpoint using the LOGISTIC option on the MONOTONE 
statement in PROC MI. 
2. Analyze each imputed dataset using the same method as the primary analysis. 
3. Repeat the process K (K=50) times. 
4. Combine results using PROC MIANALYZE. 
 
 
8.1.3.5. Supportive Analysis Using PPp Set 
 
The primary analysis will be repeated using PPp Set. 
 
 


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8.1.3.6. Supportive Analysis with Different Amoxicillin Resistance Breakpoint 
 
An analysis will also be performed to assess the sensitivity of the primary endpoint results to the 
choice of resistance breakpoint for amoxicillin. In the primary analysis of the primary endpoint, 
HP strains are considered resistant to amoxicillin if the MIC is >0.125 μg/mL.  In this sensitivity 
analysis, HP strains will be considered resistant to amoxicillin if the MIC is > 0.25 μg/mL.  This 
analysis will be based on the MITT Set and exclude subjects with a HP strain with an amoxicillin 
MIC > 0.25 μg/mL or a clarithromycin MIC ≥1 μg/mL.  
 
 
8.1.3.7. Shift Summary on Antibiotics Assessment 
 
Shift tables for the change in antibiotic susceptibility assessment from baseline to 4-Week Post-
Treatment will be presented by treatment group for the MITTp Set and the MITT Set for 
amoxicillin, clarithromycin and metronidazole separately. The baseline assessment values 
include susceptible, intermediate and resistant. The 4-Week Post-Treatment assessment values 
include HP eradicated, susceptible, intermediate, resistant, and no MIC. 
 
8.1.4. Subgroup Analysis 
 
The primary efficacy endpoint will be analyzed separately for the following subgroups using the 
same method as the primary, except MIC against H pylori (μg/mL) value. Only summary 
statistics will be reported for subgroup analysis by MIC against H pylori (μg/mL) value. 
 
• Age group at Screening (<45, ≥45 - <65, ≥65 - <75, ≥75) 
• Sex (Male, Female) 
• Race 
• Ethnicity 
• BMI category (<25, ≥25 - <30, ≥30) 
• 
MIC Against H pylori (μg/mL) value (<=0.03, 0.06, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 
64, >=128, Not Applicable) 
o Amoxicillin  
o Clarithromycin  
o Metronidazole  
• 
MIC Against H pylori (μg/mL) category 
o Amoxicillin (≤0.125, >0.125) 
o Clarithromycin (<1, ≥1) 
o Metronidazole (≤8, >8) 
• Region (United States, Europe) 
• Subregion (US-West, US-Southwest, US-Southeast, US-North, Europe-Bulgaria, Europe-
Czech Republic, Europe-United Kingdom, Europe-Hungary, Europe-Poland) 
Classification of the US study sites to subregion will be done according to the following: 
o West: California, Colorado, Nevada, Utah, Washington 
o Southwest: Arizona, Oklahoma, Texas  


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o Southeast: Alabama, Arkansas, Florida, Georgia, Louisiana, North Carolina, South 
Carolina, Tennessee, Virginia 
o North: Connecticut, Illinois, Indiana, Iowa, Maryland, Michigan, Missouri, Nebraska, 
New York, Ohio, Pennsylvania, South Dakota, Wisconsin 
• MIC Against H pylori (μg/mL) category by region  
• MIC Against H pylori (μg/mL) category by subregion  
• CYP2C19 status (extensive metabolizer, poor metabolizer) 
• Smoking status (never smoked, current smoker, ex-smoker) 
• Alcohol use (drink every day, drink a couple of days per week, drink a couple of days per 
month, never drink) 
• Clinical conditions (Dyspepsia lasting at least 2 weeks, a confirmed diagnosis of 
functional dyspepsia, a recent / new diagnosis of (non-bleeding) peptic ulcer, a history of 
peptic ulcer not previously treated for HP infection, a requirement for long-term NSAID 
treatment at a stable dose of the NSAID) 
• Study drug compliance of the complete regimen (<75%, ≥75% - 100%, ≥100% - 120%, 
≥120%) 
 
The subgroup analyses will be performed using the MITTp Set. If the number of subjects within 
a subgroup in a treatment group is not sufficient to run a Farrington and Manning test, subgroups 
might be combined to perform the test. Alternatively, only summary statistics might be reported 
for such subgroups. 
 
