Clinical trial NCT04124926
Conditions: Erosive Esophagitis
Keywords: Erosive Esophagitis Vonoprazan Lansoprazole
Sponsor: Phathom Pharmaceuticals, Inc.
Start date: 2019-10-28; Completion date: 2021-08-24
Enrollment: 1027 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy and safety of vonoprazan compared to lansoprazole in participants with erosive esophagitis.

Detailed description:

Arms: arm 1: Participants will receive oral vonoprazan 20 mg once per day (QD) for a maximum of 8 weeks. arm 2: Participants will receive oral lansoprazole 30 mg once per day (QD) for a maximum of 8 weeks. arm 3: Participants will receive oral vonoprazan 10 mg once per day (QD) for a maximum of 24 weeks. arm 4: Participants will receive oral vonoprazan 20 mg once per day (QD) for a maximum of 24 weeks. arm 5: Participants will receive oral lansoprazole 15 mg once per day (QD) for a maximum of 24 weeks.
Interventions: intervention 1: Vonoprazan intervention 2: Lansoprazole
Intervention descriptions: intervention 1: Over-encapsulated tablet administered orally with approximately 240 mL water, 30 minutes prior to the morning meal. intervention 2: Over-encapsulated capsule administered orally with approximately 240 mL water, 30 minutes prior to the morning meal.

Protocol documents:
Prot_000.pdf: 
Protocol Number: EE-301  
 
Official Title: A Phase 3, Randomized, Double-Blind, Two-Phase, Multicenter Study to
Evaluate the Efficacy and Safety of Vonoprazan 20 mg Compared to 
Lansoprazole 30 mg for Healing in Patients with Erosive Esophagitis and to
Evaluate the Efficacy and Safety of Vonoprazan (10 mg and 20 mg) Compared
to Lansoprazole 15 mg for the Maintenance of Healing in Patients with Healed
Erosive Esophagitis
 
NCT Number: NCT04124926
Document Date: 01 October 2019


CLINICAL STUDY PROTOCOL 
IND NUMBER: 79,212 
EUDRACT: 2019-002579-33 
A Phase 3, Randomized, Double-Blind, Two-Phase, Multicenter Study to 
Evaluate the Efficacy and Safety of Vonoprazan 20 mg Compared to 
Lansoprazole 30 mg for Healing in Patients with Erosive Esophagitis and 
to Evaluate the Efficacy and Safety of Vonoprazan (10 mg and 20 mg) 
Compared to Lansoprazole 15 mg for the Maintenance of Healing in 
Patients with Healed Erosive Esophagitis 
PROTOCOL NO. EE-301 
Sponsor: 
Phathom Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, CA 94025 
Sponsor Contact: 
Medical Monitor: 
 
 
Version of Protocol:  
Version 3.0, Amendment 2 
Date of Protocol:  
01 Oct 2019 
Previous Date and Version 
22 Aug 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. 
 




Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: EE-301 Version 3.0 (Amendment 2) 
01 Oct 2019 
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Protocol Approval – Principal/Coordinating Investigator 
Study Title 
A Phase 3, Randomized, Double-Blind, Two-Phase, Multicenter Study 
to Evaluate the Efficacy and Safety of Vonoprazan 20 mg Compared 
to Lansoprazole 30 mg for Healing in Patients with Erosive 
Esophagitis and to Evaluate the Efficacy and Safety of Vonoprazan 
(10 mg and 20 mg) Compared to Lansoprazole 15 mg for the 
Maintenance of Healing in Patients with Healed Erosive Esophagitis 
Protocol Number EE-301 
Protocol Date 
01 Oct 2019 
 
Protocol accepted and approved by: 
Principal/Coordinating Investigator 
 




Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: EE-301 Version 3.0 (Amendment 2) 
01 Oct 2019 
Page 5 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 3, Randomized, 
Double-Blind, Two-Phase, Multicenter Study to Evaluate the Efficacy and Safety of 
Vonoprazan 20 mg Compared to Lansoprazole 30 mg for Healing in Patients with Erosive 
Esophagitis and to Evaluate the Efficacy and Safety of Vonoprazan (10 mg and 20 mg) 
Compared to Lansoprazole 15 mg for the Maintenance of Healing in Patients with Healed 
Erosive Esophagitis” 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, Amendment 2, dated 01 Oct 2019, 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 Committees 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 
 
 
 


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Protocol: EE-301 Version 3.0 (Amendment 2) 
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Summary of Changes 
Protocol Amendment History and Reasons for Amendment 
Version 
Date 
Reasons for Amendment 
Version 1.0 
05 Aug 2019 
Original Protocol 
Version 2.0 
(Protocol 
Amendment 1) 
22 Aug 2019 
• To remove double-dummy and placebo from 
study drugs and other applicable sections 
• To change exclusion period for proton pump 
inhibitors and histamine H2 receptor 
antagonists from 14 days prior to screening to 
14 days prior to screening 13C-UBT test 
• To update footnote (a) of Table 5-2 Excluded 
Medications and Treatments regarding 
prohibition period of medications that may 
interfere with 13C-UBT test 
• To remove ‘x’ from dispense study drug at 
Maintenance Week 4 (Maintenance Day 29) 
in Table 13-1 Schedule of Events 
• To update a footnote to the Table 13-1 
Schedule of Events to clarify that subjects 
may need to return for study drug 
administration after Week 2 and Week 8 


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Protocol: EE-301 Version 3.0 (Amendment 2) 
01 Oct 2019 
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Version 
Date 
Reasons for Amendment 
Version 3.0 
(Protocol 
Amendment 2) 
01 Oct 2019 
• To remove wording from Inclusion 
criterion #3 and throughout the document 
allowing a subject’s legally acceptable 
representative to consent on their behalf.  
• To revise Exclusion criterion #1 to add 
wording allowable to extend endoscopy 
screening period to 10 days in rare instances 
with sponsor approval. Wording in 
Section 6.2.1 also updated to reflect changes 
to Exclusion criterion #1. 
• To add to exclude cytochrome P450 2C19 
(CYP3A4) substrates with a narrow 
therapeutic index in Table 5-2.  
• To add overall study stopping criteria in 
Section 6.3.1.15. 
• To clarify requirements for informed consent 
process for pharmacogenetic sampling and 
analysis in Section 6.11. 
• To add smoking status and alcohol use in 
Table 13.1 Schedule of Events and to 
Section 7.6. 
• To update Section 13.3 Appendix 3: 
The Patient Assessment of Gastrointestinal 
Disorders-Symptoms Severity Index 
(PAGI-SYM) with most recent sample 
version. 
For details of Amendments 1 and 2, see Appendix 7 (Section 13.7). 
 
 


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01 Oct 2019 
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Table of Contents 
Summary of Changes .................................................................................................................6 
Table of Contents .......................................................................................................................8 
List of Tables ............................................................................................................................12 
List of Figures ..........................................................................................................................13 
Protocol Synopsis.....................................................................................................................14 
List of Abbreviations................................................................................................................21 
1 
Introduction ......................................................................................................................23 
1.1 
Study Rationale .......................................................................................................23 
1.2 
Background .............................................................................................................23 
1.3 
Justification for Dose ..............................................................................................25 
2 
Study Objectives and Endpoints.......................................................................................27 
3 
Investigational Plan ..........................................................................................................30 
3.1 
Study Design ...........................................................................................................30 
3.1.1 
Rationale of Study Design .......................................................................32 
4 
Subject Selection and Withdrawal Criteria ......................................................................34 
4.1 
Selection of Study Population .................................................................................34 
4.1.1 
Inclusion Criteria .....................................................................................34 
4.1.2 
Exclusion Criteria ....................................................................................35 
4.1.3 
Lifestyle Considerations ..........................................................................38 
4.1.4 
Screen Failures .........................................................................................38 
4.2 
Withdrawal of Subjects From Study Drug and/or the Study ..................................38 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................38 
4.2.2 
Handling of Withdrawals .........................................................................40 
4.2.3 
Lost to Follow-up ....................................................................................40 
4.2.4 
Replacements ...........................................................................................41 
5 
Study Drugs ......................................................................................................................42 
5.1 
Method of Assigning Subjects to Treatment Groups ..............................................42 
5.2 
Treatments Administered ........................................................................................42 
5.3 
Identity of Investigational Product..........................................................................43 


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5.4 
Management of Clinical Supplies ...........................................................................44 
5.4.1 
Study Drug Packaging and Storage .........................................................44 
5.4.2 
Test Article Accountability ......................................................................44 
5.4.3 
Other Supplies .........................................................................................45 
5.5 
Overdose Management ...........................................................................................45 
5.5.1 
Treatment of Overdose ............................................................................45 
5.6 
Blinding ..................................................................................................................45 
5.6.1 
Breaking the Blind ...................................................................................45 
5.7 
Treatment Compliance ............................................................................................46 
5.8 
Prior and Concomitant Therapy ..............................................................................46 
5.8.1 
Background Medications .........................................................................47 
5.8.2 
Excluded Medications .............................................................................47 
6 
Study Assessments and Procedures ..................................................................................49 
6.1 
13 C Urea Breath Test...............................................................................................49 
6.2 
Efficacy Assessments ..............................................................................................49 
6.2.1 
Endoscopy ................................................................................................49 
6.2.2 
Adjudication of EE Grading ....................................................................51 
6.2.3 
Symptom Diary ........................................................................................52 
6.2.4 
PAGI SYM Questionnaire .......................................................................53 
6.2.5 
PAGI QoL Questionnaire .........................................................................53 
6.2.6 
EQ-5D-5L ................................................................................................54 
6.3 
Safety Assessments .................................................................................................54 
6.3.1 
Pretreatment Adverse Events and Adverse Events ..................................54 
6.3.1.1 
Definitions of Pretreatment Adverse Events ............................................54 
6.3.1.2 
Definitions of Adverse Events .................................................................54 
6.3.1.3 
Serious Adverse Events ...........................................................................54 
6.3.1.4 
Adverse Event of Special Interest ............................................................56 
6.3.1.5 
Additional Points to Consider for PTEs and AEs ....................................57 
6.3.1.6 
Assessment of Severity ............................................................................60 
6.3.1.7 
Assessment of Causality ..........................................................................60 
6.3.1.8 
Relationship to Study Procedures ............................................................61 
6.3.1.9 
Start Date .................................................................................................61 
6.3.1.10 Stop Date .................................................................................................61 


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6.3.1.11 Frequency ................................................................................................61 
6.3.1.12 Action Concerning Study Drug ...............................................................61 
6.3.1.13 Outcome ...................................................................................................61 
6.3.1.14 Time Period and Frequency for Collecting AE and SAE Information ....62 
6.3.1.15 Regulatory Reporting Requirements for SAEs ........................................65 
6.4 
Safety Monitoring Committee ................................................................................66 
6.5 
Pregnancy ................................................................................................................66 
6.6 
Laboratory Analyses ...............................................................................................66 
6.7 
Physical Examinations ............................................................................................69 
6.8 
Vital Signs ...............................................................................................................69 
6.9 
Electrocardiograms .................................................................................................69 
6.10 Gastric Mucosal Biopsy ..........................................................................................70 
6.11 Pharmacogenetics ...................................................................................................70 
7 
Statistical and Analytical Plan ..........................................................................................72 
7.1 
Primary Efficacy Endpoints ....................................................................................72 
7.2 
Secondary Efficacy Endpoints ................................................................................72 
7.3 
Exploratory Endpoints ............................................................................................73 
7.4 
Sample Size Calculations ........................................................................................74 
7.4.1 
Healing Phase ..........................................................................................74 
7.4.2 
Maintenance Phase ..................................................................................75 
7.5 
Analysis Sets ...........................................................................................................76 
7.6 
Description of Subgroups to be Analyzed ..............................................................77 
7.7 
Statistical Analysis Methodology ...........................................................................78 
7.7.1 
Analysis of Primary Efficacy Endpoint ...................................................78 
7.7.1.1 
Healing Phase ..........................................................................................78 
7.7.1.2 
Maintenance Phase ..................................................................................78 
7.7.2 
Analysis of Secondary Efficacy Endpoint ...............................................79 
7.7.2.1 
Healing Phase ..........................................................................................79 
7.7.2.2 
Maintenance Phase ..................................................................................80 
7.7.3 
Analysis of Exploratory Efficacy Endpoint .............................................81 
7.7.3.1 
Healing Phase ..........................................................................................81 
7.7.3.2 
Maintenance Phase ..................................................................................82 


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Protocol: EE-301 Version 3.0 (Amendment 2) 
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7.7.4 
Safety Analyses ........................................................................................82 
7.7.5 
Other Analyses .........................................................................................83 
7.7.6 
Interim Analyses ......................................................................................83 
8 
Data Quality Assurance ....................................................................................................84 
8.1 
Data Management ...................................................................................................84 
9 
Ethics ................................................................................................................................85 
9.1 
Independent Ethics Committee or Institutional Review Board ..............................85 
9.2 
Ethical Conduct of the Study ..................................................................................85 
9.3 
Subject Information and Consent ...........................................................................85 
10 Investigator’s Obligations ................................................................................................87 
10.1 Confidentiality ........................................................................................................87 
10.2 Financial Disclosure and Obligations .....................................................................87 
10.3 Investigator Documentation ....................................................................................88 
10.4 Study Conduct .........................................................................................................88 
10.5 Adherence to Protocol ............................................................................................88 
10.6 Adverse Events and Study Report Requirements ...................................................89 
10.7 Investigator’s Final Report .....................................................................................89 
10.8 Records Retention ...................................................................................................89 
10.9 Publications .............................................................................................................89 
11 Study Management ...........................................................................................................90 
11.1 Monitoring ..............................................................................................................90 
11.1.1 
External Data Monitoring Committee .....................................................90 
11.1.2 
Monitoring of the Study ...........................................................................90 
11.1.3 
Inspection of Records ..............................................................................90 
11.2 Management of Protocol Amendments and Deviations..........................................90 
11.2.1 
Modification of the Protocol ....................................................................90 
11.2.2 
Protocol Deviations .................................................................................91 
11.3 Study Termination ...................................................................................................91 
11.4 Final Report ............................................................................................................91 
12 Reference List...................................................................................................................93 


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13 Appendices .......................................................................................................................95 
13.1 Appendix 1: Schedule of Events .............................................................................95 
13.2 Appendix 2: Contraceptive Guidance .....................................................................99 
13.3 Appendix 3: The Patient Assessment of Gastrointestinal Disorders-Symptoms 
Severity Index (PAGI-SYM) .........................................................................101 
13.4 Appendix 4: The Patient Assessment of Upper Gastrointestinal Disorders-Quality 
of Life (PAGI-QoL) - Sample Copy ..............................................................103 
13.5 Appendix 5: EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) - Sample Copy ......106 
13.6 Appendix 6: Liver Function Tests .........................................................................108 
13.6.1 
Liver Function Test Monitoring .............................................................108 
13.6.2 
Considerations for Temporary Discontinuation of Study Drug .............108 
13.6.3 
Permanent Discontinuation of Study Drug ............................................109 
13.6.4 
Re-initiation of Study Drug ................................................................... 110 
13.7 Appendix 7: Protocol Amendments ...................................................................... 111 
13.7.1 
Protocol Amendment 1 .......................................................................... 111 
13.7.2 
Protocol Amendment 2 .......................................................................... 115 
 
List of Tables 
Table 2-1 
Objectives and Endpoints ............................................................................... 27 
Table 5-1 
Study Drugs .................................................................................................... 43 
Table 5-2 
Excluded Medications and Treatments ........................................................... 48 
Table 6-1 
LA Grade Classification .................................................................................. 50 
Table 6-2 
Definitions of Heartburn Severity (Daytime/Nighttime) ................................ 53 
Table 6-3 
Medically Significant Adverse Event List ...................................................... 55 
Table 6-4 
Adverse Events of Special Interest List .......................................................... 56 
Table 6-5 
Protocol-Required Safety Laboratory Assessments ........................................ 68 
Table 13-1 
Schedule of Events .......................................................................................... 96 


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Table 13-2 
Abnormal Liver Function Criteria For Permanent Discontinuation of Study 
Drug .............................................................................................................. 109 
 
List of Figures 
Figure 3-1 
Study Scheme.................................................................................................. 30 


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Protocol: EE-301 Version 3.0 (Amendment 2) 
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Protocol Synopsis 
Protocol 
Number: 
EE-301 
Title: 
A Phase 3, Randomized, Double-Blind, Two-Phase, Multicenter Study to 
Evaluate the Efficacy and Safety of Vonoprazan 20 mg Compared to 
Lansoprazole 30 mg for Healing in Patients with Erosive Esophagitis and 
to Evaluate the Efficacy and Safety of Vonoprazan (10 mg and 20 mg) 
Compared to Lansoprazole 15 mg for the Maintenance of Healing in 
Patients with Healed Erosive Esophagitis 
Sponsor: 
Phathom Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, CA 94025 
Study Phase: 
3 
Study Sites: 
Approximately 150 sites in the US and Europe 
Indication: 
Patients with Erosive Esophagitis 
Rationale: 
In a Phase 2 dose-ranging study of vonoprazan (TAK-438) in subjects with 
erosive esophagitis (EE) (TAK-438/CCT-001), vonoprazan was 
noninferior to lansoprazole 30 mg in healing at all doses tested (5 mg, 
10 mg, 20 mg, and 40 mg), with good tolerability. The study demonstrated 
a dose response relationship with vonoprazan. Furthermore, the rate of 
endoscopic healing of EE in subjects with more severe disease (Los 
Angeles Classification [LA classification] grades C/D) was 96% or higher 
with vonoprazan at doses 20 mg or higher compared to 87% with 
lansoprazole 30 mg. Based on the results, 20 mg of vonoprazan was 
selected as the dose for the Japan Phase 3 EE healing study 
(TAK-438/CCT-002). Study TAK-438/CCT-002 confirmed the 
noninferiority and superiority (post-hoc) of vonoprazan 20 mg to 
lansoprazole 30 mg for the healing of EE. Study TAK-438/CCT-003 
confirmed the noninferiority and superiority (post-hoc) of vonoprazan 10 
and 20 mg to lansoprazole 15 mg for the maintenance of healed EE. Study 
EE-301 will further examine the effectiveness and safety of vonoprazan in 
subjects in the US and Europe in the healing and maintenance of healed 
EE. 
Objectives: 
Healing Phase 
Primary 
• To assess the efficacy of vonoprazan (20 mg once daily [QD]) 
compared to lansoprazole (30 mg QD) in healing of EE over 8 weeks 
in subjects with endoscopically proven EE. 