8.2. Secondary Efficacy Endpoint 
 
The secondary endpoints are  
 
• Proportion of subjects with successful HP eradication after the Treatment Period, as 
determined by 13C-UBT at 4 weeks after the last dose of study drug, among subjects who 
had a clarithromycin resistant strain of HP at baseline. This analysis will be performed 
using the subset of subjects that are in MITT Set that had a clarithromycin resistant strain 
of HP at baseline. 
 
• Proportion of subjects with successful HP eradication after the Treatment Period, as 
determined by 13C-UBT, at 4 weeks after the last dose of study drug among all subjects. 
This analysis will be performed using the MITT Set. 
 
The secondary endpoints will be evaluated in a similar manner as the primary endpoint for 
superiority of vonoprazan triple therapy to lansoprazole triple therapy and of vonoprazan dual 
therapy to lansoprazole triple therapy.  
 
In addition, the analysis of both secondary endpoints will be repeated using the PP set.  
 
To assess the impact of early and late test-of-cure visits on the robustness of the analysis, a 
sensitivity analysis will be performed for both secondary endpoints in which subjects with test-


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of-cure visits outside the window of 28 to 56 days post treatment will be considered treatment 
failures, i.e. “not eradicated”.    
 
The secondary efficacy endpoint in subjects with a clarithromycin resistant strain will be 
analyzed separately, using the MITT Set, for the following subgroups. MIC against H pylori 
(μg/mL) category will be analyzed using the same method as the primary. MIC against H pylori 
(μg/mL) value will be reported only using summary statistics. 
 
• 
MIC Against H pylori (μg/mL) value 
o Amoxicillin  
o Metronidazole 
• MIC Against H pylori (μg/mL) category 
o Amoxicillin (≤0.125, >0.125) 
o Metronidazole (<8, >8) 
 
The secondary efficacy endpoint in all subjects will be analyzed separately, using the MITT Set, 
for the following subgroups. MIC against H pylori (μg/mL) category will be analyzed using the 
same method as the primary. MIC against H pylori (μg/mL) value will be reported only using 
summary statistics. 
 
• 
MIC Against H pylori (μg/mL) value 
o Amoxicillin  
o Clarithromycin 
o Metronidazole 
• MIC Against H pylori (μg/mL) category 
o Amoxicillin (≤0.125, >0.125) 
o Clarithromycin (<1, ≥1) 
o Metronidazole (≤8, >8) 
 
 
9. 
Safety Analysis 
 
Safety will be assessed by summarizing the incidence of AEs and changes in clinical laboratory 
tests, vital signs and ECG. For all safety analyses, baseline will be the last available assessment 
prior to the first dose of study drug.  
 
All safety analyses will be conducted for each treatment group and overall using the Safety Set. 
 
9.1. Adverse Events 
 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). MedDRA version used for reporting the study will be documented in the summary 
table footnotes. A treatment-emergent AE (TEAE) is defined as any event that occurs after the 
first dose of study drug or any event at baseline that worsens in either intensity or frequency after 


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the first dose of study drug.  A subject with multiple adverse events within a primary SOC or 
preferred term is only counted once towards the total for that SOC and/or preferred term. For the 
AE severity and relationship summaries, if a subject reported more than one adverse event with 
the same preferred term, the adverse event with the greatest severity or relationship will be 
presented. If a subject reported more than one adverse event within the same primary system 
organ class, then the subject will be counted only once with the greatest severity or relationship 
at the system organ class level.  For table summaries, if severity is missing then ‘severe’ is 
assumed. If relationship is missing, relationship to study drug is assumed to be ‘related’.   
 
An overall summary of the number of subjects and the number of events with TEAEs in each 
treatment group will be presented, including TEAEs, serious TEAEs, study drug related TEAEs, 
study drug related serious TEAEs, TEAEs leading to treatment discontinuation, and TEAEs 
leading to death. 
 
The number and percentage of subjects with TEAEs will be summarized in the following ways:  
• by primary system organ class, preferred term, and treatment group 
• by primary system organ class, preferred term, maximum severity, and treatment group 
• by primary system organ class, preferred term, relationship to study drug, and treatment 
group 
• by primary system organ class, preferred term, day of onset, and treatment group 
 
The number and percentage of subjects with TEAEs related to study drug will be summarized in 
the following ways:  
• by primary system organ class, preferred term, and treatment group 
• by primary system organ class, preferred term, maximum severity, and treatment group 
• by primary system organ class, preferred term, day of onset, and treatment group 
 
Summaries of TEAEs by day of onset will use the following categories: Day 1 to 14, Day 15 to 
28, Day 28 and above.   
The most common TEAEs (≥5% of subjects in any treatment group) and TEAEs related to study 
drug (≥2% of subjects in any treatment group) will be presented by preferred term in descending 
frequency starting from the most common event. The most common non-serious AEs (>5% of 
subjects in any treatment group) will be presented by primary system organ class, preferred term 
and treatment group. 
 
The number and proportion of subjects as well as the number of events (except for deaths) with 
the following types of events will be summarized by primary system organ class, preferred term 


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and treatment group: 
• Adverse events leading to treatment discontinuation 
• Serious Adverse Events (SAEs) 
• Deaths 
• Adverse events of special interest 
 
All adverse events will be included in a listing using the Screened Set. The following select adverse 
events will be displayed in separate listings using the Safety Set: 
 
• Adverse events leading to treatment discontinuation 
• SAEs 
• Deaths 
• Adverse events of special interest 
 
9.1.2. Adverse Events of Special Interests (AESI) 
The number and percentage of subjects with TEAEs and SAEs that are in one of the AESI 
categories presented in Table 4 will be summarized by AESI category, primary system organ 
class and preferred term for each treatment group and overall. The search criteria that will be 
used to identify AESIs are specified in the table.  
 
 


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Table 4 
Adverse Events of Special Interest – Search Criteria 
Adverse Event of Special Interest 
Search Criteria 
Clostridium difficile enteric infection 
Pseudomembranous colitis SMQ (Narrow) 
Bone Fracture 
Bone Fracture Custom Query (PTs defined below) 
Acetabulum fracture  
  Fractured skull depressed  
Ankle fracture  
                  Lumbar vertebral fracture  
Atypical femur fracture  
  Metaphyseal corner fracture  
Atypical fracture                    Multiple fractures  
Avulsion fracture                    Open fracture  
Bone fissure  
                  Osteoporotic fracture  
Bone fragmentation                  Patella fracture  
Chance fracture  
                  Pathological fracture  
Clavicle fracture  
                  Pelvic fracture  
Comminuted fracture  
  Pubis fracture  
Complicated fracture  
  Radius fracture  
Compression fracture  
  Rib fracture 
Craniofacial fracture  
  Sacroiliac fracture  
Epiphyseal fracture  
  Scapula fracture  
Facial bones fracture  
  Skull fracture  
Femoral neck fracture  
  Skull fractured base  
Femur fracture  
                  Spinal compression fracture  
Fibula fracture  
                  Spinal fracture  
Foot fracture  
                  Spinal fusion fracture  
Forearm fracture                    Sternal fracture  
Fracture                                    Stress fracture  
Fracture blisters  
                  Subchondral insufficiency fracture  
Fracture displacement  
  Thoracic vertebral fracture  
Fracture malunion                    Tibia fracture  
Fracture nonunion                    Torus fracture  
Fracture of clavicle         
  Traumatic fracture  
    due to birth trauma 
Fractured coccyx                    Ulna fracture  
Fractured ischium                    Upper limb fracture  
Fractured sacrum                   Wrist fracture 
Severe cutaneous adverse reactions  
Severe cutaneous adverse reactions SMQ (Narrow) 
Hepatotoxicity 
 
• Drug related hepatic disorders - comprehensive search (SMQ) 
(Narrow) 
• Cholestasis and jaundice of hepatic origin (SMQ) (Broad) 
• Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions SMQ (Broad) 
• Hepatitis, non-infectious (SMQ) (Broad) 
• Liver related investigations, signs and symptoms (SMQ) (Narrow) 
Gastric cancer 
Gastric Neoplasms Malignant MedDRA High Level Term 
Hypersensitivity 
Hypersensitivity SMQ (narrow) 
QT prolongation 
• Torsade de pointes/QT prolongation (SMQ) (Broad) 
• Seizure MedDRA Preferred Term 
MedDRA: Medical Dictionary for Regulatory Activities; PT: preferred term; SMQ: Standardized MedDRA Queries. 
 