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• To assess the safety of vonoprazan (20 mg QD) compared to 
lansoprazole (30 mg QD) in subjects with endoscopically proven EE. 
Secondary 
• To assess the efficacy of vonoprazan (20 mg QD) compared to 
lansoprazole (30 mg QD) in healing of EE over 2 weeks in subjects 
with endoscopically proven EE. 
• To assess the efficacy of vonoprazan (20 mg QD) compared to 
lansoprazole (30 mg QD) in healing of EE  in subjects with 
endoscopically proven EE LA Classification Grades C or D over 
2 weeks and 8 weeks. 
• To assess relief of heartburn of vonoprazan (20 mg QD) compared to 
lansoprazole (30 mg QD) in subjects with endoscopically proven EE 
over 8 weeks and within the first 3 days of treatment. 
Maintenance Phase 
Primary 
• To assess the efficacy in maintenance of healing of vonoprazan 
(10 mg and 20 mg QD) compared to lansoprazole (15 mg QD) in 
subjects with healed EE. 
• To assess the safety of vonoprazan (10 mg and 20 mg QD) compared 
to lansoprazole (15 mg QD) in subjects with healed EE. 
Secondary 
• To assess the efficacy in maintenance of healing of vonoprazan 
(10 mg and 20 mg QD) compared to lansoprazole (15 mg QD) in 
subjects with healed EE with baseline LA Classification Grades C or 
D. 
• To assess the efficacy of vonoprazan (10 mg and 20 mg QD) 
compared to lansoprazole (15 mg QD) in subject symptoms by subject 
daily diary. 
Study 
Population: 
Subjects aged 18 years of age or older with endoscopically confirmed EE 
of LA classification Grades A to D during the Screening Period as assessed 
by a central adjudicator. 
Study Design: 
This is a Phase 3, 2-phase multi-center, double-blind, noninferiority study 
of vonoprazan versus lansoprazole for the healing of all grades of EE and 
relief of heartburn and the maintenance of healing of all grades of EE and 
relief of heartburn. Subjects with EE (LA classification Grade A/B or C/D 
serving as a stratification at randomization) will be randomized to receive 
vonoprazan 20 mg or lansoprazole 30 mg QD for up to 8 weeks for the 
healing of EE. All subjects with endoscopic healing of EE at 2 or 8 weeks 
after the start of the study will enter a continuous 24-week Maintenance 
Phase. Subjects will be rerandomized to receive either vonoprazan 10 mg, 


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vonoprazan 20 mg, or lansoprazole 15 mg for 24 weeks. The subjects 
without confirmed endoscopic healing of EE at Week 8 will not be 
allowed to enter the Maintenance Phase. Subjects will complete an 
electronic diary twice daily to record the presence and maximum severity 
of daytime and nighttime heartburn symptoms throughout the study. 
The study will include 4 main phases: 
Screening Phase (Day -35 to Day -2): Subjects will provide informed 
consent and undergo screening assessments to determine study eligibility, 
and baseline assessment will be performed. If all eligibility criteria are 
met, the subject will enter the study. 
Healing Phase (Healing Day -1 to Healing Day 15 or 57): Subjects with 
EE whose eligibility is confirmed will be randomized to receive 
vonoprazan 20 mg or lansoprazole 30 mg QD for up to 8 weeks. The date 
of the first dosing is defined as Day 1. An endoscopy will be performed at 
Week 2. If endoscopic healing of EE is confirmed at Week 2, the subject 
will enter the Maintenance Phase. If endoscopic healing is not confirmed, 
the subject will continue to receive randomized treatment until Week 8. 
If endoscopic healing is confirmed at Week 8, the subject will enter the 
Maintenance Phase. During the Healing Phase, if the investigator deems 
that an additional endoscopy is warranted based on the subject’s 
symptoms prior to the window of the subject’s next scheduled 
per-protocol endoscopy, an unscheduled endoscopy will be permitted 
whenever required as part of routine clinical care. If the subject’s EE is 
found to have healed at this unscheduled endoscopy visit, the subject will 
be considered to have completed the Healing Phase and will undergo 
randomization for entry into the Maintenance Phase. If the subject is found 
to still have EE (of any grade) at the unscheduled endoscopy visit, the 
subject will be allowed to continue in the study within the Healing Phase 
and will undergo their subsequent per-protocol endoscopy. If endoscopic 
healing of EE is not confirmed at Week 8, the subject will discontinue the 
study without entering the Maintenance Phase and be considered as 
completed for the Healing Phase. Healing will be defined as 
endoscopically confirmed healed. 
Maintenance Phase (Maintenance Day 1 to Maintenance Day 169): 
Subjects with EE who have confirmed endoscopic healing of EE either at 
Week 2 or at Week 8 of the Healing Phase (or during an unscheduled 
endoscopy) will enter the Maintenance Phase. Subjects will be 
rerandomized to receive either vonoprazan 10 mg, vonoprazan 20 mg, or 
lansoprazole 15 mg daily for 24 weeks. Maintenance of healing will be 
assessed by endoscopy at Week 24 of the Maintenance Phase. If during the 
24-week Maintenance Phase the investigator deems that an endoscopy is 
warranted, based on subject symptoms, an unscheduled endoscopy will be 


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permitted whenever required. If the subject’s EE is found to have relapsed 
at this unscheduled endoscopy visit, the subject will be discontinued from 
the Maintenance Phase of the study, considered a treatment failure, and 
will enter the Follow-up Phase. If the subject is found to have maintained 
healing of EE at the unscheduled endoscopy visit, the subject will be 
allowed to continue in the study until Week 24. 
Follow-up Phase: A safety follow-up visit is planned at 4 weeks after the 
last dose of study drug to assess adverse events (AEs) and the serum 
gastrin level. Subjects who do not have EE healing at Week 8 and 
therefore discontinue the study after the Healing Phase will undergo the 
safety follow-up period. 
Estimated 
Study 
Duration: 
The total duration of the study is up to 41 weeks. Screening Period is up to 
35 days, Healing Phase is up to 2 or 8 weeks depending on the healing of 
EE, Maintenance Phase is up to 24 weeks, and safety follow-up is at 
4 weeks after last study drug administration. 
Efficacy 
Assessments: 
Healing Phase 
Primary 
• The percentage of subjects who have complete healing of EE by 
Week 8 as assessed by endoscopy 
Secondary 
• The percentage of subjects who have complete healing of EE at 
Week 2 as assessed by endoscopy 
• The percentage of subjects who have complete healing of EE at 
Week 2 as assessed by endoscopy for subjects with baseline LA 
Classification Grades C or D 
• The percentage of subjects who have complete healing of EE by 
Week 8 as assessed by endoscopy for subjects with baseline LA 
Classification Grades C or D 
• The percentage of 24-hour heartburn-free days over the Healing Phase 
as assessed by the daily diary 
• The percentage of subjects with onset of sustained resolution of 
heartburn by Day 3 (sustained resolution is defined as at least 
7 consecutive days with no daytime or nighttime heartburn as assessed 
by the daily diary) 
Maintenance Phase 
Primary 
• The percentage of subjects who maintain complete healing of EE after 
24 weeks as assessed by endoscopy 
 


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Secondary 
• The percentage of subjects who maintain complete healing of EE after 
24 weeks as assessed by endoscopy for subjects with baseline LA 
Classification Grades C or D. 
• The percentage of 24-hour heartburn-free days over the Maintenance 
Phase as assessed by the daily diary. 
Safety 
Assessments: 
Safety will be assessed by: 
• Adverse events 
• Laboratory test values (hematology, serum chemistry, urinalysis); 
serum gastrin and pepsinogen I/II levels 
• Gastric biopsy 
• Electrocardiogram (for Maintenance Phase only) 
• Vital signs 
Study Drug, 
Dosage, and 
Route of 
Administra-
tion: 
Healing Phase: 
Blinded study drug (vonoprazan 20 mg QD or lansoprazole 30 mg QD) to 
be taken orally for up to 8 weeks. 
Maintenance Phase: 
Blinded study drug (vonoprazan 10 mg QD, vonoprazan 20 mg QD, or 
lansoprazole 15 mg QD) to be taken orally for 24 weeks. 
Sample Size: 
Healing Phase 
A sample size of 500 subjects per treatment group provides at least 90% 
power to achieve noninferiority using a Farrington Manning test with a 
noninferiority margin of 10%, assuming EE healing rates by Week 8 of 
80% and 80% for vonoprazan and lansoprazole, respectively. 
Maintenance Phase 
All subjects who have complete healing of EE during the Healing Phase 
will enter the Maintenance Phase. It is expected that approximately 800 
subjects will enter the Maintenance Phase, but the actual number of 
subjects who enter will depend on the observed healing rates during the 
Healing Phase. During the study if less than 800 subjects are projected to 
enroll into the Maintenance Phase, additional subjects may be enrolled to 
ensure that a sufficient number of subjects enter the Maintenance Phase. 
For the maintenance of EE healing after 24 weeks, a sample size of 
265 subjects per treatment group provides at least 90% power to achieve 
noninferiority with a noninferiority margin of 10% and at least 90% power 
to achieve superiority using the Farrington Manning test, assuming 
maintenance of EE healing rates of 82% and 70% for vonoprazan and 
lansoprazole, respectively. 


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Statistical 
Methods: 
Analysis of Primary Efficacy Endpoint 
Healing Phase: The EE healing rate by Week 8 will be calculated along 
with 2-sided 95% CIs for each treatment group. A subject will be 
considered to have “complete healing of EE by Week 8” if the subject 
demonstrates healing at the Week 2 or Week 8 endoscopy. 
The noninferiority of vonoprazan to lansoprazole will be evaluated with a 
Farrington and Manning test with a noninferiority margin of 10 percentage 
points for the difference in EE rates between treatments (vonoprazan 
minus lansoprazole). The point estimate and 2-sided 95% CI of the 
difference in endoscopic healing rate between vonoprazan and 
lansoprazole will be calculated via the Miettinen and Nurminen method. 
If noninferiority is shown, superiority will also be assessed via the 
Farrington and Manning test of the null hypothesis difference ≤0 versus 
the alternative hypothesis difference >0. 
Maintenance Phase: The maintenance of healing rate during the 24-week 
Maintenance Phase will be calculated along with 2-sided 95% CIs for each 
treatment group. The noninferiority of each dose group of vonoprazan to 
lansoprazole will be evaluated with a Farrington and Manning test with a 
noninferiority margin of 10 percentage points for the difference in 
maintenance of healing rates between treatments (vonoprazan minus 
lansoprazole). The point estimate and 2-sided 95% CI of the difference in 
the maintenance of healing rate between each dose group of vonoprazan 
and lansoprazole will be calculated via the Miettinen and Nurminen 
method. 
If noninferiority is shown for a vonoprazan dose group, superiority of that 
dose group compared to lansoprazole will also be assessed via the 
Farrington and Manning test of the null hypothesis difference ≤0 versus 
the alternative hypothesis difference >0. An additional comparison will be 
made for superiority between the vonoprazan dose groups with no 
adjustment to the alpha level. 
Analysis of Secondary Efficacy Endpoint 
Healing Phase: The percentage of subjects who complete healing of EE at 
Week 2, who complete healing of EE at Week 2 for subjects with baseline 
LA Classification Grades C or D, and who complete healing of EE by 
Week 8 for subjects with baseline LA Classification Grades C or D will be 
analyzed for superiority of vonoprazan compared to lansoprazole similarly 
to the primary endpoint. 
For the percentage of 24-hour heartburn-free days over the Healing Phase 
as assessed by daily diary, a 2-sided 95% CI will be calculated for the 
difference between the treatment groups in the mean percentage of 
24-hour heartburn-free days (vonoprazan minus lansoprazole). If the lower 


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bound of this CI is greater than -15%, noninferiority will be concluded. If 
noninferiority is shown, the percentage of 24-hour heartburn-free days 
over the Healing Phase will also be compared between treatment groups 
using a Wilcoxon rank-sum test. 
The percentage of subjects with onset of sustained resolution of heartburn 
by Day 3 will be analyzed for superiority of vonoprazan compared to 
lansoprazole similarly to the primary endpoint. Sustained resolution is 
defined as at least 7 consecutive days with no daytime or nighttime 
heartburn as assessed by the daily diary. 
Maintenance Phase: The percentage of subjects who maintain complete 
healing of EE after 24 weeks for subjects with baseline LA Classification 
Grades C or D will be analyzed for superiority of each vonoprazan dose 
group compared to lansoprazole similarly to the primary endpoint. 
For the secondary endpoint of the percentage of 24-hour heartburn-free 
days over the Maintenance Phase as assessed by daily diary, a 2-sided 
95% CI will be calculated for the difference between each vonoprazan 
dose group and the lansoprazole group in the mean percentage of 24-hour 
heartburn-free days (vonoprazan minus lansoprazole). If the lower bound 
of this CI is greater than -15%, noninferiority will be concluded. If 
noninferiority is shown for a vonoprazan dose group, superiority of that 
dose group compared to lansoprazole will also be assessed using a 
Wilcoxon rank-sum test. 
Safety Analyses 
For each phase, safety will be assessed by summarizing the incidence of 
AEs and changes in clinical laboratory tests, gastrin and pepsinogen I/II 
levels, and vital signs. 
Adverse Events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). The number and percentage of subjects 
experiencing treatment-emergent AEs will be summarized by MedDRA 
system organ class and preferred term 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. 
Clinical laboratory tests, pepsinogen I/II levels, gastrin levels, and vital 
signs will be summarized with descriptive statistics at each visit by 
treatment group. A summary of change-from-baseline at each visit will 
also be summarized by treatment group. 
Version and 
Date of 
Protocol: 
Version 3.0, Amendment 2; 01 Oct 2019 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CYP2C19 
cytochrome P450 2C19  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EE 
erosive esophagitis 
EQ-5D-5L 
EuroQoL-5 Dimensions-5 Levels 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
HbsAg 
hepatitis B surface antigen 
HCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HP 
Helicobacter pylori 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LA classification 
Los Angeles Classification 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat 
PAGI-QoL 
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life 
PAGI-SYM 
Patient Assessment of Gastrointestinal Disorders-Symptom Severity 
Index  
PPI 
proton pump inhibitor 
PPS 
per-protocol set 


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Abbreviation 
Definition 
PT 
preferred term 
PTE 
pretreatment adverse event 
QD 
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SoE 
schedule of events 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 


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1 
Introduction 
Vonoprazan belongs to a new class of acid-inhibitory agents called “potassium-competitive 
acid blockers” and is being developed for healing of all grades of erosive esophagitis (EE) 
and relief of heartburn and maintenance of healing of all grades of EE and relief of heartburn. 
Vonoprazan has been studied in a number of acid-related diseases including EE healing and 
maintenance, gastric ulcer/duodenal ulcer healing, and for the prevention of recurrence of a 
gastric or duodenal ulcer during nonsteroidal anti-inflammatory drugs or aspirin 
administration and has received regulatory approval in Japan and other countries in Asia and 
Latin America for these indications. 
1.1 Study Rationale 
In a Phase 2 dose-ranging study of vonoprazan (TAK-438) in subjects with EE 
(TAK-438/CCT-001), vonoprazan was noninferior to lansoprazole 30 mg in healing at all 
doses tested (5 mg, 10 mg, 20 mg, and 40 mg), with good tolerability. The study 
demonstrated a dose response relationship with vonoprazan. Furthermore, the rate of 
endoscopic healing of EE in subjects with more severe disease (Los Angeles Classification 
[LA classification] grades C/D) was 96% or higher with vonoprazan at doses 20 mg or higher 
compared to 87% with lansoprazole 30 mg. Based on the results, 20 mg of vonoprazan was 
selected as the dose for the Japan Phase 3 EE healing study (TAK-438/CCT-002). 
Study TAK-438/CCT-002 confirmed the noninferiority and superiority (post-hoc) of 
vonoprazan 20 mg to lansoprazole 30 mg for the healing of EE. Study TAK-438/CCT-003 
confirmed the noninferiority and superiority (post-hoc) of vonoprazan 10 and 20 mg to 
lansoprazole 15 mg for the maintenance of healed EE. Study EE-301 will further examine the 
effectiveness and safety of vonoprazan in subjects in the US and Europe in the healing and 
maintenance of healed EE. 
1.2 Background 
Gastroesophageal reflux disease (GERD) is prevalent globally and represents one of the most 
common gastrointestinal diseases. The Montreal definition of GERD is a condition that 
develops when the reflux of stomach contents causes troublesome symptoms and/or 
complications (Vakil et al 2006). The term GERD covers a spectrum of conditions, including 
endoscopy-negative GERD, EE, and Barrett’s esophagus. When defining GERD as the 
presence of at least weekly heartburn and/or regurgitation, epidemiological studies reported 


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prevalence estimates of 18.1% to 27.8%, 8.8% to 25.9%, and 2.5% to 7.8% in North 
America, Europe, and East Asia, respectively (El-Serag et al 2014). Up to 50% of adults with 
GERD may develop EE (Fennerty 1997). Erosive esophagitis is one of the typical acid-
related disorders caused by reflux of gastric acid into the esophagus. The endoscopic 
classification of EE, the LA Classification proposed in 1994, introduced the concept of a 
mucosal break, which is defined as “an area of slough or erythema with a sharp line of 
demarcation from adjacent normal mucosa.” EE may be graded from A to D, according to the 
extent of mucosal break. Proton pump inhibitors (PPIs) are currently the most effective 
available anti-secretory agents for relieving GERD symptoms, healing the injured mucosa, 
and maintaining a healed mucosa (Freston 2004). 
Failure to effectively control acid reflux in patients with EE has been correlated with an 
increased morbidity leading to complications such as bleeding and strictures 
(Fennerty et al 1996). In addition, studies have shown that nighttime reflux is associated with 
a longer duration of esophageal exposure to gastric acid, leading to more severe esophageal 
and supra-esophageal injury (McGuigan et al 2004).  
Despite the availability of PPIs and other anti-secretory agents, an unmet need remains in the 
management of GERD, and up to 40% of patients report suboptimal response to once daily 
(QD) PPI therapy (Fass 2009). Therefore, a significant number of patients are prescribed 
twice daily doses of PPIs even though this dosing regimen has not been thoroughly evaluated 
and is not labeled for any PPI for use in GERD. Furthermore, patients with moderate and 
severe EE (Grades C or D, based on the LA Classification) have shown sub-optimal healing 
rates of 62% to 84% after 8 weeks of treatment (Hunt 2005). Maintenance of healing rates 
are also suboptimal, with maintenance rates for lansoprazole 15 mg ranging from 72% to 
81% after 6 months of therapy (PREVACID PI 2018 and Robinson et al 1996). 
Vonoprazan has been shown to effectively address these areas of unmet need in the healing 
and maintenance of EE (Sugano 2018). 
Vonoprazan is a potassium-competitive acid blocker, a novel class of orally active small 
molecule anti-secretory agent. It was developed by 
 Pharmaceutical Company Limited 
(
). Phathom Pharmaceuticals, Inc. (Phathom) has licensed the exclusive rights from 
to develop and commercialize vonoprazan in the US, Europe, and Canada. 
Vonoprazan is shown not only to inhibit the H+, K+ -ATPase enzyme in the final step of acid 


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secretion, as the PPIs do, but does not require the presence of acid for its activation and 
competitively inhibits the binding of potassium ions to H+, K+ -ATPase enzyme. 
Furthermore, in contrast to the PPIs which take 3 to 5 days to produce their maximum 
acid-inhibitory effects, vonoprazan is expected to produce its maximum acid-inhibitory effect 
after absorption with the first dose and has the potential to produce better outcomes with its 
potent and sustained acid-inhibitory effects (Sakurai et al 2015). 
1.3 Justification for Dose 
Selection of the vonoprazan 20 mg dose for the Healing Phase and both the vonoprazan 
10-mg and 20-mg doses for the Maintenance Phase of Study EE-301 is based on the data 
generated from the 
 Japan development program as well as the 
Asian Phase 3 
studies. 
 conducted an 8-week, Phase 2 dose-ranging study evaluating healing of EE at 
vonoprazan doses of 5, 10, 20, and 40 mg. While Week 4 healing rates for subjects with LA 
Classification A or B were comparable across the groups (91.5% to 97.6%), those with LA 
Classification C or D had improved healing rates at the higher doses of 20 mg and 40 mg 
(5 mg: 87.3% and 10 mg: 86.4%, versus 20 mg: 100% and 40 mg: 96.0%). The vonoprazan 
20 mg dose was subsequently selected for evaluation in the Phase 3 EE healing studies. 
Phase 3 
EE healing Studies TAK-438/CCT-002 (Japan) and TAK-438-303 (Asia) 
demonstrated noninferiority of vonoprazan 20 mg to lansoprazole 30 mg for healing of EE. 
In a post hoc analysis, vonoprazan was superior to lansoprazole at Week 8 in the study 
conducted in Japan. The 20 mg dose is now approved for healing of EE in Japan and other 
markets and is the dose selected for healing of EE in Study EE-301. 
For the PPIs, a frequently used approach for maintenance of healed EE is to step down to a 
lower dose than the dose used for healing. Several comparative EE maintenance studies have 
demonstrated that subjects with more severe grades of EE at baseline have high relapse rates 
(21% to 56%) after 6 months of treatment with lower maintenance doses (Lauritsen et al 
2003, Labenz et al 2005, DeVault 2006). The clinical benefit of greater acid suppression in 
maintenance of healed EE is supported by data from a 2004 Cochrane review, which reported 
a higher maintenance rate in subjects who continued with healing doses of PPIs compared 
with subjects who were stepped down to a lower maintenance dose (advantage of 11.5 
percentage points) in trials of 24 to 52 weeks duration (Hunt 2005). 


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In both the
 Japan (TAK-438/CCT-003) and Asia (TAK-438-305, preliminary data) EE 
maintenance studies, vonoprazan 10 and 20 mg were compared with the approved step-down 
dose of lansoprazole 15 mg. In both studies, vonoprazan 10 and 20 mg were superior to 
lansoprazole 15 mg in post hoc analyses in maintenance of healing of all grades of EE. 
The 20-mg vonoprazan dose demonstrated a numerically greater improvement in 
maintenance of healing rate in subjects with LA Classification C or D than the 10-mg 
vonoprazan dose. 
The safety profile of vonoprazan in Phase 3 studies showed there was no evidence of a 
dose-related increase in adverse effects with vonoprazan, and the safety profile of 
vonoprazan was similar to that of lansoprazole. 
Therefore, based on the results of completed Japanese and Asian studies in the maintenance 
of EE, the vonoprazan 10 mg and 20 mg doses have been selected for maintenance of healed 
EE in Study EE-301. 
The regulatory approved doses of lansoprazole 30 mg and 15 mg have been selected for the 
Healing and Maintenance Phase, respectively, as these are approved therapeutic doses in the 
US and Europe. 


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2 
Study Objectives and Endpoints 
Table 2-1 
Objectives and Endpoints 
Objectives 
Endpoints 
Healing Phase 
 
Primary 
 
• To assess the efficacy of vonoprazan (20 mg QD) 
compared to lansoprazole (30 mg QD) in healing 
of EE over 8 weeks in subjects with 
endoscopically proven EE. 
• To assess the safety of vonoprazan (20 mg QD) 
compared to lansoprazole (30 mg QD) in subjects 
with endoscopically proven EE. 
• 
The percentage of subjects who have complete 
healing of EE by Week 8 as assessed by 
endoscopy 
 
• 
Safety will be assessed by the following: 
o Adverse events 
o Laboratory test values (hematology, serum 
chemistry, urinalysis); serum gastrin and 
pepsinogen I/II levels 
o Vital signs 
Secondary 
 
• To assess the efficacy of vonoprazan (20 mg QD) 
compared to lansoprazole (30 mg QD) in healing 
of EE over 2 weeks in subjects with 
endoscopically proven EE. 
• To assess the efficacy of vonoprazan (20 mg QD) 
compared to lansoprazole (30 mg QD) in healing 
of EE in subjects with endoscopically proven EE 
LA Classification Grades C or D over 2 weeks and 
8 weeks. 
 
 
 
 
• To assess relief of heartburn of vonoprazan 
(20 mg QD) compared to lansoprazole 
(30 mg QD) in subjects with endoscopically 
proven EE over 8 weeks and within the first 3 
days of treatment. 
• 
The percentage of subjects who have complete 
healing of EE at Week 2 as assessed by 
endoscopy 
 
• 
The percentage of subjects who have complete 
healing of EE at Week 2 as assessed by 
endoscopy for subjects with baseline LA 
Classification Grades C or D 
• 
The percentage of subjects who have complete 
healing of EE by Week 8 as assessed by 
endoscopy for subjects with baseline LA 
Classification Grades C or D 
 
• 
The percentage of 24-hour heartburn-free days 
over the Healing Phase as assessed by the daily 
diary 
• 
The percentage of subjects with onset of 
sustained resolution of heartburn by Day 3 
(sustained resolution is defined as at least 
7 consecutive days with no daytime or nighttime 
heartburn as assessed by the daily diary) 


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Objectives 
Endpoints 
Exploratory 
 
• To assess the efficacy of vonoprazan (20 mg QD) 
compared to lansoprazole (30 mg QD) in subject 
symptoms by subject daily diary. 
• 
The percentage of days without daytime 
heartburn over the Healing Phase as assessed by 
the daily diary 
• 
The percentage of days without nighttime 
heartburn over the Healing Phase as assessed by 
the daily diary 
• 
The mean severity of daytime and nighttime 
heartburn over the Healing Phase as assessed by 
the daily diary 
• 
The mean severity of daytime heartburn over the 
Healing Phase as assessed by the daily diary 
• 
The mean severity of nighttime heartburn over 
the Healing Phase as assessed by the daily diary 
• 
The time to sustained resolution of heartburn 
(sustained resolution is defined as at least 
7 consecutive days with no daytime or nighttime 
heartburn as assessed by the daily diary) 
• 
The change from baseline to the end of the 
Healing Phase for each subscale and the total 
score of the PAGI-SYM questionnaire 
• 
The change from baseline to the end of the 
Healing Phase for each subscale and the total 
score of the PAGI-QoL questionnaire 
• 
The change from baseline to the end of the 
Healing Phase for the EQ-5D-5L 
Maintenance Phase 
 
Primary 
 
• To assess the efficacy in maintenance of healing 
of vonoprazan (10 mg and 20 mg QD) compared 
to lansoprazole (15 mg QD) in subjects with 
healed EE. 
• To assess the safety of vonoprazan (10 mg and 
20 mg QD) compared to lansoprazole (15 mg QD) 
in subjects with healed EE. 
 
• 
The percentage of subjects who maintain 
complete healing of EE after 24 weeks as 
assessed by endoscopy 
• 
Safety will be assessed by the following: 
o AEs 
o Laboratory test values (hematology, serum 
chemistry, urinalysis); serum gastrin and 
pepsinogen I/II levels 
o Gastric biopsy 
o Electrocardiogram 
o Vital signs 


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Objectives 
Endpoints 
Secondary 
 
• To assess the efficacy in maintenance of healing 
of vonoprazan (10 mg and 20 mg QD) compared 
to lansoprazole (15 mg QD) in subjects with 
healed EE with baseline LA Classification Grades 
C or D. 
• To assess the efficacy of vonoprazan (10 mg and 
20 mg QD) compared to lansoprazole (15 mg QD) 
in subject symptoms by subject daily diary. 
 
• 
The percentage of subjects who maintain 
complete healing of EE after 24 weeks as 
assessed by endoscopy for subjects with baseline 
LA Classification Grades C or D 
• 
The percentage of 24-hour heartburn-free days 
over the Maintenance Phase as assessed by the 
daily diary 
Exploratory 
 
To assess the efficacy of vonoprazan (10 mg and 
20 mg QD) compared to lansoprazole (15 mg QD) in 
subject symptoms by subject daily diary. 
• 
The percentage of days without daytime 
heartburn over the Maintenance Phase as 
assessed by the daily diary 
• 
The percentage of days without nighttime 
heartburn over the Maintenance Phase as 
assessed by the daily diary 
• 
The mean severity of daytime and nighttime 
heartburn over the Maintenance Phase as 
assessed by the daily diary 
• 
The mean severity of daytime heartburn over the 
Maintenance Phase as assessed by daily diary 
• 
The mean severity of nighttime heartburn over 
the Maintenance Phase as assessed by the daily 
diary 
• 
The percentage of 24-hour heartburn-free days 
during the Follow-up Phase as assessed by the 
daily diary 
• 
The change from maintenance baseline to the end 
of the Maintenance Phase for each subscale and 
the total score of the PAGI-SYM questionnaire 
• 
The change from maintenance baseline to the end 
of the Maintenance Phase for each subscale and 
the total score of the PAGI-QoL questionnaire 
• 
The change from baseline to the end of the 
Maintenance Phase for the EQ-5D-5L 
Abbreviations: EE, erosive esophagitis; EQ-5D-5L, EuroQoL-5 Dimensions-5 Levels; LA classification, Los 
Angeles Classification; PAGI-SYM, Patient Assessment of Gastrointestinal Disorders-Symptom Severity 
Index; PAGI-QoL, Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life; QD, once a day 
 


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3 
Investigational Plan 
3.1 Study Design 
This is a Phase 3, 2-phase multi-center, double-blind, noninferiority study of vonoprazan 
versus lansoprazole for the healing of all grades of EE and relief of heartburn and the 
maintenance of healing of all grades of EE and relief of heartburn. Subjects with EE with the 
LA classification Grade A/B or C/D serving as a stratification at randomization (see 
Table 6-1 for LA Classification definitions) will be randomized to receive vonoprazan 20 mg 
or lansoprazole 30 mg given QD for up to 8 weeks for the healing of EE. All subjects with 
endoscopic healing of EE at 2 or 8 weeks after the start of the study will enter a continuous 
24-week Maintenance Phase. Subjects will be rerandomized to receive either vonoprazan 10 
mg, vonoprazan 20 mg, or lansoprazole 15 mg for 24 weeks. The subjects without confirmed 
endoscopic healing of EE at Week 8 will not be allowed to enter the Maintenance Phase. 
Subjects will complete the Patient Assessment of Gastrointestinal Disorders-Symptom 
Severity Index (PAGI-SYM), Patient Assessment of Upper Gastrointestinal 
Disorders-Quality of Life (PAGI-QoL), and the EuroQoL-5 Dimensions-5 Levels 
(EQ-5D-5L) during each site visit and an electronic diary twice daily to record the presence 
and maximum severity of daytime and nighttime heartburn symptoms throughout the study. 
A schematic diagram of the overall study design is presented in Figure 3-1. 
Figure 3-1 
Study Scheme 
 
In Healing Phase, if endoscopic healing of EE is confirmed at Week 2, the subject will enter the Maintenance 
Phase. If endoscopic healing is not confirmed at Week 2 then the subject will continue to receive treatment until 
Week 8. 
 


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The study will include 4 main phases: 
1. Screening Phase (Day -35 to Day -2): Subjects will provide informed consent and
undergo screening assessments as noted in Table 13-1 to determine study eligibility,
and baseline assessment will be performed. If all eligibility criteria are met, the
subject will enter the study.
2. Healing Phase (Healing Day -1 to Healing Day 15 or 57): Subjects with EE whose
eligibility is confirmed will be randomized to receive vonoprazan 20 mg or
lansoprazole 30 mg QD for up to 8 weeks. The date of the first dosing is defined as
Day 1. An endoscopy will be performed at Week 2. If endoscopic healing of EE is
confirmed at Week 2, the subject will enter the Maintenance Phase. If endoscopic
healing is not confirmed, the subject will continue to receive randomized treatment
until Week 8. If endoscopic healing is confirmed at Week 8, the subject will enter the
Maintenance Phase. During the Healing Phase, if the investigator deems that an
additional endoscopy is warranted based on the subject’s symptoms prior to the
window of the subject’s next scheduled per-protocol endoscopy, an unscheduled
endoscopy will be permitted whenever required as part of routine clinical care. If the
subject’s EE is found to have healed at this unscheduled endoscopy visit, the subject
will be considered to have completed the Healing Phase and will undergo
randomization for entry into the Maintenance Phase. If the subject is found to still
have EE (of any grade) at the unscheduled endoscopy visit, the subject will be
allowed to continue in the study within the Healing Phase and will undergo their
subsequent per-protocol endoscopy. If endoscopic healing of EE is not confirmed at
Week 8, the subject will discontinue the study without entering the Maintenance
Phase and be considered as completed for the Healing Phase. Healing will be defined
as endoscopically confirmed healed.


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3. Maintenance Phase (Maintenance Day 1 to Maintenance Day 169): Subjects with EE 
who have confirmed endoscopic healing of EE either at Week 2 or at Week 8 of the 
Healing Phase (or during an unscheduled endoscopy) will enter the Maintenance 
Phase. Subjects will be rerandomized to receive either vonoprazan 10 mg, 
vonoprazan 20 mg, or lansoprazole 15 mg daily for 24 weeks. Maintenance of healing 
will be assessed by endoscopy at Week 24 of the Maintenance Phase. If during the 
24-week Maintenance Phase the investigator deems that an endoscopy is warranted, 
based on subject symptoms, an unscheduled endoscopy will be permitted whenever 
required. If the subject’s EE is found to have relapsed at this unscheduled endoscopy 
visit, the subject will be discontinued from the Maintenance Phase of the study, 
considered a treatment failure, and will enter the Follow-up Phase. If the subject is 
found to have maintained healing of EE at the unscheduled endoscopy visit, the 
subject will be allowed to continue in the study until Week 24. 
4. Follow-up Phase: A safety follow-up visit is planned at 4 weeks after the last dose of 
study drug to assess adverse events (AEs) and the serum gastrin level. Subjects who 
do not have EE healing at Week 8 and therefore discontinue the study after the 
Healing Phase will undergo the safety follow-up period. 
End-of-study definition: A subject will be considered to have completed the study if the 
subject completes the safety follow-up visit. 
3.1.1 Rationale of Study Design 
This study is designed as a randomized, double-blind, active-control comparison of 
vonoprazan versus the PPI lansoprazole. The objective is to demonstrate the noninferiority of 
vonoprazan to lansoprazole for the healing and the maintenance of healing of EE. 
Lansoprazole was chosen as the active control as it is well established and used globally. In a 
Phase 2 dose-ranging study and a Phase 3 study in Japan, a higher rate of healing for 
vonoprazan compared with lansoprazole was demonstrated in subjects with more severe EE 
(baseline LA classification grades C or D). Therefore, the present study is planned to enrich 
the C or D population to 30% of subjects to further assess the potential benefit of vonoprazan 
in treating subjects with more severe EE. Healing will be assessed at Week 2 and Week 8 
based on the results of the Japanese as well as an Asian Phase 3 healing study, which 
demonstrate that a large majority of vonoprazan- and lansoprazole-treated subjects heal by 
Week 2, and a greater percentage heal by Week 8. 


Phathom Pharmaceuticals, Inc. 
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The 6-month Maintenance Phase is consistent with the treatment duration for PPIs. The 
Phase 3 study in Japan reported 6-month maintenance rates of 94.9% and 98.0% for 
vonoprazan 10 mg and 20 mg, respectively, compared with 83.2% for lansoprazole 15 mg. 
Therefore, endoscopies will only be performed at Week 24 or at study termination to reduce 
the burden of these procedures on subjects. If deemed clinically necessary by the 
investigator, an additional endoscopy can be conducted earlier during the 24-week 
Maintenance Phase whenever required. 


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4 
Subject Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
This study will be conducted at approximately 150 sites in the US and Europe with an 
estimated total of 1000 randomized subjects (500 subjects in each treatment group during the 
Healing Phase). The target number of subjects with LA classification Grade C or-D will be 
approximately 30% of the total number of subjects (300 total). Enrollment of EE subjects 
with Grade A or B will be stopped when 700 or 70% of the total planned subjects with 
Grade A or B EE are enrolled. 
Deviations from the inclusion and exclusion criteria will not be allowed since 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 subinvestigators, 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. 


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4. The subject is found to have endoscopically confirmed EE of LA Classification 
Grades A to D during the Screening Period (Visit 1) as assessed by a central 
adjudicator. The target number of subjects with LA classification Grade C or D will 
be approximately 30% of the total number of subjects (300 total). Enrollment of EE 
subjects with Grade A or B will end when the number of subjects with Grade A or B 
EE is approximately 700 or 70% of the total planned number of subjects. Given the 
invasive nature of an endoscopy, any endoscopic confirmation performed in a routine 
clinical setting before signing the informed consent will be acceptable to use for the 
purpose of fulfilling the screening requirement if all of the following apply: 
(1) appropriate endoscopy pictures were taken; (2) appropriate gastric biopsy samples 
were taken; (3) the endoscopy pictures can be sent to the central adjudicator via the 
adjudication systems; and (4) all screening procedures (including the completion of 
adjudication) AND randomization can be completed within a 7-day period after the 
date of the endoscopy. 
5. A female subject of childbearing potential who is or may be sexually active with a 
nonsterilized male partner agrees to routinely use adequate contraception from the 
signing of informed consent 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’s endoscopic examination for entering this study fails to confirm EE 
within 7 days (no later than 10 days on rare occasion with sponsor approval) prior to 
randomization. 
2. The subject is determined to be positive for Helicobacter pylori (HP) or has had an 
HP infection within 45 days of randomization. 
3. The subject has endoscopic Barrett’s esophagus (>1 cm of columnar-lined esophagus) 
and/or definite dysplastic changes in the esophagus. 


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4. The subject has any other condition affecting the esophagus, including eosinophilic 
esophagitis; esophageal varices; viral or fungal infection; esophageal stricture; a 
history of radiation therapy, radiofrequency ablation, endoscopic mucosal resection, 
or cryotherapy to the esophagus; or any history of caustic or physiochemical trauma 
(including sclerotherapy or esophageal variceal band ligation). However, subjects 
diagnosed with Schatzki’s ring (mucosal tissue ring around lower esophageal 
sphincter) are eligible to participate. 
5. The subject has scleroderma (systemic sclerosis). 
6. The subject has a history of surgery or endoscopic treatment affecting 
gastroesophageal reflux, including fundoplication and dilation for esophageal 
stricture (except Schatzki’s ring) or a history of gastric or duodenal surgery (except 
endoscopic removal of benign polyps). 
7. The subject has an active gastric or duodenal ulcer at the start of the Screening 
Period. Additionally, subjects with gastric or duodenal erosions are permitted to 
participate. 
8. 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 been screen failed from another clinical study and who has not been 
dosed may be considered for enrollment in this study. 
9. 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 the conduct of 
this study (eg, spouse, parent, child, sibling) or who may have consented under 
duress. 
10. The subject has cutaneous lupus erythematosus or systemic lupus erythematosus. 
11. The subject has had clinically significant upper or lower gastrointestinal bleeding 
within 4 weeks prior to randomization. 
12. The subject has Zollinger-Ellison syndrome or other gastric acid hypersecretory 
conditions. 


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13. 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, or red or yellow ferric oxide), PPIs, or any excipients 
used in the 13C-urea breath test: mannitol, citric acid, or aspartame. Skin testing may 
be performed according to local standard practice to confirm hypersensitivity. 
14. The subject has a history of alcohol abuse, illegal drug use, or drug addiction within 
the 12 months prior to screening, or regularly consumes >21 units of alcohol 
(1 unit = 12 oz/300 mL beer, 1.5 oz/25 mL hard liquor/spirits, or 5 oz/100 mL wine) 
per week based on self-report. Subjects must have a negative urine drug screen at 
screening. 
15. The subject is taking any excluded medications or treatments listed in the protocol 
(Section 5.8.2). 
16. 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. 
17. 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. 
18. 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. 
19. 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). 
20. 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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21. 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 entered in the study. 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 AE (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. 
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. 
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 


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(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 event 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 6 (Section 13.6) to monitor LFT 
abnormalities and 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. 
7. Pregnancy: The subject is found to be pregnant. Note: If the subject is found to be 
pregnant, the subject must be withdrawn immediately from the treatment. See 
Section 6.5 for further instructions on pregnancy. 


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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 will be recorded in the 
eCRF where appropriate. 
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. 
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 assessments. Subjects who fail to 
return for final assessments will be contacted by the site to make every attempt to 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 schedule of events (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. 
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 
3 scheduled visits and is unable to be contacted by the study site. 


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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 within 6 weeks of most recent planned visit). 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 
randomized at the baseline/randomization visit (Visit 2; Day -1) to receive vonoprazan 20 mg 
QD or lansoprazole 30 mg QD using a 1:1 allocation ratio in the Healing Phase of the study. 
Upon verification of healing, subjects will be randomized to receive either vonoprazan 10 mg 
QD, vonoprazan 20 mg QD, or lansoprazole 15 mg QD for 24 weeks in the Maintenance 
Phase of the study using a 1:1:1 allocation ratio. 
An interactive response technology (IRT) system 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. The randomization for 
both the Healing and Maintenance Phases will be stratified by baseline LA classification 
(Grades A/B and Grades C/D; see Table 6-1 for LA Classification definitions). The 
randomization will also use an appropriate block size, which will not be revealed. 
5.2 Treatments Administered 
Healing Phase: 
Blinded study drug (vonoprazan 20 mg QD or lansoprazole 30 mg QD) to be taken orally for 
up to 8 weeks. 
Maintenance Phase: 
Blinded study drug (vonoprazan 10 mg QD, vonoprazan 20 mg QD, or lansoprazole 15 mg 
QD) to be taken orally for 24 weeks. 
Study drug administration will be as presented in Table 5-1. 


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Table 5-1 
Study Drugs 
Study Drugs 
Treatment arm 
 
Vonoprazan 
Healing 
Lansoprazole 
Healing 
Vonoprazan 
Maintenance 
Lansoprazole 
Maintenance 
Vonoprazan 20 mg 
X 
 
X 
 
 
Vonoprazan 10 mg 
 
 
 
X 
 
Lansoprazole 30 mg 
 
X 
 
 
 
Lansoprazole 15 mg 
 
 
 
 
X 
 
Subjects should be instructed as follows: 
• To take study drugs with approximately 240 mL (8 oz) water 30 minutes before morning 
meal at about the same time each day. 
• 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 drugs (if appropriate) after study procedures are completed. 
5.3 Identity of Investigational Product 
Vonoprazan 
Vonoprazan study medication will be supplied as 10-mg and 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, 
, Rockford, IL, 
USA.
 Pharmaceutical Company, Ltd, Hikari, Japan manufactures the vonoprazan 
drug substance and tablet drug product. 
The over-encapsulated vonoprazan 10-mg and 20-mg strengths will be identical in 
appearance. They will be packaged in a blister card. 