 
 


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9.2. Clinical Laboratory Evaluations 
 
Descriptive statistics for clinical laboratory values ((hematology, chemistry and urinalysis 
laboratory tests; in SI units and in US conventional units) will be presented by treatment group 
and overall. Changes from baseline will also be presented for quantitative variables by treatment 
group and overall. For categorical variables (ie, normal or abnormal findings, or qualitative 
clinical laboratory tests), shift tables for the change from baseline to each post-baseline time 
point will be presented by treatment group and overall.  
 
Abnormal liver function tests are defined as liver test values that meet at least one of the criteria 
listed below. The number and percentage of subjects with at least one post-baseline abnormal 
liver function test and with the test value higher than baseline, if available, will be presented by 
treatment group and overall.  A supportive listing of subjects with such post-baseline elevations 
will be provided including the subject ID, baseline, and post-baseline values. 
 
• ALT > 3xULN 
• ALT > 5xULN 
• ALT > 10xULN 
• ALT > 3xULN and Total Bilirubin > 2xULN 
 
• AST > 3xULN 
• AST > 5xULN 
• AST > 10xULN 
• AST > 3xULN and Total Bilirubin > 2xULN 
 
• Total Bilirubin > 2xULN 
 
• AST > 3xULN or ALT > 3xULN 
• AST > 5xULN or ALT > 5xULN 
• AST > 10xULN or ALT > 10xULN 
• (AST > 3xULN or ALT > 3xULN) and Total Bilirubin > 2xULN 
 
• AST > 3xULN and ALT > 3xULN 
• AST > 5xULN and ALT > 5xULN 
• AST > 10xULN and ALT > 10xULN 
• AST > 3xULN and ALT > 3xULN and Total Bilirubin > 2xULN 
 
• Alkaline phosphatase > 1.5xULN 
• ALT > 3xULN and Alkaline phosphatase > 1.5xULN 
• AST > 3xULN and Alkaline phosphatase > 1.5xULN 
 
• Alkaline phosphatase > 3xULN 
• ALT > 3xULN and Alkaline phosphatase > 3xULN 


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• AST > 3xULN and Alkaline phosphatase > 3xULN 
 
9.3. Vital Sign 
 
Descriptive statistics for vital signs, including body temperature, systolic blood pressure, 
diastolic blood pressure and pulse rate, will be presented by treatment group and overall. 
Changes from baseline will also be presented by treatment group and overall. 
 
Abnormal vital sign values are defined as vital sign values that meet one of the criteria listed 
below. The number and percentage of subjects with at least one post-baseline abnormal vital sign 
value and with the value higher than the baseline value, if available, will be presented by 
treatment group and overall. A supportive listing of subjects with such post-baseline elevations 
will be provided including the subject ID, baseline, and post-baseline values. 
 
• Systolic blood pressure (mmHg):  
o <50 
o >180 
• Diastolic blood pressure (mmHg):  
o <50 
o >100 
• Heart rate (bpm): 
o <50 
o >120 
 
 
9.4.  Physical Examination 
 
All data collected from the physical examinations assessments must be available in the source 
documents but will not be added to the analysis database. 
 
9.5. Electrocardiogram 
 
Descriptive statistics for ECG parameters, including heart rate, RR interval, PR interval, QT 
interval, QTc Fridericia (QTcF), and QRS interval, will be presented by treatment group and 
overall. All ECG assessment values and interpretations will be listed for all subjects in the Safety 
Set.  
 
Changes from baseline will also be presented for quantitative variables by treatment group and 
overall.  
 


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For ECG interpretations (within normal limits, abnormal but not clinically significant, or 
abnormal and clinically significant), shift tables for the change from baseline to each post-
baseline time point will be presented by treatment group and overall.  
 
Abnormal QTcF values are defined as ECG values that meet at least one of the criteria listed 
below, the number and percentage of subjects with at least one of the post-baseline abnormal 
values and with post-baseline value higher than baseline value, if available, will be presented by 
treatment group and overall. A supportive listing of subjects with such post-baseline elevations 
will be provided including the subject ID, baseline, and post-baseline values. 
• 
Absolute QTcF interval prolongation: 
o QTc interval > 450 
o QTc interval > 480  
o QTc interval > 500  
 
• Change from baseline in QTcF interval: 
o QTc interval increases from baseline >30  
o QTc interval increases from baseline >60 
o  QTc interval > 450 with increase from baseline >30  
 
10. Pharmacokinetics 
 
A data listing with plasma concentration data will be provided based on the PK Set. 
11. Interim Analysis/Other Analyses 
11.1. Interim Analysis 
 
No interim analysis is planned. 
 