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Lansoprazole 
Commercially available 15 mg and 30 mg lansoprazole capsules will be supplied by 
 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, 
, Rockford, IL. 
The over-encapsulated lansoprazole 15 mg and 30 mg will be packaged in a blister card. 
Each blister card 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 drug 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 as blister 
cards and shipped by 
. Each blister card will contain a (randomized) dosage for 1 subject 
and a sufficient quantity for dispensing during the Healing and Maintenance Phases of the 
study. 
Study supplies must be stored in a secure area (eg, a locked cabinet), protected from 
moisture, and kept at a controlled room temperature (20°-25°C [68°-77°F]; excursions 
allowed between 15°-30°C [59°- 86°F]) until they are used or returned to the sponsor or 
designee for destruction. Study drug must be stored under the conditions specified on the 
label and remain in the original container until dispensed. 
5.4.2 Test Article Accountability 
The investigator will maintain accurate records of receipt of all test articles, 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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5.4.3 Other Supplies 
An electronic diary will be provided to each subject to record the presence and maximum 
severity of daytime and nighttime heartburn twice daily (in the morning to capture heartburn 
during the night and in the evening to capture heartburn during the day). 
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 6.3.1.14.1. The SAEs associated with overdose should be reported according to the 
procedure outlined in Section 6.3.1.14.2. 
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 will be maintained using the IRT. 
A double-blind design is employed so that both the investigators and the subjects will be 
unaware of the treatment assignment during the whole study. Moreover, study center staff 
involved in study drug administration and study endpoint assessments, 
 personnel, and 
the Phathom team including the study statistician will be blinded to the treatment received. 
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 


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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 at home, compliance with study drug is to be 
assessed at each visit. Compliance will be assessed by direct questioning and counting 
returned capsules during the site visits which will be documented in the source documents 
and eCRF. Subject treatment compliance assessment results should be recorded in the eCRF. 
A record of the number of study drug capsules dispensed to and taken by each subject must 
be maintained and reconciled with study drug and compliance records. Treatment start and 
stop dates, including dates for delays and/or dose reductions will also be recorded in the 
eCRF. 
Noncompliance is defined as (taking less than 80% or more than 120% of study drug during 
any evaluation period [visit to visit]). Subjects exhibiting poor compliance as assessed by 
capsule counts should be counseled on the importance of good compliance to the study 
dosing regimen. 
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 subinvestigators. However, single-
use medications for endoscopic examination and topical medications, including liniments, 


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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 a gastric or duodenal ulcer (see Section 4.1.2) during 
the screening period, and who are compliant with the dosage as instructed by the medication 
package insert, are permitted to continue, but the dose and administration method are not 
permitted to change. Switching between QD and once weekly regimens is permitted for 
drugs containing the same active ingredient: 
• Bisphosphonates 
• Antiplatelets (includes low-dose aspirin) 
• Anticoagulants 
• Psychotropics 
• Antidepressants 
• Methotrexate 
• Nonsteroidal anti-inflammatory drugs 
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 
Medications for gastrointestinal tract 
 
Proton pump inhibitors 
14 days prior to screening 
13C-UBT 
End of the study 
Histamine H2 receptor antagonists 
14 days prior to screening 
13C-UBT 
End of treatment 
Muscarinic antagonists (eg, hyoscyamine), 
gastrointestinal motility stimulants, oral 
anticholinergic drugs, prostaglandins, 
sucralfate 
Start of the Screening Period 
End of the study 
Bismuth 
30 days prior to screening 
13C-UBT 
End of the study 
Medications that may interfere with 13C-UBT(a) 
14 days prior to screening 
13C-UBT 
End of Screening 
Period 
Antibiotics 
30 days prior to screening 
13C-UBT 
End of Screening 
Period 
Strong inhibitors or inducers of CYP2C19 (eg, 
fluconazole, fluoxetine, fluvoxamine, ticlopidine, 
rifampicin, ritonavir) 
14 days prior to study 
treatment 
End of treatment 
Strong inhibitors or inducers of CYP3A4 (eg, 
itraconazole, ketoconazole, indinavir, nelfinavir, 
ritonavir, saquinavir, telithromycin) 
4 days prior to study 
treatment 
End of treatment 
CYP3A4 substrates with a narrow therapeutic 
index 
4 days prior to study 
treatment 
End of treatment 
Atazanavir sulfates; rilpivirine hydrochloride 
(contraindicated with vonoprazan) 
5 days prior to Day 1 
End of the study 
Surgical or endoscopic treatment of EE (eg, 
fundoplication, LINX procedure) 
Start of the Screening Period 
End of the study 
Any upper gastrointestinal tract surgery except for 
endoscopic removal of benign gastric polyps. 
Start of the Screening Period 
End of the study 
Other investigational products 
30 days before the start of the 
Screening Period 
End of the study 
Abbreviations: CYP2C19, cytochrome P450 2C19; CYP3A4, cytochrome P450 3A4; EE, erosive 
esophagitis; UBT, urea breath test 
(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 
Prior to undergoing any protocol-specific procedures or assessments, all potential subjects 
must sign and date the 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. 
Study procedures and their timing are summarized in the SoE (Section 13.1). Adherence to 
the study design requirements, including those specified in the SoE, is essential and required 
for study conduct. 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. 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 13 C Urea Breath Test 
To establish HP infection status, a 13C urea breath test will be performed during the Screening 
Phase. 
Medications such as PPIs are to be stopped at least 14 days before taking the 13C-urea breath 
test in order to exclude false negative results. Antibiotics (particularly those with 
antihelicobacter action, and bismuth preparations) are to be stopped 30 days before taking the 
test. See Table 5-2. 
Exhaled air samples will be taken in accordance with instructions for use of centrally 
provided testing kits for HP infection status determination and protocol eligibility. 
6.2 Efficacy Assessments 
6.2.1 Endoscopy 
During the Screening Period, at the Week 2 visit, and at the Week 8 visit (if a subject’s EE 
has not healed at Week 2), an endoscopy will be performed on all subjects to document the 
presence/absence of EE. The screening endoscopy should be performed after the subject has 
fulfilled all other admission criteria and within 7 days (no later than 10 days on rare occasion 
with sponsor approval) prior to randomization. (Given the invasive nature of an endoscopy, 


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any endoscopic confirmation performed in a routine clinical setting before signing the 
informed consent will be acceptable to use for the purpose of fulfilling the screening 
requirement if all of the following apply: (1) appropriate endoscopy pictures were taken; 
(2) appropriate gastric biopsy samples were taken; (3) the endoscopy pictures can be sent to 
the central adjudicator via the adjudication systems; and (4) all screening procedures 
(including the completion of adjudication) AND randomization can be completed within a 
7-day period after the date of the endoscopy). During the Healing Phase, if the investigator 
deems that an additional endoscopy is warranted based on subject symptoms prior to the 
window of the subject’s next scheduled per-protocol endoscopy, an unscheduled endoscopy 
will be permitted whenever required as part of routine clinical care. If the subject’s EE is 
found to have healed at this unscheduled endoscopy visit, the subject will be considered to 
have completed the Healing Phase and will be randomized for entry into the Maintenance 
Phase. 
During the Maintenance Phase an endoscopy will be performed at the Maintenance Week 24 
visit to document the presence/absence of healed EE. If deemed clinically necessary by the 
investigator, an additional endoscopy can be conducted earlier or whenever required during 
the 24-week Maintenance Phase. If an unscheduled endoscopy conducted earlier documents 
the recurrence of EE, the subject will be considered to have recurrence of EE and will enter 
the Follow-up Phase. 
Esophagitis will be graded according to the LA Classification of Esophagitis Grading Scale 
as defined in Table 6-1. 
Table 6-1 
LA Grade Classification 
Grade A 
One or more mucosal breaks with a length of no longer than 5 mm that does 
not extend between the tops of 2 mucosal folds 
Grade B 
One or more mucosal breaks with a length of longer than 5 mm that does not 
extend between the tops of 2 mucosal folds 
Grade C 
One or more mucosal breaks that are continuous between the tops of 2 or 
more mucosal folds, which involves less than 75% of the circumference 
Grade D 
One or more mucosal breaks, which involves at least 75% of the 
circumference 
A mucosal break is defined as “an area of slough or erythema with a sharp line of demarcation from adjacent 
normal mucosa” 
 


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6.2.2 Adjudication of EE Grading  
Adjudication Process 
A central adjudication committee will assess the subject’s screening endoscopy in order to 
determine whether the subject meets the LA grade eligibility criterion. Additionally, the 
central adjudicator will review images from all other study-related endoscopies. The 
adjudicators will be composed of independent experts who are highly experienced in 
endoscopic grading of EE. 
During the screening endoscopy procedure, the investigator/endoscopist will take pictures of 
the lower third of the esophagus (to ensure inclusion of the proximal extent of the EE) 
documenting the investigator’s/endoscopist’s visual assessment of the subject’s EE LA 
grade. These pictures will then be sent via the adjudication vendors electronic system to a 
blinded central adjudicator for an independent standardized review of the endoscope pictures. 
Given the invasive nature of an endoscopy, any endoscopic confirmation performed in a 
routine clinical setting before signing the informed consent will be acceptable for entrance 
criteria if all of the following apply: (1) appropriate endoscopy pictures were taken; (2) 
appropriate gastric biopsy samples were taken; (3) the endoscopy pictures can be sent to the 
central adjudicator via the adjudication systems; and (4) all screening procedures (including 
the completion of adjudication) AND randomization can be completed within a 7-day period 
after the date of the endoscopy. 
The adjudicator will have up to 2 business days to review the endoscopic pictures and 
provide their assessment. If the adjudicator’s rating agrees with the investigator, the subject 
will be enrolled, based on their rating. If the adjudicator and investigator assessments are 
misaligned, a second blinded adjudicator will review the endoscopic pictures within another 
2 business days. The subject will be enrolled, based on the 2 matching LA grade ratings. If 
there are 3 different ratings across the 2 adjudicators and the investigator, the 2 adjudicators 
will discuss their assessments and reach alignment on the LA grade rating. If the adjudicators 
are unable to reach consensus, the primary adjudicator's assessment will be used to determine 
the subject’s eligibility. Once the adjudication process has been completed, the results will be 
communicated to the investigator via the central adjudication system. The investigator should 
not change his/her initial grading if the final assessment is different from the initial 
assessment. Both the investigator’s and adjudicator’s assessment will be entered into the 


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clinical database. The central adjudication system will allocate all of an individual subject’s 
future endoscope pictures to the same adjudicator. 
All other study-related endoscopies will be evaluated in a similar manner as described above 
with both the investigator’s and adjudicator’s assessments documented in the eCRF. The 
central adjudicator’s assessment will be used to determine whether the subject’s EE has 
healed during the Healing Phase or recurred during the Maintenance Phase. 
6.2.3 Symptom Diary 
Subjects will download an electronic diary application on his/her own phone during the 
Screening Period. For subjects who do not have a phone or whose phone does not support the 
electronic diary application, the sponsor will provide a device with the electronic diary 
downloaded on it. Throughout the Screening Period (at least 7 days), Healing Phase, 
Maintenance Phase, and Follow-up Phase, subjects will document the presence and 
maximum severity of daytime and nighttime heartburn symptoms twice daily in their diary. If 
the subject experiences no heartburn on any given day, they should also provide this 
information. The electronic diary should be completed every morning upon waking (to record 
the previous evening's heartburn severity rating) and every evening before bedtime (to record 
that day's heartburn severity rating). The last entry that the subject will make to their 
electronic diary should be on the morning of the Safety Follow-up Visit, prior to their site 
visit. 
The severity of heartburn will be graded by the subject according to the definitions outlined 
in Table 6-2. 


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Table 6-2 
Definitions of Heartburn Severity (Daytime/Nighttime) 
Definitions of Daytime Heartburn Severity (Daytime=Awake Time) 
None - No heartburn 
Mild - Occasional heartburn, can be ignored, does not influence daily routine 
Moderate - Heartburn cannot be ignored and/or occasionally influences daily routine 
Severe - Heartburn present most of day and/or regularly influences daily routine 
Very Severe - Constant heartburn and/or markedly influences daily routine 
Definitions of Nighttime Heartburn Severity (Nighttime=Sleep Time) 
None - No heartburn 
Mild - Occasional heartburn, can be ignored, does not influence sleep 
Moderate - Heartburn cannot be ignored and/or occasionally influences sleep 
Severe - Heartburn present most of night and/or regularly influences sleep 
Very Severe - Constant heartburn and/or markedly influences sleep 
 
In the Follow-up Phase, the use of antacid and H2 receptor antagonist medications will also 
be collected in the electronic diary. 
6.2.4 PAGI SYM Questionnaire 
On Study Day -1, Week 2, and Week 8 (unless the subject is healed at Week 2) of the Healing 
Phase and Week 4, 12, and 24 of the Maintenance Phase (or upon premature termination), 
each subject will self-administer a paper version of the PAGI-SYM. 
Subjects will record their responses directly on each questionnaire. The data from the 
questionnaires will be entered into the eCRF, and the originals will remain at the site as 
source documentation. Refer to Section 13.3 for samples of the questionnaire. 
6.2.5 PAGI QoL Questionnaire 
On Study Day -1, Week 2, and Week 8 (unless the subject is healed at Week 2) of the Healing 
Phase and Weeks 4, 12, and 24 of the Maintenance Phase (or upon premature termination), 
each subject will self-administer a paper version of the PAGI-QoL. 
Subjects will record their responses directly on each questionnaire. The data from the 
questionnaires will be entered into the eCRF, and the originals will remain at the site as 
source documentation. Refer to Section 13.4 for samples of the questionnaire. 


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6.2.6 EQ-5D-5L 
On Study Day -1, Week 2, and 8 (unless the subject is healed at Week 2) of Healing Phase, 
Week 4, 12, and 24 of Maintenance Phase (or upon premature termination), each subject will 
self-administer a paper version of the EQ-5D-5L. 
Subjects will record their responses directly on each questionnaire. The data from the 
questionnaires will be entered into the eCRF and the originals will remain at the site as 
source documentation. Refer to Section 13.5 for samples of the questionnaire. 
6.3 Safety Assessments 
6.3.1 Pretreatment Adverse Events and Adverse Events 
6.3.1.1 Definitions of Pretreatment 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. 
6.3.1.2 Definitions of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to study drug. An AE can therefore be an 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 in that phase or any event at baseline that worsens in either intensity or frequency 
after the first dose of study drug in that phase. 
6.3.1.3 Serious Adverse Events 
An SAE is defined as any untoward medical occurrence at any dose for which the following 
occurs:  
1. Results in DEATH.  


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2. Is LIFE-THREATENING. The term “life-threatening” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe.  
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.  
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Is CONGENITAL ANOMALY/BIRTH DEFECT.  
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:  
• May require intervention to prevent items 1 through 5 above 
• May include any event or symptoms described in the medically significant AE list 
(Table 6-3) 
• Exposes the subject to danger, even though the event is not immediately life-
threatening or fatal or does not result in hospitalization 
Table 6-3 
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 
 


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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 6.3.1.14.2 and 
Section 6.3.1.14.3). 
If a subject is noted to have an ALT or AST value >3 × ULN and a total bilirubin value 
>2 × ULN, for which an alternative etiology has not been identified, the event should be 
recorded as an SAE and reported as per Section 6.3.1.14.2. 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 
or concurrent medical conditions. Follow-up laboratory tests as described in Section 6.6 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 6.3.1.14.2). 
6.3.1.4 
Adverse Event of Special Interest 
An AE of special interest is a noteworthy event for the particular product or class of products 
that a sponsor may wish to monitor carefully. It could be serious or nonserious (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. 
Adverse events of special interest include any event described in the Table 6-4. 
Table 6-4 
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 13.6. 


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6.3.1.5 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); these events should be 
recorded as a PTE/AE. 
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 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 retest 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. 


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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…”).  
• 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. 


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Changes in severity of AEs /Serious PTEs: 
• If the subject experiences change 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 planned procedure should be reported as AEs. 
Elective surgeries or procedures:  
• Elective procedures performed where there is no change in the subject’s medical 
condition should not be recorded as PTEs or AEs but should be documented in the 
subject’s source documents. Complications resulting from an elective surgery should be 
reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action should NOT be recorded 
as an AE. The investigator must make the distinction between exacerbation of 
pre-existing illness and lack of therapeutic efficacy. 
Overdose: 
• Any manifested side effects will be considered AEs and will be recorded on the AE page 
of the eCRF. 


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6.3.1.6 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. 
6.3.1.7 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to 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. 
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 
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 study drug, such as underlying diseases, complications, concomitant 
drugs, and concurrent treatments, may also be responsible. 
Not 
related: 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained by other 
factors, such as underlying diseases, complications, concomitant drugs, and 
concurrent treatments. 
 


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6.3.1.8 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. 
6.3.1.9 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. 
6.3.1.10 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. 
6.3.1.11 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. 
6.3.1.12 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. 
• 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. 
6.3.1.13 Outcome 
• Recovered/resolved: Subject returned to baseline status with respect to the AE/PTE. 


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• 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; or the subject died from another cause with the particular AE/PTE state 
remaining “Not recovered/not resolved.” 
• Resolved with sequelae: 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. 
6.3.1.14 Time Period and Frequency for Collecting AE and SAE 
Information 
6.3.1.14.1 
Collection and Reporting of Adverse Events 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study 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 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. 
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. Nonserious PTEs, related or unrelated to the study procedure, need not to be 


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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 
6.3.1.14.2 
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 first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious 
• Subject identification number 
• Investigator’s name 
• Name of the study drug(s) 


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• 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 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 
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. 
6.3.1.14.3 
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. 


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6.3.1.14.4 
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 (EMA), 
investigators, and the IRB/IEC, 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. 
6.3.1.15 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. 
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 SUSAR 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. 


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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. 
6.4 Safety Monitoring Committee 
Not applicable. 
6.5 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn, and any 
sponsor-supplied drug (vonoprazan active or lansoprazole 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 6.3.1.14.2. 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 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. 
6.6 Laboratory Analyses 
See Table 6-5 for the list of clinical laboratory tests to be performed and to the SoE 
(Section 13.1) for the timing and frequency. 


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• 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 case report 
form. 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 abnormal 
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. 
o All protocol-required laboratory assessments, as defined in Table 6-5, 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, 
AE, or dose modification), then the results must be recorded in the unscheduled 
laboratory 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. 
All study-required laboratory assessments will be performed by a central laboratory. 


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Table 6-5 
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 
chemistry(a) 
• 
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 suspected(b) 
• 
Urine drug screen including amphetamines (including methamphetamine), 
barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, methadone, and 
phencyclidine(c) 
• 
Serum hCG pregnancy test(d) at Screening Visit 1 
• 
Urine hCG pregnancy test(d) at randomization and all other study visits 
• 
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody; hepatitis C, 
Viral Load RNA(e) [Qualitative]) 
• 
Serum gastrin and serum pepsinogen I and II levels will also be evaluated as 
exploratory safety/PD biomarkers at screening; Weeks 2 and 8 (if not healed) 
during the Healing Phase; Weeks 4, 12, and 24 of the Maintenance Phase; and 
the safety follow-up visit. Gastrin and pepsinogen I and II results will not be 
reported to investigative sites or other blinded personnel until the study blind is 
broken. 


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Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; FSH, follicle-stimulating 
hormone; GGT, gamma-glutamyl transferase; HBsAg, hepatitis B surface antigen; hCG, human 
chorionic gonadotropin; HIV, human immunodeficiency virus; MCH, mean corpuscular hemoglobin; 
MCV, mean corpuscular volume; PD, pharmacodynamics; RBC, red blood cells; SGOT, serum 
glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase; WBC, white blood 
cells. 
(a)  See Section 13.4 for the appropriate guidance on reporting of abnormal liver function tests. For liver test 
monitoring, see Section 13.6.1. For temporary and permanent discontinuation of study drugs due to 
abnormal liver function tests, see Section 13.6.2 and Section 13.6.3, 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. During the Healing Phase and Maintenance Phase, 
serum pregnancy test will be performed if the urine pregnancy test is positive. 
(e)  Reflex - if Hepatitis C positive. 
 
Investigators must document their review of each laboratory safety report. 
6.7 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. 
6.8 Vital Signs 
Vital signs will include body temperature (oral, temporal, or tympanic 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.  
6.9 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, 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. 
6.10 Gastric Mucosal Biopsy 
Four biopsies (one each from the greater and lesser curvature of the body, and one each from 
the greater and lesser curvature of the antrum) will be taken during the baseline endoscopy of 
the Healing Phase, as well as the Week 24 /Final Visit of the Maintenance Phase for all 
subjects. In addition, gastric biopsies are to be done on any subject who prematurely 
terminates from the study at any time, including those subjects whose EE is not healed at the 
Week 8 Healing Phase endoscopy. 
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 of active and chronic inflammation, atrophy, intestinal metaplasia, changes in 
endocrine cell density, and enterochromaffin-like (ECL) cell hyperplasia. 
Detail on processes for collection and shipment of these samples can be found in the 
laboratory manual. 
6.11 Pharmacogenetics 
Collection for genotyping: Every subject must sign the informed consent/be consented in 
order to participate in the pharmacogenetic analysis. The informed consent can be part of the 
main consent or a separate consent for pharmacogenetics, depending on country-specific 
requirements. This sample is optional, but sites are encouraged to discuss the importance of 
sample collection with the subjects. During the study, a blood sample will be collected for 
cytochrome P450 2C19 (CYP2C19) genotype testing to determine the subject's metabolizer 
status, unless prohibited by local or ethical 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 an issue with the analysis for CYP2C19, 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. 


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Details on processes for collection and 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 Endpoints 
Healing Phase: 
The percentage of subjects who have complete healing of EE by Week 8 as assessed by 
endoscopy 
Maintenance Phase: 
The percentage of subjects who maintain complete healing of EE after 24 weeks as assessed 
by endoscopy 
7.2 Secondary Efficacy Endpoints 
Healing Phase: 
• The percentage of subjects who have complete healing of EE at Week 2 as assessed by 
endoscopy 
• The percentage of subjects who have complete healing of EE at Week 2 as assessed by 
endoscopy for subjects with baseline LA Classification Grades C or D 
• The percentage of subjects who have complete healing of EE by Week 8 as assessed by 
endoscopy for subjects with baseline LA Classification Grades C or D 
• The percentage of 24-hour heartburn–free days over the Healing Phase as assessed by the 
daily diary 
• The percentage of subjects with onset of sustained resolution of heartburn by Day 3 
(sustained resolution is defined as at least 7 consecutive days with no daytime or 
nighttime heartburn as assessed by the daily diary) 


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Maintenance Phase: 
• The percentage of subjects who maintain complete healing of EE after 24 weeks as 
assessed by endoscopy for subjects with baseline LA Classification Grades C or D 
• The percentage of 24-hour heartburn–free days over the Maintenance Phase as assessed 
by the daily diary 
7.3 Exploratory Endpoints 
Healing Phase: 
• The percentage of days without daytime heartburn over the Healing Phase as assessed by 
the daily diary 
• The percentage of days without nighttime heartburn over the Healing Phase as assessed 
by the daily diary 
• The mean severity of daytime and nighttime heartburn over the Healing Phase as 
assessed by the daily diary 
• The mean severity of daytime heartburn over the Healing Phase as assessed by the daily 
diary 
• The mean severity of nighttime heartburn over the Healing Phase as assessed by the daily 
diary 
• The time to sustained resolution of heartburn (sustained resolution is defined as at least 
7 consecutive days with no daytime or nighttime heartburn as assessed by the daily diary) 
• The change from baseline to the end of the Healing Phase for each subscale and the total 
score of the PAGI-SYM questionnaire 
• The change from baseline to the end of the Healing Phase for each subscale and the total 
score of the PAGI-QoL questionnaire 
• The change from baseline to the end of the Healing Phase for the EQ-5D-5L 
Maintenance Phase: 
• The percentage of days without daytime heartburn over the Maintenance Phase as 
assessed by the daily diary 


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• The percentage of days without nighttime heartburn over the Maintenance Phase as 
assessed by the daily diary 
• The mean severity of daytime and nighttime heartburn over the Maintenance Phase as 
assessed by the daily diary 
• The mean severity of daytime heartburn over the Maintenance Phase as assessed by the 
daily diary 
• The mean severity of nighttime heartburn over the Maintenance Phase as assessed by the 
daily diary 
• The percentage of 24-hour heartburn-free days over the Follow-up Phase as assessed by 
the daily diary 
• The change from maintenance baseline to the end of the Maintenance Phase for each 
subscale and the total score of the PAGI-SYM questionnaire 
• The change from maintenance baseline to the end of the Maintenance Phase for each 
subscale and the total score of the PAGI-QoL questionnaire 
• The change from maintenance baseline to the end of the Maintenance Phase for the 
EQ-5D-5L 
7.4 Sample Size Calculations 
7.4.1 Healing Phase 
A sample size of 500 subjects per treatment group provides at least 90% power to achieve 
noninferiority using a Farrington Manning test with a noninferiority margin of 10%, 
assuming EE healing rates by Week 8 of 80% and 80% for vonoprazan and lansoprazole, 
respectively. 
A fixed noninferiority margin of -10% is justified based on historical results from 
2 randomized, double-blind, placebo-controlled studies that evaluated EE healing rates after 
8 weeks with lansoprazole, the active comparator in the current study. In these studies, the 
EE healing rates with placebo were compared to lansoprazole 15 mg, lansoprazole 30 mg, or 
lansoprazole 60 mg (Earnest et al 1998) or to lansoprazole 15 mg, lansoprazole 30 mg, or 
omeprazole 20 mg (Castell et al 1996). The difference in the EE healing rate between 
lansoprazole 30 mg and placebo reported by Earnest was 40% (87% vs 47%) and by Castell 


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was 55% (87% vs 32%) with lower limits of the 2-sided 95% confidence interval of 26% and 
48%, respectively. Using the most conservative assumption of the lower bound of 26% as the 
estimate of the treatment effect of lansoprazole 30 mg compared to placebo, a -10% 
noninferiority margin would assure that vonoprazan retains at least 60% of the treatment 
effect of lansoprazole 30 mg. 
The current study will enroll approximately 30% of subjects with more severe EE (Grade C 
or Grade D). The historical EE healing rates are from studies in which the percentage of 
subjects with more severe EE (Grade 3 or Grade 4) ranged from 35% (Castell et al 1996) to 
63% (Earnest et al 1998). The grading scale used in the historical data was different but does 
provide information that the percentage of subjects with more severe EE that were enrolled in 
these studies is similar or higher than the 30% of Grade C or Grade D subjects planned for 
the current study. Therefore, these rates are considered relevant to informing the 
noninferiority margin for the primary endpoint for the Healing Phase and a fixed 
noninferiority margin of -10% is justified. 
7.4.2 Maintenance Phase 
All subjects who have complete healing of EE during the Healing Phase will enter the 
Maintenance Phase. It is expected that approximately 800 subjects will enter the 
Maintenance Phase, but the actual number of subjects who enter will depend on the observed 
healing rates during the Healing Phase. During the study if less than 800 subjects are 
projected to enroll into the Maintenance Phase, additional subjects may be enrolled to ensure 
that a sufficient number of subjects enter the Maintenance Phase. 
For the maintenance of EE healing after 24 weeks, a sample size of 265 subjects per 
treatment group provides at least 90% power to achieve noninferiority with a noninferiority 
margin of 10% and at least 90% power to achieve superiority using the Farrington Manning 
test, assuming maintenance of EE healing rates of 82% and 70% for vonoprazan and 
lansoprazole, respectively. 
Two randomized, double-blind studies were conducted that evaluated maintenance of EE 
healing after a 12-month maintenance treatment period with lansoprazole 15 mg QD, 
lansoprazole 30 mg QD, or placebo (PREVACID PI 2018). In these 2 studies, the differences 
in the Month 6 maintenance of EE healing rate between lansoprazole 15 mg and placebo 
were 54% (81% vs 27%) and 59% (72% vs 13%) with lower limits of the 2-sided 95% 


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confidence interval of 39% and 43%, respectively. Using the most conservative assumption 
of the lower bound of 39% as the estimate of the treatment effect of lansoprazole 15 mg 
compared to placebo, a -10% noninferiority margin would assure that vonoprazan retains at 
least 75% of the treatment effect of lansoprazole 15 mg. In these historical maintenance 
studies, the percentage of subjects with Grade 3 or Grade 4 EE was approximately 45% 
which is similar or higher than the 30% of subjects with Grade C or Grade D EE planned for 
the current study. Therefore, these rates are considered relevant to informing the 
noninferiority margin for the primary endpoint for the Maintenance Phase and a fixed 
noninferiority margin of -10% is justified. 
7.5 Analysis Sets 
The following analysis sets will be used in the statistical analysis. 
The efficacy endpoints for each phase will be summarized using the modified intent-to-treat 
(MITT) analysis set defined for that phase. The primary endpoint for each phase will also be 
summarized using the per-protocol set defined for that phase. The MITT analysis set will be 
considered the primary population for efficacy analysis. 
Modified Intent to Treat Analysis Set: 
All analyses using the MITT set will group subjects according to the randomized treatment. 
Healing Phase: The MITT set will be defined as all subjects randomized into the Healing 
Phase who have documented EE at baseline and receive at least 1 dose of study drug during 
the Healing Phase. 
For the analyses of endpoints assessed by endoscopy, subjects who do not have a 
postbaseline endoscopy during the Healing Phase will be considered “not healed.” 
Maintenance Phase: The MITT set will be defined as all subjects randomized into the 
Maintenance Phase who have healed EE and receive at least 1 dose of study drug during the 
Maintenance Phase. 
For the analyses of endpoints assessed by endoscopy, subjects who do not have an endoscopy 
during the Maintenance Phase will be considered “recurred.” 


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Per-Protocol Set: 
All analyses using the per-protocol set (PPS) will group subjects according to the randomized 
treatment. 
Healing Phase: The PPS will consist of all MITT subjects who have been compliant with the 
protocol, including those subjects who are compliant with study treatment, have not taken 
PPIs or H2 receptor antagonist, did not have any major protocol deviations, and have results 
from endoscopy performed at the end of the Healing Phase unless the subject was a treatment 
failure. 
Maintenance Phase: The PPS will consist of all MITT subjects who have been compliant 
with the protocol, including those subjects who are compliant with study treatment, have not 
taken any PPIs or H2 receptor antagonist, did not have any major protocol deviations, and 
have results from endoscopy performed at the end of the Maintenance Phase unless the 
subject was a treatment failure. 
Safety Set: 
All analyses using the safety set will group subjects according to the treatment actually 
received. 
Healing Phase: The safety set will be defined as all randomized subjects who receive at least 
1 dose of study drug during the Healing Phase. 
Maintenance Phase: The safety set will be defined as all randomized subjects who receive at 
least 1 dose of study drug during the Maintenance Phase. 
7.6 Description of Subgroups to be Analyzed 
Subgroup analyses for the primary endpoint in each phase will be conducted for demographic 
and other relevant clinical variables, including age, sex, body mass index, smoking status, 
alcohol use, region, baseline EE grade (both separately A, B, C, and D and with Grades A or 
B and C or D combined), and CYP2C19 status (extensive metabolizer versus poor 
metabolizer). Subgroup analyses for the primary endpoint in the Maintenance Phase will also 
be conducted by Healing Phase treatment and by duration of Healing Phase treatment. 


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7.7 Statistical Analysis Methodology 
Baseline for the Healing Phase will be the last visit prior to the first dose of study drug in the 
Healing Phase. Baseline for the Maintenance Phase will be the last visit during the Healing 
Phase prior to the first dose of study drug in the Maintenance Phase.  
Efficacy endpoints assessed by results from endoscopy will be based on the assessment from 
the central adjudication. 
7.7.1 Analysis of Primary Efficacy Endpoint 
7.7.1.1 Healing Phase 
The EE healing rate by Week 8 will be calculated along with 2-sided 95% CIs for each 
treatment group. A subject will be considered to have “complete healing of EE by Week 8” if 
the subject demonstrates healing at the Week 2 or Week 8 endoscopy. 
The noninferiority of vonoprazan to lansoprazole will be evaluated with a Farrington and 
Manning test with a noninferiority margin of 10 percentage points for the difference in EE 
rates between treatments (vonoprazan minus lansoprazole). The point estimate and 2-sided 
95% CI of the difference in endoscopic healing rate between vonoprazan and lansoprazole 
will be calculated via the Miettinen and Nurminen method. 
If noninferiority is shown, superiority will also be assessed via the Farrington and Manning 
test of the null hypothesis difference ≤0 versus the alternative hypothesis difference >0. 
7.7.1.2 Maintenance Phase 
The maintenance of healing rate during the 24-week Maintenance Phase will be calculated 
along with 2-sided 95% CIs for each treatment group. The noninferiority of each dose group 
of vonoprazan to lansoprazole will be evaluated with a Farrington and Manning test with a 
noninferiority margin of 10 percentage points for the difference in maintenance of healing 
rates between treatments (vonoprazan minus lansoprazole). The point estimate and 2-sided 
95% CI of the difference in the maintenance of healing rate between each dose group of 
vonoprazan and lansoprazole will be calculated via the Miettinen and Nurminen method. 


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If noninferiority is shown for a vonoprazan dose group, superiority of that dose group 
compared to lansoprazole will also be assessed via the Farrington and Manning test of the 
null hypothesis difference ≤0 versus the alternative hypothesis difference >0. 
Methodology for control of type I error for the comparisons of each dose group of 
vonoprazan to lansoprazole will be addressed in the SAP. An additional comparison will be 
made for superiority between the vonoprazan dose groups with no adjustment to the alpha 
level. 
7.7.2 Analysis of Secondary Efficacy Endpoint 
7.7.2.1 Healing Phase 
The percentage of subjects who complete healing of EE at Week 2, who complete healing of 
EE at Week 2 for subjects with baseline LA Classification Grades C or D, and who complete 
healing of EE by Week 8 for subjects with baseline LA Classification Grades C or D will be 
analyzed for superiority of vonoprazan compared to lansoprazole similarly to the primary 
endpoint. 
For the secondary endpoint of the percentage of 24-hour heartburn–free days over the 
Healing Phase as assessed by daily diary, a 2-sided 95% CI will be calculated for the 
difference between the treatment groups in the mean percentage of 24-hour heartburn–free 
days (vonoprazan minus lansoprazole). If the lower bound of this CI is greater than -15%, 
noninferiority will be concluded. If noninferiority is shown, the percentage of 24-hour 
heartburn–free days over the Healing Phase will also be compared between treatment groups 
using a Wilcoxon rank-sum test. 
A fixed noninferiority margin of -15% is justified based on results from a randomized, 
double-blind study in 1284 subjects that evaluated EE healing with placebo, lansoprazole 
15 mg, lansoprazole 30 mg, or omeprazole 20 mg (Castell et al 1996). In this study, a twice 
daily patient diary was used to collect daytime and nighttime heartburn symptoms. The diary 
was very similar to the diary being used in the current study, except that it used a 4-point 
severity scale (none, mild, moderate, severe) rather than a 5-point severity scale (none, mild, 
moderate, severe, very severe). Given that the secondary endpoint is based on presence or 
absence of any degree of heartburn, these minor scale differences are not relevant for the 
purpose of establishing the noninferiority margin. The difference in the mean percentage of 


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24-hour heartburn–free days between lansoprazole 30 mg (72.6%) and placebo (31.6%) was 
41.0%; the lower limit of the 2-sided 95% CI was 35.8%. Hence, even with a conservative 
assumption of this lower bound as the true treatment effect of lansoprazole 30 mg, a 
noninferiority margin of -15% assures that vonoprazan retains at least 58% of the treatment 
effect of lansoprazole 30 mg compared with placebo. 
The percentage of subjects with onset of sustained resolution of heartburn by Day 3 will be 
analyzed for superiority of vonoprazan compared to lansoprazole similarly to the primary 
endpoint. Sustained resolution is defined as at least 7 consecutive days with no daytime or 
nighttime heartburn as assessed by the daily diary. 
Methodology for control of type I error for the secondary endpoints for the Healing Phase 
will be addressed in the SAP. 
7.7.2.2 Maintenance Phase 
The percentage of subjects who maintain complete healing of EE after 24 weeks for subjects 
with baseline LA Classification Grades C or D will be analyzed for superiority of each 
vonoprazan dose group compared to lansoprazole similarly to the primary endpoint. 
For the secondary endpoint of the percentage of 24-hour heartburn–free days over the 
Maintenance Phase as assessed by daily diary, a 2-sided 95% CI will be calculated for the 
difference between each vonoprazan dose group and the lansoprazole group in the mean 
percentage of 24-hour heartburn–free days (vonoprazan minus lansoprazole). If the lower 
bound of this CI is greater than -15%, noninferiority will be concluded. If noninferiority is 
shown for a vonoprazan dose group, superiority of that dose group compared to lansoprazole 
will also be assessed using a Wilcoxon rank-sum test. 
A fixed noninferiority margin of -15% is justified based on results from a randomized, 
double-blind study that evaluated maintenance of EE healing over 6 months with placebo, 
dexlansoprazole 30 mg QD, and dexlansoprazole 60 mg QD (Metz et al 2009). This study 
used the same twice daily patient diary to collect daytime and nighttime heartburn symptoms 
that will be used in the current study. 
Data for the relief of heartburn based on a daily patient diary from a maintenance of EE 
healing study that compared the efficacy of lansoprazole 15 mg QD to placebo are not 
available, as the maintenance of EE healing studies for lansoprazole demonstrated superior 


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relief of symptoms including heartburn based on the investigator’s assessment. However, 
data are available from a study comparing dexlansoprazole, the R-enantiomer of 
lansoprazole, to placebo, and results for the approved dexlansoprazole maintenance dose of 
30 mg are considered relevant to inform the noninferiority margin for the approved 
lansoprazole maintenance dose of 15 mg. 
The difference in the mean percentage of 24-hour heartburn–free days between 
dexlansoprazole 30 mg (83.3%) and placebo (36.0%) was 47.3%; the lower limit of the 
2-sided 95% CI was 40.3%. Hence, even with a conservative assumption of this lower bound 
as the true treatment effect of lansoprazole 15 mg, a noninferiority margin of -15% assures 
that vonoprazan retains at least 62% of the treatment effect of lansoprazole 15 mg compared 
with placebo. 
Methodology for control of type I error for the secondary endpoints for the Maintenance 
Phase will be addressed in the SAP. For each secondary endpoint, an additional comparison 
will be made for superiority between the vonoprazan dose groups with no adjustment to the 
alpha level. 
7.7.3 Analysis of Exploratory Efficacy Endpoint 
For the exploratory efficacy endpoints, all comparisons between treatment groups will be 
performed with no adjustment to the alpha level. 
7.7.3.1 Healing Phase 
The percentage of days without daytime heartburn, the percentage of days without nighttime 
heartburn, the mean severity of daytime and nighttime heartburn, the mean severity of 
daytime heartburn, the mean severity of nighttime heartburn, and the change from baseline to 
the end of the Healing Phase for the EQ-5D-5L and for each subscale and the total score of 
the PAGI-SYM and PAGI-QoL questionnaires will be compared between treatment groups 
using a Wilcoxon rank-sum test. 
For analysis of the daytime and nighttime heartburn symptoms from the daily diary, the 
maximum severity of heartburn will be coded as 0=None, 1=Mild, 2=Moderate, 3=Severe, or 
4=Very Severe. 


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The time to sustained resolution of heartburn (defined as at least 7 consecutive days with no 
daytime or nighttime heartburn as assessed by daily diary) will be analyzed with a 
time-to-event analysis. 
7.7.3.2 Maintenance Phase 
The percentage of days without daytime heartburn, the percentage of days without nighttime 
heartburn, the mean severity of daytime and nighttime heartburn, the mean severity of 
daytime heartburn, the mean severity of nighttime heartburn, and the change from 
maintenance baseline (the last visit during the Healing Phase prior to the first dose of the 
study drug in the Maintenance Phase) to the end of the Maintenance Phase for the EQ-5D-5L 
and for each subscale and the total score of the PAGI-SYM and PAGI-QoL questionnaires 
will be compared between treatment groups using a Wilcoxon rank-sum test. Comparisons 
will be made between each dose group of vonoprazan and the lansoprazole treatment group 
as well as between the 2 vonoprazan dose groups. 
The percentage of 24-hour heartburn-free days over the Follow-up Phase will also be 
summarized by maintenance treatment group. 
7.7.4 Safety Analyses 
For each phase, safety will be assessed by summarizing the incidence of AEs and changes in 
clinical laboratory tests, gastrin and pepsinogen I/II levels, and vital signs. 
Adverse Events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of subjects experiencing 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. 


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Clinical laboratory tests, pepsinogen I/II levels, gastrin levels, and vital signs will be 
summarized with descriptive statistics at each visit by treatment group. A summary of 
change-from-baseline at each visit will also be summarized by treatment group. 
7.7.5 Other Analyses 
For each phase, demographics and other baseline characteristics will be summarized overall 
and by treatment group using the MITT, PPS, and safety sets. Summary statistics (N, mean, 
median, standard deviation, and range) will be generated for continuous variables (eg, age 
and weight). The number and percentage of subjects will be presented for categorical 
variables (eg, sex and baseline EE grade). 
7.7.6 Interim Analyses 
An analysis of the Healing Phase data may be performed after all subjects have completed 
the Healing Phase. The data for the Healing Phase would be locked and the blind broken in 
order to perform this analysis. This analysis would be conducted after all subjects have been 
randomized into the Maintenance Phase, and no changes to the conduct of the Maintenance 
Phase of the study would be made based on the results from the Healing Phase. 


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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, and ECG strips.  
Investigative site personnel will enter subject data into electronic data capture. 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 the 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 respective 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 and approval before 


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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 any regulatory authority(ies), 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 time line 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, acting as the main line of communication between the sponsor (or 
designee) and the investigator and 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 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 
Castell DO, Richter JE, Robinson M, et al. Efficacy and safety of lansoprazole in the 
treatment of erosive reflux esophagitis. The Lansoprazole Group. Am J Gastroenterol. 
1996;91(9):1749-57. 
DeVault KR. Review article: the role of acid suppression in patients with non-erosive 
reflux disease or functional heartburn. Aliment Pharmacol Ther. 2006;23 Suppl 1:33-9. 
Earnest DL, Dorsch E, Jones J, et al. A placebo-controlled dose-ranging study of 
lansoprazole in the management of reflux esophagitis. Am J Gastroenterol. 
1998;93(2):238-43. 
El-Serag HB, Sweet S, Winchester CC, et al. Update on the epidemiology of gastro-
oesophageal reflux disease: a systematic review. Gut. 2014;63(6):871-80. 
Fass R. Proton pump inhibitor failure--what are the therapeutic options? Am J 
Gastroenterol. 2009;104 Suppl 2:S33-8. 
Fennerty MB, Castell D, Fendrick AM, et al. The diagnosis and treatment of 
gastroesophageal reflux disease in a managed care environment, Suggested disease 
management guidelines. Arch Intern Med 1996;156(5):477-84. 
Fennerty MB. Medical treatment of gastroesophageal reflux disease in the managed care 
environment. Semin Gastrointest Dis. 1997;8(2):90-9. 
Freston JW. Therapeutic choices in reflux disease: defining the criteria for selecting a 
proton pump inhibitor. Am J Med. 2004;117(Suppl 5A):14S-22S. 
Hunt RH. Review article: the unmet needs in delayed-release proton-pump inhibitor 
therapy in 2005. Aliment Pharmacol Ther. 2005;22(Suppl 3):10-9. 
Labenz J, Armstrong D, Lauritsen K, et al. Esomeprazole 20 mg vs. pantoprazole 20 mg 
for maintenance therapy of healed erosive oesophagitis: results from the EXPO study. 
Aliment Pharmacol Ther. 2005;22(9):803-11. 