11.2. Coronavirus Pandemic 
 
Shortly after this study began enrolling subjects, the SARS-COV-2 virus, which causes COVID-
19 was declared a global pandemic by the World Health Organization. In accordance with 
guidance issued by regulatory agencies, study data collection has been amended for subjects to 
capture visits missed/delayed due to COVID-19 related reasons, and assessment completed via 
alternative method due to COVID-19 related reasons.     
 
 
COVID-19 impacts on individual subjects collected on COVID-19 CRF pages will be listed for 
the Randomized Set. Protocol deviations related to COVID-19 will be marked in the protocol 
deviation listing for the Randomized Set. Delayed or missed 13C-UBT due to COVID-19 will be 
identified in the 13C-UBT listing for the Randomized Set. 
 


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The anticipated impact of COVID-19 is widely regarded as unknown. If the impact of COVID-
19 on the conduct of this study is observed to be significant, further summaries and listings of the 
impact will be explored. 
 
12. Changes in the Planned Analysis 
 
The following change to the analysis specified in Protocol Amendment 2, dated 11May2020 has 
been made. 
 
In the first amendment to the SAP, to account for the COVID-19 impact, subjects with out-of-
window 13C-UBT results that are late (>56 days post treatment) due to COVID-19 were planned 
to be included in the 4-Week Post-Treatment visit in the efficacy analyses. 
 
Beyond those that were directly cited as related to COVID-19, there were many cases of indirect 
effects of COVID-19 on the visit schedules.  To maximize obtaining 13C-UBT results, some sites 
needed to use discretion and flexibility for subject visits including those subjects that needed to 
return to the site for a repeat 13C-UBT that was initially indeterminate.   
 
Based on the complex operational conditions that were faced during this study, the visit window 
was modified to allow late (>56 days post treatment) 13C-UBT results as well as those obtained 
one day early (day 27 posttreatment) to be included in the MITT analyses for the primary and 
secondary endpoints. 
 
Sensitivity analyses were added to assess the impact of this change. 
 
13. References 
Bretz F, et al. Graphical approaches for multiple comparison procedures using weighted 
Bonferroni, Simes, or parametric tests. Biometrical Journal 53(2011) 6, 894-913. 
 
Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial 
trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med 
1990;9:1447–54. 
 
Harford W, Lanza F, Arora A, et al. Double-blind, multicenter evaluation of lansoprazole and 
amoxicillin dual therapy for the cure of Helicobacter pylori infection. Helicobacter 
1996;1(4):243-50. 
 
Megraud F. The challenge of Helicobacter pylori resistance to antibiotics: the comeback of 
bismuth-based quadruple therapy. Therap Adv Gastroenterol 2012;5(2):103-9. 
 
Meyer JM, Silliman NP, Wang W, et al. Risk factors for Helicobacter pylori resistance in the 
United States: the surveillance of H. pylori antimicrobial resistance partnership (SHARP) study, 
1993-1999. Ann Intern Med 2002;136(1):13-24. 
 


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PREVACID (lansoprazole) delayed-release Capsules, PREVACID SoluTab (lansoprazole) 
delayed-release orally disintegrating tablets. Full Prescribing Information including Medication 
Guide. Deerfield, IL: Takeda Pharmaceuticals America, Inc., Revised Jun 2018. 
 
PRILOSEC® (omeprazole) delayed-release capsules PRILOSEC® (omeprazole magnesium) for 
delayed-release oral suspension [package insert]. AstraZeneca Pharmaceuticals LP Wilmington 
(DE); 2016. 
 
Savoldi A, Carrara E, Graham DY, Conti M, Tacconelli E. Prevalence of antibiotic resistance in 
Helicobacter pylori: A systematic review and meta-analysis in World Health Organization 
regions. Gastroenterology 2018;155(5):1372-82 e17. 
 