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Lauritsen K, Devière J, Bigard MA, et al. Esomeprazole 20 mg and lansoprazole 15 mg 
in maintaining healed reflux oesophagitis: Metropole study results. Aliment Pharmacol 
Ther. 2003;17(3):333-41. 
McGuigan JE, Belafsky PC, Fromer L,  et al. Review article: diagnosis and management 
of night-time reflux. Aliment Pharmacol Ther. 2004;20 (Suppl 9):57-72. 
Metz DC, Howden CW, Perez MC, et al. Clinical trial: dexlansoprazole MR, a proton 
pump inhibitor with dual delayed-release technology, effectively controls symptoms and 
prevents relapse in patients with healed erosive oesophagitis. Aliment Pharmacol Ther. 
2009;29(7):742-54. 
PREVACID (lansoprazole) delayed-release Capsules, PREVACID SoluTab 
(lansoprazole) delayed-release orally disintegrating tablets. Full Prescribing Information 
including Medication Guide. Deerfield, IL: 
 Pharmaceuticals America, Inc., 
Revised Jun 2018. 
Robinson M, Lanza F, Avner D, et al. Effective maintenance treatment of reflux 
esophagitis with low-dose lansoprazole. A randomized, double-blind, placebo-controlled 
trial. Ann Intern Med. 1996;124(10):859-67. 
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, 
Sugano K. Vonoprazan fumarate, a novel potassium-competitive acid blocker, in the 
management of gastroesophageal reflux disease: safety and clinical evidence to date. 
Therap Adv Gastroenterol. 2018;11. 
Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of 
gastroesophageal reflux disease: a global, evidence-based consensus. Am J Gastroenterol. 
2006;101(8):1900-20. 


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13 Appendices 
13.1 Appendix 1: Schedule of Events 


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Table 13-1 
Schedule of Events 
 
Screening 
Period (a) 
Healing Phase 
 
Maintenance Phase 
Safety 
F/U 
(e) 
Un-
sched-
uled 
Visit 
(f) 
Timing 
 
Healing 
Day -1 
(b) 
Healing 
Day 
1(b) 
Week 2 
(c) 
Healing 
Day 15 
Week 8 
(c,m) 
Healing 
Day 57 
 
Main 
Week 4 
Main 
Day 29 
Main 
Week 12 
Main 
Day 85 
Main 
Week 16 
Main 
Day 113 
Main 
Week 
20 
Main 
Day 141 
Main 
Week 24 
Main Day 169 
Final Visit/ET 
(d) 
Visit Windows (Days) 
Day-35 
to -2 
- 
 
12 to 18 
54 to 60 
 
26 to 36 
82 to 92 
110 to 
120 
138 to 
148 
166 to 176 
- 
- 
Visit Number: 
1 
2 
 
3 
4 
 
M1 
M2 
M3 
M4 
M5 
F/U 
- 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic and medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking status and alcohol use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination(g) 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
Vital signs  
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
Concurrent medical conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FSH(h) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C; HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory test 
including hematology, serum 
chemistry, and urinalysis(i) 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
 
 
13C-UBT Breath Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CYP2C19 genotyping test 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Serum gastrin/pepsinogen I/II 
levels(j) 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
Pregnancy test (serum HCG)(k) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine HCG)(k) 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
Guidance on avoidance of 
pregnancy 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
 


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Screening 
Period (a) 
Healing Phase 
 
Maintenance Phase 
Safety 
F/U 
(e) 
Un-
sched-
uled 
Visit 
(f) 
Timing 
 
Healing 
Day -1 
(b) 
Healing 
Day 
1(b) 
Week 2 
(c) 
Healing 
Day 15 
Week 8 
(c,m) 
Healing 
Day 57 
 
Main 
Week 4 
Main 
Day 29 
Main 
Week 12 
Main 
Day 85 
Main 
Week 16 
Main 
Day 113 
Main 
Week 
20 
Main 
Day 141 
Main 
Week 24 
Main Day 169 
Final Visit/ET 
(d) 
Visit Windows (Days) 
Day-35 
to -2 
- 
 
12 to 18 
54 to 60 
 
26 to 36 
82 to 92 
110 to 
120 
138 to 
148 
166 to 176 
- 
- 
Visit Number: 
1 
2 
 
3 
4 
 
M1 
M2 
M3 
M4 
M5 
F/U 
- 
Subject's diary; distribute and/or 
review(l) 
X(r) 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
PAGI-SYM 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
PAGI-QoL 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
EQ-5D-5L 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
Endoscopy 
X 
 
 
X 
X 
 
 
 
 
 
X 
 
 
Gastric biopsy(n) 
X 
 
 
 
X(s) 
 
 
 
 
 
X 
 
 
Randomization  
 
X 
 
X(o) 
X(o) 
 
 
 
 
 
 
 
 
Dispense study drug 
 
X(p) 
 
X(q) 
X(q) 
 
 
X 
 
 
 
 
 
First day of study drug 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Drug return/accountability/ 
review treatment compliance(q) 
 
 
 
X 
X 
 
X 
X 
 
 
X 
 
 
Phone call to subject 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
AE/pretreatment event 
assessment 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE, adverse events; CYP2C19, cytochrome P450 2C19; ECG, electrocardiogram; EQ-5D-5L, EuroQol-5 Dimensions-5 Levels; FSH, follicle-
stimulating hormone; F/U, follow-up; HCG, human chorionic gonadotropin; HIV, human immunodeficiency virus; Main, maintenance; PAGI-SYM, 
Patient Assessment of Gastrointestinal Disorders-Symptoms Severity Index; PAGI-QoL, Patient Assessment of Upper Gastrointestinal Disorders-Quality 
of Life; UBT, urea breath test 
(a)  Visit window is Day -35 to Day -2 for assessment of Helicobacter pylori, serum gastrin and pepsinogen I/II values, ECG, and endoscopy in the Screening 
Period. However, given the invasive nature of an endoscopy, any endoscopic confirmation performed in a routine clinical setting before informed consent 
signing which would have included standard of care gastric mucosa sampling, endoscopy images available for adjudication and done within 7 days of 
randomization/dosing is acceptable to use for the purpose of fulfilling the Screening requirement, and repeat endoscopic examination during the 
Screening Period will not be required. 
(b)  The date of randomization is defined as Day -1. The date of first dosing day is defined as Day 1 for both the Healing and Maintenance Phases. 


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(c)  If the subject is confirmed as healed and rerandomized to the Maintenance Phase, this visit is considered the baseline visit for the Maintenance Phase, and 
subjects who prematurely discontinue from the Healing Phase or who are not healed at Week 8 should undergo Maintenance Phase Week 24/Final 
Visit/ET procedures (including gastric biopsy). 
(d)  For early discontinuations, the assessments mentioned for Week 24 are required to be performed. 
(e)  A safety follow-up visit is to be scheduled 4 weeks after the last dose of study drug administration. Subjects whose healing is not confirmed after Week 8 
and who discontinued the study after the Healing Phase will undergo a safety follow-up visit 4 weeks after the last dose of study drug administration. 
(f)  At an unscheduled visit, the following procedures are to be completed with additional procedures at the investigator’s discretion: a brief physical 
examination, vital sign measurements, concomitant medication assessment, and adverse event assessment. If the visit results in premature termination, 
then all procedures outlined for Maintenance Phase Week 24 /Final visit should be performed. 
(g)  Full physical examination is performed at baseline; a brief physical examination is performed at all other visits. 
(h)  If menopause is suspected. 
(i)  See Section 6.6 for all protocol-required laboratory assessments. 
(j)  Gastrin and pepsinogen I and II results will not be reported to investigative sites or other blinded personnel until the study blind is broken. 
(k)  Only female subjects with childbearing potential. 
(l)  Subjects should be instructed to complete the electronic diary every morning upon waking (for nighttime symptoms) and every evening before bedtime 
(for daytime symptoms) on each day of the study.  
(m)  Visit to be performed if not healed at Week 2. 
(n)  Four gastric mucosal biopsies (1 each from the greater and lesser curvature of the body and 1 each from the greater and lesser curvature of the antrum) 
should be obtained at each time point a gastric biopsy is done. 
(o)  Subjects with confirmed endoscopic healing at Week 2 or Week 8 will be rerandomized to the Maintenance Phase. 
(p)  Subjects are to start dose administration from Day 1. 
(q)  Subjects are to visit the study site without taking the study drug at Week 2 and Week 8 visits. For subjects without confirmed endoscopic healing of 
erosive esophagitis at Week 2, the daily dose of the study drug is to be administered after completion of assessments scheduled on that day. Subjects may 
need to return to the site a few days after Week 2 and Week 8 visits to receive a new allotment of study drug. No study procedures will be performed. 
(r)  Complete at least 7 days of diary during screening period 
(s)  only if EE not healed (follow Week 24 Final Visit/ET procedures) 
 
 


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13.2 Appendix 2: Contraceptive Guidance 
Contraception Guidance: 
From signing of informed consent, 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 nonsterilized male partner** must use adequate contraception. In addition, they must 
be advised not to donate ova during this period. 
*Females NOT of childbearing potential are defined as those who have been 
surgically sterilized (hysterectomy, bilateral oophorectomy, or tubal ligation) or who 
are postmenopausal (eg, defined as at least 1 year since last regular menses with an 
FSH >40 IU/L or at least 5 years since last regular menses, confirmed before any 
study 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 that you have intercourse): 
• 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 
Intrauterine Devices (IUDs) 
• Copper T PLUS condom or spermicide 
• Progesterone T PLUS condom or spermicide 
Hormonal Contraceptives 
• Implants 
• Hormone shot/injection 
• Combined pill 


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• 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 (Section 13.1). 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: The Patient Assessment of Gastrointestinal Disorders-
Symptoms Severity Index (PAGI-SYM) 
 


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13.4 Appendix 4: The Patient Assessment of Upper Gastrointestinal 
Disorders-Quality of Life (PAGI-QoL) - Sample Copy 
 


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13.5 Appendix 5: EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) - Sample 
Copy 
 


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13.6 Appendix 6: Liver Function Tests 
13.6.1 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, g-glutamyl transferase, 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, γ-glutamyl transferase, 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, γ-glutamyl transferase, and INR) should be repeated within a maximum 
of 48 hours after the abnormality was found. 
13.6.2 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 occurs 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 
drug, and possible alternative etiologies. 


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13.6.3 Permanent Discontinuation of Study Drug 
If any of the circumstances occur as mentioned in Table 13-2 at any time during treatment, 
the study drug 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 drug 
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 in conjunction with 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 drug, 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 or recommended. The reason for discontinuation of study drug 
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:  
 
13.6.4 Re-initiation of Study Drug 
If the study drug is discontinued due to any of the scenarios provided above, study drug must 
not be re-initiated without consultation with the medical monitor. 
 
 


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13.7 Appendix 7: 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. 
13.7.1 Protocol Amendment 1 
Protocol Synopsis 
Study Drug, Dosage, and Route of Administration: 
Healing Phase: 
Blinded study drug (vonoprazan 20 mg QD or lansoprazole 30 mg QD) to be taken orally for 
up to 8 weeks. 
To maintain study treatment blind, subject will also receive a placebo dose to match the 
treatment arm to which they are not assigned. 
Maintenance Phase: 
Blinded study drug (vonoprazan 10 mg QD, vonoprazan 20 mg QD, or lansoprazole 15 mg 
QD) to be taken orally for 24 weeks. 
To maintain study treatment blind, subject will also receive a placebo dose to match the 
treatment arm to which they are not assigned. 
Exclusion Criteria (Section 4.1.2) 
Numbering of exclusion criteria was corrected. 
 
Treatment Administered (Section 5.2) 
Study drug administration will be To maintain the study treatment blind, a double-dummy 
approach will be used, ie, the subject will also receive a placebo dose to match the treatment 
arm to which they are not assigned as presented in Table 5-1. 


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Table 5-1 Study Drugs 
Study Drugs 
Treatment arm 
 
Vonoprazan 
Healing 
Lansoprazole 
Healing 
Vonoprazan 
Maintenance 
Lansoprazole 
Maintenance 
Vonoprazan 20 mg 
X 
 
X 
 
 
Vonoprazan 10 mg 
 
 
 
X 
 
Lansoprazole 30 mg 
 
X 
 
 
 
Lansoprazole 15 mg 
 
 
 
 
X 
Placebo to match 
vonoprazan 
 
X 
 
 
X 
Placebo to match 
lansoprazole 30 mg 
X 
 
 
 
 
Placebo to match 
lansoprazole 15 mg 
 
 
X 
X 
 
 
Identity of Investigational Product (Section 5.3) 
Vonoprazan 
Vonoprazan study medication will be supplied as 10-mg and 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, 
, Rockford, IL, 
, Sauderton, PA USA. 
 Pharmaceutical Company, Ltd, Hikari, Japan 
manufactures the vonoprazan drug substance and tablet drug product. 
The over-encapsulated vonoprazan 10-mg and 20-mg strengths and placebo for vonoprazan 
will be identical in appearance. They will be packaged in a 7-count blister cardstrip. 
Lansoprazole 
Commercially available 15 mg and 30 mg lansoprazole capsules will be supplied by 
 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, 
, Rockford, IL.
, 
Sauderton, PA USA will manufacture matching plain white placebo capsules. 


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The over-encapsulated lansoprazole and placebo will be white hard gelatin capsules size #3 
for 15 mg and size # 1 for 30 mg, and they  will be packaged in a 7-count blister cardstrip. 
Subject Kits 
A 7-count blister strip of vonoprazan 10 mg or 20 mg and a 7-count blister strip of placebo 
for lansoprazole 15 mg or 30 mg will be packaged in a single child-resistant wallet. 
Additionally, a 7-count blister strip of lansoprazole 15 mg or 30 mg and a 7-count blister strip 
of placebo for vonoprazan will be packaged in a single child-resistant wallet. 
Dosing consists of 1 active capsule plus 1 placebo capsule daily. Cartons of either 3, 7, or 13 
wallets will be supplied at study visits. 
Each blister cardwallet 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 drug is dispensed. 
Study Drug Packaging and Storage (Section 5.4.1) 
Over-encapsulated vonoprazan and over-encapsulated lansoprazole, and matching placebos 
will be prepared in kits (cartons) containing walleted as blister cardsstrips and shipped by 
. Each kit blister card will contain a (randomized) dosage for 1 subject and a 
sufficient quantity for dispensing during the Healing and Maintenance Phases of the study. 
Blinding (Section 5.6) 
A double-dummy and double-blind design is employed so that both the investigators and the 
subjects will be unaware of the treatment assignment during the whole study. 


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Table 5-2 Excluded Medications and Treatments 
Excluded Medications and Treatments 
Beginning of Exclusion 
End of Exclusion 
Medications for gastrointestinal tract 
 
Proton pump inhibitors 
14 days prior to start of the 
screening 13C-UBTScreening 
Period 
End of the study 
Histamine H2 receptor antagonists 
14 days prior to start of the 
screening 13C-UBTScreening 
Period 
End of treatment 
Muscarinic antagonists (eg, hyoscyamine), 
gastrointestinal motility stimulants, oral 
anticholinergic drugs, prostaglandins, 
sucralfate 
Start of the Screening Period 
End of the study 
Medications that may interfere with 13C-UBT(a) 
14 days prior to screening 
13C-UBT 
End of Screening 
Period 
(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. 
Pregnancy (Section 6.5) 
If any subject is found to be pregnant during the study she should be withdrawn, and any 
sponsor-supplied drug (vonoprazan active or lansoprazole active, and matching placebo) 
should be immediately discontinued. 
Table 13-1 Schedule of Events 
• ‘x’ is removed for study drug dispensing at Maintenance Week 4 visit (Maintenance 
Day 29) 
• Footnote (q) Subjects are to visit the study site without taking the study drug at Week 2 
and Week 8 visits. For subjects without confirmed endoscopic healing of erosive 
esophagitis at Week 2, the daily dose of the study drug is to be administered after 
completion of assessments scheduled on that day. Subjects may need to return to the 
site a few days after Week 2 and Week 8 visits to receive a new allotment of study 
drug. No study procedures will be performed. 


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13.7.2 Protocol Amendment 2 
Inclusion Criteria (Section 4.1.1) 
3. The subject or, when applicable, the subject’s legally acceptable representative, 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. 
This change also affected the Protocol Synopsis, Section 3.1 (Study Design), Section 4.2.1 
(Reasons for Withdrawal/Discontinuation), Section 9.1 (Independent Ethics Committee or 
Institutional Review Board), Section 9.3 (Subject Information and Consent), Section 10.1 
(Confidentiality), and Section 10.3 (Investigator Documentation). 
Exclusion Criteria (Section 4.1.2) 
1. The subject’s endoscopic examination for entering this study fails to confirm EE 
within 7 days (no later than 10 days on rare occasion with sponsor approval) prior 
to randomization. 
This change also affected Section 6.2.1 (Endoscopy). 
Table 5-2 Excluded Medications and Treatments 
Excluded Medications and Treatments 
Beginning of Exclusion 
End of Exclusion 
Strong inhibitors or inducers of CYP3A4 (eg, 
itraconazole, ketoconazole, indinavir, nelfinavir, 
ritonavir, saquinavir, telithromycin) 
4 days prior to study 
treatment 
End of treatment 
CYP3A4 substrates with a narrow therapeutic 
index 
4 days prior to study 
treatment 
End of treatment 
Atazanavir sulfates; rilpivirine hydrochloride 
(contraindicated with vonoprazan) 
5 days prior to Day 1 
End of the study 
 
Endoscopy (Section 6.2.1) 
During the Screening Period, at the Week 2 visit, and at the Week 8 visit (if a subject’s EE 
has not healed at Week 2), an endoscopy will be performed on all subjects to document the 


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presence/absence of EE. The screening endoscopy should be performed after the subject has 
fulfilled all other admission criteria and within 7 days (no later than 10 days on rare 
occasion with sponsor approval) prior to randomization dosing. 
Regulatory Reporting Requirements for SAEs (Section 6.3.1.15) 
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 6.11) 
Collection for genotyping: Every subject must sign the informed consent/be consented in 
order to participate in the pharmacogenetic analysis this study. The informed consent can 
be part of the main consent or a separate consent for pharmacogenetics, depending on 
country-specific requirements. The sample is optional, but sites are encouraged to 
discuss the importance of sample collection with the subjects. During the study, a blood 
sample will be collected for cytochrome P450 2C19 (CYP2C19) genotype testing to 
determine the subject's metabolizer status, unless prohibited by local or ethical 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 an issue with the analysis for CYP2C19 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. 
Description of Subgroups to be Analyzed (Section 7.6) 
Subgroup analyses for the primary endpoint in each phase will be conducted for demographic 
and other relevant clinical variables, including age, sex, body mass index, smoking status, 


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alcohol use, region, baseline EE grade (both separately A, B, C, and D and with Grades A or 
B and C or D combined), and CYP2C19 status (extensive metabolizer versus poor 
metabolizer). Subgroup analyses for the primary endpoint in the Maintenance Phase will also 
be conducted by Healing Phase treatment and by duration of Healing Phase treatment. 
 


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Table 13-1 Schedule of Events 
 
Screening 
Period (a) 
Healing Phase 
 
Maintenance Phase 
Safety 
F/U 
(e) 
Un-
sched-
uled 
Visit 
(f) 
Timing 
 
Healing 
Day -1 
(b) 
Healing 
Day 
1(b) 
Week 2 
(c) 
Healing 
Day 15 
Week 8 
(c,m) 
Healing 
Day 57 
 
Main 
Week 4 
Main 
Day 29 
Main 
Week 12 
Main 
Day 85 
Main 
Week 16 
Main 
Day 113 
Main 
Week 
20 
Main 
Day 141 
Main 
Week 24 
Main Day 169 
Final Visit/ET 
(d) 
Visit Windows (Days) 
Day-35 
to -2 
- 
 
12 to 18 
54 to 60 
 
26 to 36 
82 to 92 
110 to 
120 
138 to 
148 
166 to 176 
- 
- 
Visit Number: 
1 
2 
 
3 
4 
 
M1 
M2 
M3 
M4 
M5 
F/U 
- 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic and medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking status and alcohol 
use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3: The Patient Assessment of Gastrointestinal Disorders-Symptoms 
Severity Index (PAGI-SYM) (Section 13.3) 
The sample copy of the PAGI-SYM questionnaire was replaced with an updated version. 
Appendix 6: Liver Function Tests (Section 13.6) 
Permanent Discontinuation of Study Drug (Section 13.6.3) 
If a subject meets the liver safety criteria and must be discontinued from study drug, 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 or recommended. The reason for discontinuation of study drug 
should be listed as an LFT abnormality AE. 
 