 
 
14. Appendices 
 
 


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14.1. Schedule of Events 
 
Table 5  
Schedule of Events 
 
  
Screening 
Period 
 
Treatment Period 
Follow-Up Period 
Early 
Termination 
Timing 
 
Day -1 a 
Week 0 
Day 1 
Week 1 
Day 8  
Week 2 
Day 15  
Week 4 
Day 29 
4-Week  
Post-
Treatment 
Visit Windows (Days): 
-35 to -2 
- 
- 
6 to 10 
15 to 18 
26 to 32  
42 to 70 
 
Visit Number: 
1 
2 
NA 
Phone call b 
3 
Phone call c 
4 
- 
Informed consent 
Xd 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
Smoking status and alcohol use 
X 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
Physical examination e 
X 
X 
 
 
X 
X 
X 
Vital signs  
X 
X 
 
 
X 
X 
X 
Weight and height 
X 
 
 
 
Concomitant medications 
X 
X 
 
X b  
X 
X c 
X 
X 
Concurrent medical conditions 
X 
 
 
 
13C-UBT for HP infection status 
X f 
 
 
X g 
X h 
Hepatitis B & C + HIV 
X 
 
 
 
Urine drug screen 
X 
 
 
 
Clinical laboratory test including 
hematology, serum chemistry, urinalysis 
X 
 
 
X 
X 
FSH i 
X 
 
 
 
 
 
 
 


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Screening 
Period 
 
Treatment Period 
Follow-Up Period 
Early 
Termination 
Timing 
 
Day -1 a 
Week 0 
Day 1 
Week 1 
Day 8  
Week 2 
Day 15  
Week 4 
Day 29 
4-Week  
Post-
Treatment 
Visit Windows (Days): 
-35 to -2 
- 
- 
6 to 10 
15 to 18 
26 to 32  
42 to 70 
 
Visit Number: 
1 
2 
NA 
Phone call b 
3 
Phone call c 
4 
- 
Pregnancy test (serum hCG) j, k 
X 
 
 
 
Pregnancy test (urine hCG) j, k 
X 
 
 
X 
X 
X 
Guidance on avoidance of pregnancy 
X 
X 
 
 
X 
 
 
X 
CYP2C19 genotyping test  
 
 
X l 
 
ECG 
X 
 
 
 
X 
 
 
X 
Endoscopy 
X 
 
 
 
 
 
X g 
 
Gastric mucosa biopsy for antibiotic 
susceptibility test m, n 
X o 
 
 
 
 
 
X g 
 
Gastric mucosa biopsy for presence of 
HP n, p 
X 
 
 
 
 
 
 
 
Randomization  
 
X a 
 
 
 
 
 
 
Dispense study drug 
 
X 
 
 
 
 
 
 
First day of study drug administration  
 
 
X 
 
 
 
 
 
Study drug return/ accountability/review 
treatment compliance q 
 
 
 
X b  
X 
 
 
X 
Pharmacokinetics r 
 
 
 
 
X 
 
 
  
AE/pre-treatment event assessment 
X 
X 
 
X b 
X 
X c 
X 
X 
Abbreviations: AE, adverse events; CYP2C19, cytochrome P450 2C19; ECG, electrocardiogram; FSH, follicle-stimulating hormone; hCG, human chorionic 
gonadotropin; HIV, human immunodeficiency virus; HP, Helicobacter pylori; NA, not applicable; PPI, proton pump inhibitor; UBT, urea breath test. 
a 
The date of randomization is defined as Day -1. 
b 
Subjects will receive a phone call for Week 1, Day 8 that will include a compliance reminder, and an assessment of concomitant medications and any 
AEs. 
c 
Subjects will receive a phone call for Week 4, Day 29 that will include an assessment of concomitant medications and any AEs. 
d 
Subjects may be pre-screened for HP infection using a fingerstick test performed not more than 30 days prior to screening. The subjects will sign a pre-
screening ICF for optional fingerstick test of HP status. 


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Screening 
Period 
 
Treatment Period 
Follow-Up Period 
Early 
Termination 
Timing 
 
Day -1 a 
Week 0 
Day 1 
Week 1 
Day 8  
Week 2 
Day 15  
Week 4 
Day 29 
4-Week  
Post-
Treatment 
Visit Windows (Days): 
-35 to -2 
- 
- 
6 to 10 
15 to 18 
26 to 32  
42 to 70 
 
Visit Number: 
1 
2 
NA 
Phone call b 
3 
Phone call c 
4 
- 
e 
Full physical examination is performed at baseline; a brief physical examination is performed at all other visits. 
f 
If the subject takes PPI prior to 13C-UBT test, it may show false negative, for those cases retest can be allowed 2 weeks after the PPI discontinuation when 
appropriate in investigator’s judgment. 
g 
If subject’s 13C-UBT test is positive at 4 weeks post-treatment, an endoscopy and antibiotic susceptibility testing should be performed within 4 weeks of a 
positive 13C-UBT test result. The subject can then be treated as per standard of care.  
h 
Should be performed between 4-weeks and 8-weeks after last dose of study medication. 
i 
If menopause is suspected. 
j 
Only female subjects of childbearing potential. 
k 
If the urine hCG is positive, serum hCG to be performed. 
l 
Collection for genotyping is optional. Subjects willing to participate must sign the informed consent form. 
m Gastric mucosa is to be sampled: one from the greater curve of the antrum and one from the lesser curve of the gastric body. This sample to be taken prior 
to the histopathology sample for HP. 
n 
Gastric mucosal biopsy specimens that were not used for culture (and subsequent antimicrobial susceptibility testing) or histopathology evaluation may be 
available from the central laboratory and may be used for possible future genomic analysis of HP in the specimens. 
o 
If the subject fails screening, susceptibility test is not to be performed with the collected sample. 
p 
Gastric mucosa is to be sampled: one each from the greater and lesser curve of the gastric body, and one each from the greater and lesser curve of the 
antrum and sent to a central laboratory at the start of study to document HP infection. 
q 
As subjects will self-administer study drug(s) at home, compliance with study drug will be assessed at each visit. For on-site visits, compliance will be 
assessed by direct questioning and counting returned tablets/capsules during the site visits. For phone visits, a compliance reminder will be provided to the 
subjects; compliance will be assessed by direct questioning. Subject treatment compliance assessment results will be documented in the source documents 
and eCRF. 
r 
For pharmacokinetic analysis of drug concentrations, blood samples will be collected at the Week 2 Visit, unless prohibited by local regulations. Date and 
time of blood sample, as well as date and time of last study drug(s) dose will be collected in source documents and eCRF.  
 
 


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14.2.  Imputation Rules for Missing Date Information 
14.2.1.  Rules for Concomitant Medication Start Date Imputation 
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
 
Missing day and month 
• If the year of the incomplete start date is the same as the year of the date of the first dose of 
study drug, then the day and month of the date of the first dose of study drug will be 
assigned to the missing fields. 
• If the year of the incomplete start date is before the year of the date of the first dose of study 
drug, then 31 December will be assigned to the missing fields. 
• If the year of the incomplete start date is after the year of the date of the first dose of study 
drug, then 01 January will be assigned to the missing fields. 
 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
 
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of study drug, then the day of the date of the first dose of study drug 
will be assigned to the missing day. 
• If either the year is before the year of the date of the first dose of study drug or if both years 
are the same but the month is before the month of the date of the first dose of study drug, 
then the last day of the month will be assigned to the missing day. 
• If either the year is after the year of the date of the first dose of study drug or if both years 
are the same but the month is after the month of the date of the first dose of study drug, then 
the first day of the month will be assigned to the missing day. 
 
14.2.2.  Rules for Concomitant Medication End Date Imputation 
The following rules will be applied to impute the missing numerical fields.  If the date of the last 
dose of study drug is missing, then replace it with the last visit date.  If the imputed stop date is 
before the start date (imputed or non-imputed start date), then the imputed stop date will be equal 
to the start date. 
 
 


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Missing day and month 
• If the year of the incomplete stop date is the same as the year as of the date of the last dose 
of study drug, then the day and month of the date of the last dose of study drug will be 
assigned to the missing fields. 
• If the year of the incomplete stop date is before the year of the date of the last dose of study 
drug, then 31 December will be assigned to the missing fields. 
• If the year of the incomplete stop date is after the year of the date of the last dose of study 
drug, then 01 January will be assigned to the missing fields. 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
Missing day only 
• If the month and year of the incomplete stop date are the same as the month and year of the 
date of the last dose of study drug, then the day of the date of the last dose of study drug will 
be assigned to the missing day. 
• If either the year is before the year of the date of the last dose of study drug or if both years 
are the same but the month is before the month of the date of the last dose of study drug, 
then the last day of the month will be assigned to the missing day. 
• If either the year is after the year of the last dose of study drug or if both years are the same 
but the month is after the month of the date of the last dose of study drug, then the first day 
of the month will be assigned to the missing day. 
 
14.2.3. Rules for AE Start Date Imputation 
 
For AEs, incomplete (i.e., partially missing) start dates will be imputed and will follow the same 
rules as in Section 14.2.1.  Incomplete stop dates will not be imputed.