SAP_001.pdf: 
Protocol Number: EE-301  
 
Official Title: A Phase 3, Randomized, Double-Blind, Two-Phase, Multicenter Study to
Evaluate the Efficacy and Safety of Vonoprazan 20 mg Compared to 
Lansoprazole 30 mg for Healing in Patients with Erosive Esophagitis and to
Evaluate the Efficacy and Safety of Vonoprazan (10 mg and 20 mg) Compared
to Lansoprazole 15 mg for the Maintenance of Healing in Patients with Healed
Erosive Esophagitis
 
Document Date: 13 August 2021 
NCT Number: NCT04124926


 
Confidential  
 
 
 
 
 
 
 
 
 
Phathom Pharmaceuticals, Inc. 
 
EE-301 
 
A Phase 3, Randomized, Double-Blind, Two-Phase, Multicenter Study to 
Evaluate the Efficacy and Safety of Vonoprazan 20 mg Compared to 
Lansoprazole 30 mg for Healing in Patients with Erosive Esophagitis and to 
Evaluate the Efficacy and Safety of Vonoprazan (10 mg and 20 mg) Compared 
to Lansoprazole 15 mg for the Maintenance of Healing in Patients with Healed 
Erosive Esophagitis 
 
13Aug2021 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Prepared by: 
 
 
 
 
 
 
 
 
 


Phathom Pharmaceuticals, Inc. 
Statistical Analysis Plan, Version 3.0 
EE-301 
Date Issued: 13Aug2021 
 
 
Signature Page 
 
Study Title 
A Phase 3, Randomized, Double-Blind, Two-Phase, Multicenter Study 
to Evaluate the Efficacy and Safety of Vonoprazan 20 mg Compared to 
Lansoprazole 30 mg for Healing in Patients with Erosive Esophagitis 
and to Evaluate the Efficacy and Safety of Vonoprazan (10 mg and 
20 mg) Compared to Lansoprazole 15 mg for the Maintenance of 
Healing in Patients with Healed Erosive Esophagitis 
Protocol Number EE-301 
 
 
 
 
 
 
Approved by: 
 
 
Senior Director, Biostats & Programming 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
DocuSign Envelope ID: 207DE564-932D-49A3-90EE-7DE5E83430DF


Phathom Pharmaceuticals, Inc. 
 
 
 
 
 
 
Statistical Analysis Plan, Version 3.0 
EE-301 
 
 
 
 
 
 
 
 
 
  Date Issued: 13Aug2021 
 
 
 
3
TABLE OF CONTENTS 
DOCUMENT HISTORY – CHANGES COMPARED TO FINAL VERSION 1.0 .......................6 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1.0 
INTRODUCTION .............................................................................................................10 
2.0 
OBJECTIVES AND ESTIMANDS ..................................................................................10 
2.1 
Healing Phase...............................................................................................................10 
2.2 
Maintenance Phase.......................................................................................................11 
3.0 
INVESTIGATIONAL PLAN ............................................................................................11 
3.1 
Overall Study Design and Plan ....................................................................................11 
3.2 
Study Endpoints ...........................................................................................................12 
3.2.1 Healing Phase.........................................................................................................12 
3.2.2 Maintenance Phase.................................................................................................13 
3.3 
Treatments....................................................................................................................14 
3.3.1 Healing Phase.........................................................................................................14 
3.3.2 Maintenance Phase.................................................................................................14 
3.4 
Dose Adjustment/Modifications ..................................................................................15 
4.0 
GENERAL STATISTICAL CONSIDERATIONS ...........................................................15 
4.1 
Sample Size ..................................................................................................................16 
4.1.1 Healing Phase.........................................................................................................16 
4.1.2 Maintenance Phase.................................................................................................16 
4.2 
Randomization and Blinding .......................................................................................17 
4.3 
Assessment Windows ..................................................................................................17 
4.3.1 Study Day...............................................................................................................17 
4.3.2 Unscheduled Endoscopy Assessments ..................................................................18 
4.3.3 Visit Window for Analysis ....................................................................................18 
4.4 
Analysis Set .................................................................................................................19 
4.4.1 Screened Set ...........................................................................................................19 
4.4.2 Randomized Set .....................................................................................................20 
4.4.3 Modified Intent-to-Treat (MITT) Set.....................................................................20 
4.4.4 Per Protocol (PP) Set .............................................................................................20 
4.4.5 Safety Set ...............................................................................................................21 
4.5 
Missing Data Handling for Endoscopy Assessments ..................................................21 
5.0 
SUBJECT DISPOSITION .................................................................................................22 
5.1 
Disposition ...................................................................................................................22 
5.1.1 Screened and Screen Failure Subjects ...................................................................22 
5.1.2 Healing Phase Randomized Subjects .....................................................................22 
5.1.3 Maintenance Phase Randomized Subjects .............................................................23 
5.1.4 Healing Phase Treatment Period ............................................................................23 


Phathom Pharmaceuticals, Inc. 
 
 
 
 
 
 
Statistical Analysis Plan, Version 3.0 
EE-301 
 
 
 
 
 
 
 
 
 
  Date Issued: 13Aug2021 
 
 
 
4
5.1.5 Maintenance Phase Treatment Period ....................................................................24 
5.2 
Protocol Deviations ......................................................................................................24 
6.0 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................24 
6.1 
Demographics and Baseline Characteristics ................................................................24 
6.2 
Medical History ...........................................................................................................25 
6.2.1 General Medical History ........................................................................................25 
7.0 
TREATMENTS AND MEDICATIONS ...........................................................................26 
7.1 
Prior and Concomitant Medications ............................................................................26 
7.2 
Study Treatments .........................................................................................................27 
7.2.1 Extent of Exposure .................................................................................................27 
7.2.2 Treatment Compliance ...........................................................................................28 
8.0 
EFFICACY ANALYSIS ...................................................................................................29 
8.1 
Primary Efficacy Endpoint ..........................................................................................33 
8.1.1 Primary Analysis ....................................................................................................33 
8.1.2 Assumption Testing ...............................................................................................34 
8.1.3 Sensitivity and Supportive Analyses .....................................................................34 
8.1.4 Subgroup Analysis .................................................................................................36 
8.2 
Secondary Efficacy Endpoint ......................................................................................37 
8.2.1 Subgroup Analysis .................................................................................................39 
8.2.2 Sensitivity Analysis ...............................................................................................39 
8.3 
Exploratory Endpoints .................................................................................................40 
9.0 
SAFETY ANALYSIS ........................................................................................................42 
9.1 
Adverse Events ............................................................................................................42 
9.1.1 Adverse Events of Special Interests (AESI) ..........................................................44 
9.2 
Clinical Laboratory Evaluations ..................................................................................45 
9.3 
Vital Signs ....................................................................................................................47 
9.4 
Physical Examination...................................................................................................47 
9.5 
Electrocardiogram ........................................................................................................47 
9.6 
Gastric Biopsy ..............................................................................................................48 
10.0 
INTERIM ANALYSIS/OTHER ANALYSES ..................................................................48 
10.1 
Interim Analysis ...........................................................................................................48 
10.2 
Coronavirus Pandemic .................................................................................................48 
11.0 
CHANGES IN THE PLANNED ANALYSIS ..................................................................49 
12.0 
REFERENCES ..................................................................................................................50 
13.0 
APPENDICES ...................................................................................................................50 
13.1 
Schedule of Events .......................................................................................................51 
13.2 
Imputation Rules for Missing Date Information ..........................................................54 
13.2.1 Rules for Concomitant Medication Start Date Imputation ....................................54 


Phathom Pharmaceuticals, Inc. 
 
 
 
 
 
 
Statistical Analysis Plan, Version 3.0 
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  Date Issued: 13Aug2021 
 
 
 
5
13.2.2 Rules for Concomitant Medication End Date Imputation .....................................54 
13.2.3 Rules for AE Start Date Imputation .......................................................................55 
13.3 
LA Classification of Esophagitis Grading ...................................................................56 
13.4 
Symptom Diary ............................................................................................................56 
13.4.1 Data Handling for Subject Daily Diary .................................................................56 
13.4.2 Baseline Summary of Subject Diary ......................................................................57 
13.4.3 Sustained Resolution of Heartburn .....................................................................58 
13.5 
PAGI-QOL and PAGI-SYM Scoring .......................................................................58 
13.5.1 PAGI-QOL .............................................................................................................58 
13.5.2 PAGI-SYM ............................................................................................................59 
13.5.3 EQ-5D-5L ..............................................................................................................61 
13.6 
Estimands and Sensitivity Analysis .............................................................................62 
13.6.1 Healing Phase.........................................................................................................62 
13.6.2 Maintenance Phase.................................................................................................70 
 
LIST OF IN-TEXT TABLES 
Table 1 
Analysis Visit Windows ........................................................................................19 
Table 2 
Adverse Events of Special Interest – Search Criteria ............................................45 
Table 3 
Schedule of Events .................................................................................................51 
Table 4 
LA Grade Classification ........................................................................................56 
Table 5 
Definitions of Heartburn Severity (Daytime/Nighttime) .......................................56 
Table 6 
Intercurrent Event Types........................................................................................62 
Table 7 
Objectives, Endpoints, and Estimands ...................................................................63 
Table 8 
Summary of Estimands and Strategies for Managing Intercurrent Events ............64 
Table 9 
Summary of Statistical Methods and Sensitivity Analyses ...................................67 
Table 10 
Intercurrent Event Types........................................................................................70 
Table 11 
Objectives, Endpoints, and Estimands ...................................................................71 
Table 12 
Summary of Estimands and Strategies for Managing Intercurrent Events ............72 
Table 13 
Summary of Statistical Methods and Sensitivity Analyses ...................................75 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Scheme.........................................................................................................12 
Figure 2 
Prior and Concomitant Medications ......................................................................26 
Figure 3 
Testing Hierarchy...................................................................................................31 
 
 
 


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DOCUMENT HISTORY – CHANGES COMPARED TO FINAL VERSION 1.0 
Version 
Date 
Changes 
Final version 1.0 
30-Oct-2019 
Final version 
 
Final version 2.0 
 
25-Nov-2020 
 
1. Information was incorporated into Section 2, Section 8.1, and 
Section 8.1.3. to reflect the sensitivity and supportive analyses 
described in Appendix 13.6. There was no change to content. 
 
2. Changed rules on how actual treatment received is defined for 
safety analyses using the Safety Set in Section 4.  
 
3. Changed significance level for non-inferiority  tests from 1-sided at 
the 5% significance level to 1-sided at the 2.5% significance level in 
Section 4. 
 
4. In Section 4.4, changed the definition of the MITT Set for both the 
Healing and Maintenance Phase to exclude subjects with no post-
baseline endoscopy due to COVID-19 related reasons. Since these 
subjects will be excluded from the MITT Set, it was clarified in 
Section 4.5 that missing data for these subjects will not be imputed. 
 
5. Updated definition of Per Protocol Sets in Section 4.4.4 to exclude 
subjects with major protocol deviations regardless of study outcome 
for each phase (healed or not healed during the Healing Phase and 
remained healed or recurred during the Maintenance Phase). 
 
6. In Section 5 “Subject Disposition”, subsections were reorganized 
and the summary of protocol deviations was clarified. 
 
7. 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. 
 
8. Updated wording describing hypothesis testing during the 
Maintenance Phase in Section 8 to reflect that the Hochberg 
procedure is an alpha-exhaustive testing procedure. The secondary 
endpoints for the Maintenance Phase will only be tested if both 
vonoprazan doses are found to be non-inferior to lansoprazole for the 
primary endpoint. 
 
9. Changed the sequential testing hierarchy for the Maintenance Phase 
in Figure 3  to include the superiority tests for the primary endpoint 
and to reorder the secondary endpoints. 
 
10. Added subgroup analyses for race and ethnicity for the primary 
endpoint in each phase. 
 
11. In Section 8.2, clarified that the difference in means and the 95% 
CI for the percentage of 24-hour heartburn free days will be computed 
using Welch’s t-test. Added sensitivity analysis of 24-hour heartburn 
free days in which the days after a subject discontinues treatment will 
be imputed as non-responder days. For each phase, included the 
justification of the NI margin for the percentage of 24-hour heartburn 
free days from the protocol into the SAP for completeness and added 


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Version 
Date 
Changes 
subgroup analyses by baseline adjudicated EE grade category (A/B, 
C/D) for the percentage of 24-hour heartburn free days. 
 
12. Added the details of SMQs and CQs to identify Adverse Events of 
Special Interest in Section 9.1.2. 
 
13. 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. 
 
14. Added criteria for abnormal vital signs and abnormal ECG values 
in Section 9.3 and 9.5, respectively. 
 
15. It was decided not to conduct an analysis at the end of the  
Healing Phase. Therefore, paragraphs in Section 4.2 and Section 10 
“Final Analysis of the Healing Phase” that described this potential 
analysis were deleted and replaced with a new Section 10.1 indicating 
that no interim analysis is planned for the study. 
 
16. Added Section 10.2 to describe the handling of impacts from 
COVID-19 pandemic. 
 
17. Added Section 11 Changes in the Planned Analysis to describe 
changes from the planned analysis in the protocol including updating 
the definition of the MITT set to address the impact of COVID-19 
pandemic and removing wording related to a potential analysis at the 
end of the Healing Phase. 
 
18. In Section 13.4.1, added clarifications on the analysis of the diary 
data including that maximum severity will be considered as 0 
(0=None) if the presence of heartburn is answered as “no” in a diary. 
 
19. Throughout the document, additional edits were made for clarity 
and formatting with no change to content. 
 
Final version 3.0 
 
13-Aug-2021 
 
1. Visit windows for the Week 2 visit during the Healing Phase and 
for the Week 24 visit during the Maintenance Phase were updated in 
Table 1. 
2. In Section 4.4, changed the definition of the MITT Set for both the 
Healing and Maintenance Phase to remove the phrase that subjects 
with no post-baseline endoscopy due to COVID-19 related reasons 
will be excluded from the MITT Set (which had been added in 
Amendment 1). These subjects will now be included in the MITT Set 
and missing data due to COVID-19 will be imputed using a missing at 
random assumption as described in Section 4.5. This change was also 
reflected in revisions to Section 10.2 Coronavirus Pandemic and 
Section 11.0 Changes in the Planned Analysis. 
3. Significant protocol deviations are to be summarized by protocol 
deviation subtype category. 
 


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Version 
Date 
Changes 
4. Additional exploratory endpoints for daytime and nighttime 
heartburn were added to Section 8.3. 
 
5. Additional terms were added to the custom query for the Adverse 
Events of Special Interest of Bone Fracture in Section 9.1.2. 
 
6. The MedDRA version was updated to version 23. 
 
7. A summary of the number and percentage of subjects with elevated 
gastrin values was added. 
 
8. The summarization of subjects with abnormal vital signs values 
was corrected to include subjects with at least 1 post-baseline 
abnormal vital sign value that met prespecified criteria and with a 
vital sign value worse than the baseline value. 
 
9. Updated Section 11 Changes in the Planned Analysis to describe 
the imputation of missing data due to the COVID-19 pandemic. 
 
10. The summary of concomitant medications was clarified. 
 
11. Details were provided for the calculation of study drug 
compliance. 
 
12. Appendix 13.6 was updated to reflect the missing data imputation 
for COVID-19 pandemic related reasons, including adding a new 
intercurrent event of unable to perform endoscopy assessment due to 
COVID-19 related reasons. 
 
13. Additional edits were made for clarity and formatting with no 
change to content. 
 
 
 
 


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LIST OF ABBREVIATIONS  
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
COVID-19 
coronavirus disease 2019 
CQ 
customized queries 
CRF 
case report form 
CYP2C19 
cytochrome P450 2C19  
ECG 
electrocardiogram 
EE 
erosive esophagitis 
EQ-5D-5L 
EuroQoL-5 Dimensions-5 Levels 
HCG 
human chorionic gonadotropin 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
LA Classification 
Los Angeles Classification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat 
PAGI-QoL 
Patient Assessment of Upper Gastrointestinal 
Disorders-Quality of Life 
PAGI-SYM 
Patient Assessment of Gastrointestinal 
Disorders-Symptom Severity Index 
PPI 
proton pump inhibitor 
PPS 
per protocol set 
PT 
preferred term 
QD 
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMQ 
standardized MedDRA queries 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 


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1.0 
INTRODUCTION 
Vonoprazan belongs to a new class of acid-inhibitory agents called “potassium-competitive acid 
blockers” and is being developed for healing of all grades of erosive esophagitis (EE) and relief 
of heartburn and maintenance of healing of all grades of EE and relief of heartburn. 
Vonoprazan has been studied in a number of acid-related diseases including EE healing and 
maintenance, gastric ulcer/duodenal ulcer healing, and for the prevention of recurrence of a 
gastric or duodenal ulcer during nonsteroidal anti-inflammatory drugs or aspirin administration 
and has received regulatory approval in Japan and other countries in Asia and Latin America for 
these indications. Study EE-301 will further examine the effectiveness and safety of vonoprazan 
in subjects in the US and Europe in the healing and maintenance of healed EE. 
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 01Oct2019. 
2.0 
OBJECTIVES AND ESTIMANDS 
2.1 
Healing Phase 
The primary objectives of this phase are as follows: 
• To assess the efficacy of vonoprazan 20 mg compared to lansoprazole 30 mg in healing 
of EE over 8 weeks in subjects with endoscopically proven EE. 
• To assess the safety of vonoprazan 20 mg compared to lansoprazole 30 mg in subjects 
with endoscopically proven EE. 
 
The secondary objectives of this phase are as follows: 
• To assess the efficacy of vonoprazan 20 mg compared to lansoprazole 30 mg in healing 
of EE over 2 weeks in subjects with endoscopically proven EE. 
• To assess the efficacy of vonoprazan 20 mg compared to lansoprazole 30 mg in healing 
of EE in subjects with endoscopically proven EE LA Classification Grades C or D over 
2 weeks and 8 weeks. 
• To assess relief of heartburn of vonoprazan 20 mg compared to lansoprazole 30 mg in 
subjects with endoscopically proven EE over 8 weeks and within the first 3 days of 
treatment. 
 


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The exploratory objectives of this phase are as follows: 
• To assess the efficacy of vonoprazan 20 mg compared to lansoprazole 30 mg in subject 
symptoms by subject daily diary. 
 
The estimands of the Healing Phase are described in Table 7 of Section 13.6.1.2. 
2.2 
Maintenance Phase 
The primary objectives of this phase are as follows: 
• To assess the efficacy in maintenance of healing of vonoprazan 10 mg and vonoprazan 
20 mg compared to lansoprazole 15 mg in subjects with healed EE. 
• To assess the safety of vonoprazan 10 mg and vonoprazan 20 mg compared to 
lansoprazole 15 mg in subjects with healed EE. 
 
The secondary objectives of this phase are as follows: 
• To assess the efficacy in maintenance of healing of vonoprazan 10 mg and vonoprazan 
20 mg compared to lansoprazole 15 mg in subjects with healed EE with baseline LA 
Classification Grades C or D. 
• To assess the efficacy of vonoprazan 10 mg and vonoprazan 20 mg compared to 
lansoprazole 15 mg in subject symptoms by subject daily diary. 
 
The exploratory objectives of this phase are as follows: 
• To assess the efficacy of vonoprazan 10 mg and vonoprazan 20 mg compared to 
lansoprazole 15 mg in subject symptoms by subject daily diary. 
 
The estimands of the Maintenance Phase are described in Table 11 of Section 13.6.2.2. 
3.0 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 3, 2-phase multi-center, double-blind, noninferiority study of vonoprazan versus 
lansoprazole for the healing of all grades of EE and relief of heartburn and the maintenance of 
healing of all grades of EE and relief of heartburn. Subjects with EE with the LA classification 
Grade A/B or C/D serving as a stratification at randomization (see Table 4 for LA Classification 
definitions) will be randomized to receive vonoprazan 20 mg or lansoprazole 30 mg given QD 
for up to 8 weeks for the healing of EE. All subjects with endoscopic healing of EE at 2 or 
8 weeks after the start of the study will enter a continuous 24-week Maintenance Phase. Subjects 
will be rerandomized to receive either vonoprazan 10 mg, vonoprazan 20 mg, or lansoprazole 


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15 mg for 24 weeks. The subjects without confirmed endoscopic healing of EE at Week 8 will 
not be allowed to enter the Maintenance Phase. Subjects will complete the Patient Assessment of 
Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM), Patient Assessment of Upper 
Gastrointestinal Disorders-Quality of Life (PAGI-QoL), and the EuroQoL-5 Dimensions-5 
Levels (EQ-5D-5L) during each site visit and an electronic diary twice daily to record the 
presence and maximum severity of daytime and nighttime heartburn symptoms throughout the 
study. 
A schematic diagram of the overall study design is presented in Figure 1. 
Figure 1 
Study Scheme 
 
In Healing Phase, if endoscopic healing of EE is confirmed at Week 2, the subject will enter the Maintenance Phase. 
If endoscopic healing is not confirmed at Week 2 then the subject will continue to receive treatment until Week 8. 
 
3.2 
Study Endpoints 
3.2.1 
Healing Phase 
The primary efficacy endpoint of the Healing Phase is as follows: 
• The percentage of subjects who have complete healing of EE by Week 8 as assessed by 
endoscopy 
 
The secondary efficacy endpoints of the Healing Phase are as follows: 
• The percentage of 24-hour heartburn–free days over the Healing Phase as assessed by the 
daily diary 
• The percentage of subjects who have complete healing of EE at Week 2 as assessed by 
endoscopy for subjects with baseline LA Classification Grades C or D 


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• The percentage of subjects with onset of sustained resolution of heartburn by Day 3 
(sustained resolution is defined as at least 7 consecutive days with no daytime or 
nighttime heartburn as assessed by the daily diary) 
• The percentage of subjects who have complete healing of EE by Week 8 as assessed by 
endoscopy for subjects with baseline LA Classification Grades C or D 
• The percentage of subjects who have complete healing of EE at Week 2 as assessed by 
endoscopy 
 
The exploratory efficacy endpoints of the Healing Phase are as follows: 
• The percentage of days without daytime heartburn over the Healing Phase as assessed by 
the daily diary 
• The percentage of days without nighttime heartburn over the Healing Phase as assessed 
by the daily diary 
• The mean severity of daytime and nighttime heartburn over the Healing Phase as 
assessed by the daily diary 
• The mean severity of daytime heartburn over the Healing Phase as assessed by the daily 
diary 
• The mean severity of nighttime heartburn over the Healing Phase as assessed by the daily 
diary  
• The time to sustained resolution of heartburn (sustained resolution is defined as at least 
7 consecutive days with no daytime or nighttime heartburn as assessed by the daily diary) 
• The change from baseline to the end of the Healing Phase for each subscale and the total 
score of the PAGI-SYM questionnaire 
• The change from baseline to the end of the Healing Phase for each subscale and the total 
score of the PAGI-QoL questionnaire 
• The change from baseline to the end of the Healing Phase for the EQ-5D-5L 
 
3.2.2 
Maintenance Phase 
The primary efficacy endpoint of the Maintenance Phase is as follows: 
• The percentage of subjects who maintain complete healing of EE after 24 weeks as 
assessed by endoscopy 
 
The secondary efficacy endpoints of the Maintenance Phase are as follows: 
• The percentage of 24-hour heartburn–free days over the Maintenance Phase as assessed 
by the daily diary 
• The percentage of subjects who maintain complete healing of EE after 24 weeks as 
assessed by endoscopy for subjects with baseline LA Classification Grades C or D 


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The exploratory efficacy endpoints of the Maintenance Phase are as follows: 
• The percentage of days without daytime heartburn over the Maintenance Phase as 
assessed by the daily diary 
• The percentage of days without nighttime heartburn over the Maintenance Phase as 
assessed by the daily diary 
• The mean severity of daytime and nighttime heartburn over the Maintenance Phase as 
assessed by the daily diary 
• The mean severity of daytime heartburn over the Maintenance Phase as assessed by the 
daily diary 
• The mean severity of nighttime heartburn over the Maintenance Phase as assessed by the 
daily diary 
• The percentage of 24-hour heartburn-free days over the Follow-up Phase as assessed by 
the daily diary 
• The change from maintenance baseline to the end of the Maintenance Phase for each 
subscale and the total score of the PAGI-SYM questionnaire 
• The change from maintenance baseline to the end of the Maintenance Phase for each 
subscale and the total score of the PAGI-QoL questionnaire 
• The change from maintenance baseline to the end of the Maintenance Phase for the 
EQ-5D-5L 
 
3.3 
Treatments 
3.3.1 
Healing Phase 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized on Day -1 of the Healing Phase to receive blinded treatments for the Healing Phase 
using a 1:1 allocation ratio.  
The blinded treatments for the Healing Phase are: 
• Vonoprazan 20 mg, taken orally for up to 8 weeks, once daily 
• Lansoprazole 30 mg, taken orally for up to 8 weeks, once daily 
3.3.2 
Maintenance Phase 
Upon verification of healing, subjects will be randomized to receive blinded treatments for the 
Maintenance Phase using a 1:1:1 allocation ratio. 


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The blinded treatments for the Maintenance Phase are: 
• Vonoprazan 10 mg, taken orally for 24 weeks, once daily 
• Vonoprazan 20 mg, taken orally for 24 weeks, once daily 
• Lansoprazole 15 mg, taken orally for 24 weeks, once daily 
3.4 
Dose Adjustment/Modifications 
No dose adjustments or modifications are allowed for this study. 
4.0 
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.  
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. If a subject receives more than one type of study drug during a phase, the planned 
treatment will be assigned as the actual treatment received for this subject in the safety summary 
tables for this phase. If a subject receives only one type of study drug during a phase, but this 
study drug type is inconsistent with the planned treatment, the actual treatment received will be 
assigned as the actual treatment for this subject in the safety summary tables for this phase. See 
Section 4.4 for the Safety Set definition. 
Statistical tests for noninferiority will be 1-sided and will be conducted at the 2.5% significance 
level. All the other statistical tests will be 2-sided and will be conducted at the 5% significance 
level, unless otherwise specified. 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. 


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4.1 
Sample Size 
4.1.1 
Healing Phase 
A sample size of 500 subjects per treatment group provides at least 90% power to achieve 
noninferiority using a Farrington Manning test with a noninferiority margin of 10%, assuming 
EE healing rates by Week 8 of 80% and 80% for vonoprazan and lansoprazole, respectively. 
A fixed noninferiority margin of -10% is justified based on historical results from 2 randomized, 
double-blind, placebo-controlled studies that evaluated EE healing rates after 8 weeks with 
lansoprazole, the active comparator in the current study. In these studies, the EE healing rates 
with placebo were compared to lansoprazole 15 mg, lansoprazole 30 mg, or lansoprazole 60 mg 
(Earnest et al 1998) or to lansoprazole 15 mg, lansoprazole 30 mg, or omeprazole 20 mg (Castell 
et al 1996). The difference in the EE healing rate between lansoprazole 30 mg and placebo 
reported by Earnest was 40% (87% vs 47%) and by Castell was 55% (87% vs 32%) with lower 
limits of the 2-sided 95% confidence interval of 26% and 48%, respectively. Using the most 
conservative assumption of the lower bound of 26% as the estimate of the treatment effect of 
lansoprazole 30 mg compared to placebo, a -10% noninferiority margin would assure that 
vonoprazan retains at least 60% of the treatment effect of lansoprazole 30 mg. 
The current study will enroll approximately 30% of subjects with more severe EE (Grade C or 
Grade D). The historical EE healing rates are from studies in which the percentage of subjects 
with more severe EE (Grade 3 or Grade 4) ranged from 35% (Castell et al 1996) to 63% (Earnest 
et al 1998). The grading scale used in the historical data was different but does provide 
information that the percentage of subjects with more severe EE that were enrolled in these 
studies is similar or higher than the 30% of Grade C or Grade D subjects planned for the current 
study. Therefore, these rates are considered relevant to informing the noninferiority margin for 
the primary endpoint for the Healing Phase and a fixed noninferiority margin of -10% is 
justified. 
4.1.2 
Maintenance Phase 
All subjects who have complete healing of EE during the Healing Phase will enter the 
Maintenance Phase. It is expected that approximately 800 subjects will enter the Maintenance 
Phase, but the actual number of subjects who enter will depend on the observed healing rates 
during the Healing Phase. During the study if less than 800 subjects are projected to enroll into 
the Maintenance Phase, additional subjects may be enrolled to ensure that a sufficient number of 
subjects enter the Maintenance Phase. 
For the maintenance of EE healing after 24 weeks, a sample size of 265 subjects per treatment 
group provides at least 90% power to achieve noninferiority with a noninferiority margin of 10% 


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and at least 90% power to achieve superiority using the Farrington Manning test, assuming 
maintenance of EE healing rates of 82% and 70% for vonoprazan and lansoprazole, respectively. 
Two randomized, double-blind studies were conducted that evaluated maintenance of EE healing 
after a 12-month maintenance treatment period with lansoprazole 15 mg QD, lansoprazole 30 mg 
QD, or placebo (PREVACID PI 2018). In these 2 studies, the differences in the Month 6 
maintenance of EE healing rate between lansoprazole 15 mg and placebo were 54% (81% vs 
27%) and 59% (72% vs 13%) with lower limits of the 2-sided 95% confidence interval of 39% 
and 43%, respectively. Using the most conservative assumption of the lower bound of 39% as 
the estimate of the treatment effect of lansoprazole 15 mg compared to placebo, a -10% 
noninferiority margin would assure that vonoprazan retains at least 75% of the treatment effect 
of lansoprazole 15 mg. In these historical maintenance studies, the percentage of subjects with 
Grade 3 or Grade 4 EE was approximately 45% which is similar or higher than the 30% of 
subjects with Grade C or Grade D EE planned for the current study. Therefore, these rates are 
considered relevant to informing the noninferiority margin for the primary endpoint for the 
Maintenance Phase and a fixed noninferiority margin of -10% is justified. 
4.2 
Randomization and Blinding 
Subjects will be randomized to receive vonoprazan 20 mg QD or lansoprazole 30 mg QD using a 
1:1 allocation ratio in the Healing Phase of the study. Upon verification of healing, subjects will 
be randomized to receive either vonoprazan 10 mg QD, vonoprazan 20 mg QD, or lansoprazole 
15 mg QD for 24 weeks in the Maintenance Phase of the study using a 1:1:1 allocation ratio. The 
randomization for both the Healing and Maintenance Phases will be stratified by baseline LA 
classification (Grades A/B and Grades C/D). 
4.3 
Assessment Windows 
4.3.1 
Study Day 
The date of first dosing day is defined as Day 1 for both the Healing and Maintenance Phases. 
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. 


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4.3.2 
Unscheduled Endoscopy Assessments 
During the Healing Phase, if the investigator deems that an additional endoscopy is warranted 
based on the subject’s symptoms prior to the window of the subject’s next scheduled per protocol 
endoscopy, an unscheduled endoscopy will be permitted whenever required as part of routine 
clinical care. If the subject’s EE is found to have healed at this unscheduled endoscopy visit, the 
subject will be considered to have completed the Healing Phase. If the subject is found to still 
have EE (of any grade) at the unscheduled endoscopy visit, the subject will be allowed to 
continue in the study within the Healing Phase and will undergo their subsequent per-protocol 
endoscopy.  
During the Maintenance Phase, if the investigator deems that an endoscopy is warranted, based 
on subject symptoms, an unscheduled endoscopy will be permitted whenever required. If the 
subject’s EE is found to have relapsed at this unscheduled endoscopy visit, the subject will be 
discontinued from the Maintenance Phase of the study, considered a treatment failure, and will 
enter the Follow-up Phase. If the subject is found to have maintained healing of EE at the 
unscheduled endoscopy visit, the subject will be allowed to continue in the study until Week 24. 
All subjects who discontinue study drug or withdraw from the study prematurely will undergo all 
end-of-study assessments, including the endoscopy, whenever possible.  
For purposes of reporting unscheduled endoscopy assessments during the Healing Phase, a “By 
Week 8” will be identified for endoscopy assessments as the last valid endoscopy assessment 
obtained after baseline and while on study drug of this phase. The number and percentage of 
subjects who have unscheduled endoscopy assessments will be reported for each phase by 
treatment group and overall. All scheduled and unscheduled endoscopy assessments will be 
listed. 
4.3.3 
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. For the Healing Phase, 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. For the Maintenance Phase, the closest visit in the Healing Phase with non-
missing assessment on or before the date of re-randomization will be used as baseline. All 
by-visit summary and analysis will be based on the analysis visit windows in Table 1. 


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Table 1 
Analysis Visit Windows 
Phase 
Nominal Visit 
(recorded on 
eCRF) 
Analysis Visit 
Target Study 
Day of Visit 
Analysis Visit Window 
Healing 
Visit 1 
Screening 
-35 to -2 
NA 
Healing 
Visit 2 
Baseline 
-1 
NA 
Healing 
Visit 3 
Week 2 
15 
8 to 22 days 
Healing 
Visit 4 
Week 8 
57 
23 to 71 days 
Maintenance 
Visit M1 
Week 4 
29 
26 to 57 days 
Maintenance 
Visit M2 
Week 12 
85 
58 to 99 days 
Maintenance 
Visit M3 
Week 16 
113 
100 to 127 days 
Maintenance 
Visit M4 
Week 20 
141 
128 to 155 days 
Maintenance 
Visit M5 
Week 24 
169 
156 or greater 
 
Unscheduled 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 these 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 
Endoscopy 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 Healing Phase. 
Screen failures are defined as subjects who were not randomized into the Healing Phase. 


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4.4.2 
Randomized Set 
4.4.2.1 
Healing Phase 
All subjects randomly assigned to receive study drug regardless of whether or not they received a 
dose of study drug during the Healing Phase.  
4.4.2.2 
Maintenance Phase 
All subjects randomly assigned to receive study drug regardless of whether or not they received a 
dose of study drug during the Maintenance Phase.  
4.4.3 
Modified Intent-to-Treat (MITT) Set 
4.4.3.1 
 Healing Phase 
The MITT set will be defined as all subjects randomized into the Healing Phase who have 
documented EE at baseline and receive at least 1 dose of study drug during the Healing Phase. 
All analyses using the MITT set will group subjects according to the randomized treatment. 
4.4.3.2 
 Maintenance Phase 
The MITT set will be defined as all subjects randomized into the Maintenance Phase who have 
healed EE at the end of the Healing Phase and receive at least 1 dose of study drug during the 
Maintenance Phase. All analyses using the MITT set will group subjects according to the 
randomized treatment. 
4.4.4 
Per Protocol (PP) Set 
4.4.4.1 
Healing Phase 
The PP Set will consist of all MITT subjects who have all of the following: 
• at least 80% and no greater than 120% compliance with study treatment 
• have not taken a proton pump inhibitor or H2 receptor antagonist during the Healing 
Phase 
• endoscopy performed by Week 8 
• have no other major protocol deviations that could affect the primary analysis of the 
Healing Phase 
 
Per definition, the PP Set will only include subjects who received the study drug to which they 
were randomly assigned. All analyses using the PP Set will group subjects according to the 
randomized treatment. 


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4.4.4.2 
 Maintenance Phase 
The PP Set will consist of all MITT subjects who have all of the following: 
• at least 80% and no greater than 120% compliance with study treatment 
• have not taken a proton pump inhibitor or H2 receptor antagonist during the Maintenance 
Phase 
• endoscopy performed at Week 24 
• have no other major protocol deviations that could affect the primary analysis of the 
Maintenance Phase. 
 
Per definition, the PP Set will only include subjects who received the study drug to which they 
were randomly assigned. All analyses using the PP Set will group subjects according to the 
randomized treatment. 
4.4.5 
Safety Set 
4.4.5.1 
 Healing Phase 
The safety set will be defined as all randomized subjects who receive at least 1 dose of study 
drug during the Healing Phase. All analyses using the safety set will group subjects according to 
the treatment actually received. 
4.4.5.2 
Maintenance Phase 
The safety set will be defined as all randomized subjects who receive at least 1 dose of study 
drug during the Maintenance Phase. All analyses using the safety set will group subjects 
according to the treatment actually received. 
4.5 
Missing Data Handling for Endoscopy Assessments 
If the post-baseline endoscopy was missing due to the COVID-19 pandemic, the missing data 
will be imputed using a missing at random (MAR) assumption.  Subjects with missing 
endoscopy data not due to the COVID-19 pandemic will be imputed as non-responders. 
For the primary endpoint during the Healing Phase, subjects with missing data not due to the 
COVID-19 pandemic, ie, those who do not have a post-baseline endoscopy by Week 8, will be 
considered “not healed” for the primary analysis. 
For the primary endpoint during the Maintenance Phase, subjects with missing data not due to 
the COVID-19 pandemic, ie, those who do not have endoscopy results at Week 24, will be 
considered “recurred” for the primary analysis. 


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The analyses of the secondary endpoints assessed by endoscopy will follow the same missing 
data handling as the primary endpoints for both Healing Phase and Maintenance Phase.  
For subgroup analyses for the primary endpoint during both the Healing Phase and the 
Maintenance Phase, all missing endoscopy results will be imputed as non-responders, given the 
complexity of implementing the multiple imputation for missing data due to COVID-19 related 
reasons within each subgroup for the relatively low number of subjects with missing results 
within each subgroup. 
5.0 
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 
Healing Phase Randomized Subjects 
The number of subjects included in each analysis set will be presented by treatment group and 
overall for all randomized subjects.  
The following will be summarized for the Healing Phase Randomized Set: 
• The number of randomized subjects. 
• The number and percentage of subjects who completed the treatment period of the 
Healing Phase. 
• The number and percentage of subjects who discontinued from the treatment period of 
the Healing Phase.  
• The number and percentage of subjects who entered the Maintenance Phase. 
• The number and percentage of subjects who did not enter the Maintenance Phase. 
• The number and percentage of subjects who completed the participation of the entire 
study after Discontinuing from the Healing Phase. 


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• The number and percentage of subjects who completed or discontinued from the 
follow-up period after Discontinuing from the Healing Phase. 
• Reasons for not entering the Maintenance Phase. 
• Reasons for discontinuation from the study participation. 
Percentages will be based on the number of subjects in the Randomized Set. 
Subject disposition data for subjects who completed the study will be listed for the Randomized 
Set. Disposition data will be listed separately for subjects who discontinued during the Healing 
Phase for the Randomized Set. 
5.1.3 
Maintenance Phase Randomized Subjects 
The number of subjects included in each analysis set will be presented by treatment group and 
overall for all randomized subjects.  
The following will be summarized for the Randomized Set: 
• The number of randomized subjects. 
• The number and percentage of subjects who completed the treatment period of the 
Maintenance Phase. 
• The number and percentage of subjects who discontinued from the treatment period of 
the Maintenance Phase.  
• 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 of the Maintenance Phase. 
• Reasons for discontinuation from the study participation. 
All percentages will be based on the number of subjects in the Randomized Set. 
Subject disposition data for the treatment period of the Maintenance Phase 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.  
5.1.4 
Healing Phase Treatment Period 
The following will be summarized for the Healing Phase Safety Set: 
• The number and percentage of subjects in the Safety Set, MITT Set, and  PP Set. 
• The number and percentage with each reason for exclusion from the MITT Set and the PP 
Set. 
• Reasons for discontinuation from the study drug. 


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Subject disposition data for the treatment period of the Healing Phase will be listed for the Safety 
Set. 
5.1.5 
Maintenance Phase Treatment Period 
The following will be summarized for the Maintenance Phase Safety Set: 
• The number and percentage of subjects in the Safety Set, MITT Set, and PP Set. 
• The number and percentage with each reason for exclusion from the MITT Set and the PP 
Set. 
• Reasons for discontinuation from the study drug. 
Subject disposition data for the treatment period of the Maintenance Phase will be listed for the 
Safety 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.  
For each phase, the number and percentage of subjects with subject-specific significant protocol 
deviations will be summarized by CTMS activity 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. 
6.0 
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 for both phases. Continuous 
variables, including age (years), body mass index, weight, height, mean severity of daytime and 
nighttime heartburn will be summarized using descriptive statistics for each treatment group and 
overall. The following categorical variables will be summarized by reporting the number and 
percentage of subjects in each category for each treatment group and overall using the MITT Set, 
PP Set, and Safety Set.  
• Age group at Screening (<45, ≥45 - <65, ≥65 - <75, ≥75) 
• Age group 2 at Screening (≥18 - ≤64, ≥65 - ≤84, ≥85) 


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• Sex (Male, Female) 
• BMI category (<25, ≥25 - <30, ≥30) 
• LA Classification Adjudicator Grade (A, B, C, D) 
• LA Classification Adjudicator Grade (A/B, C/D) 
• LA Classification Investigator Grade (A, B, C, D) 
• LA Classification Investigator Grade (A/B, C/D) 
• Serum gastrin (<200 pg/mL, ≥200 pg/mL) 
• Pepsinogen I/II level (≤2, >2 - ≤3, >3) 
• 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) 
• Country 
In addition, the following variables will be summarized based on symptoms reported in the daily 
diary from the last 7 days prior to Day-1 of the Healing Phase: 
• Mean severity of: 
o Daytime/Nighttime Heartburn (0, >0 - ≤1, >1 - ≤2, >2 - ≤3, >3 - ≤4) 
o Heartburn during the day (0, >0 - ≤1, >1 - ≤2, >2 - ≤3, >3 - ≤4) 
o Heartburn at night (0, >0 - ≤1, >1 - ≤2, >2 - ≤3, >3 - ≤4) 
• Number of days with: 
o Daytime or nighttime heartburn (≥0 - ≤3, >3 - ≤5, >5 - ≤7) 
o Daytime heartburn (≥0 - ≤3, >3 - ≤5, >5 - ≤7) 
o Nighttime heartburn (≥0 - ≤3, >3 - ≤5, >5 - ≤7) 
Refer to Section 13.4.2 for calculations of baseline summary of symptom diary variables. 
Demographic and baseline characteristics data will be listed using the Randomized Set. 
6.2 
Medical History 
6.2.1 
General Medical History 
Medical history will be coded using Version 23 of the Medical Dictionary for Regulatory 
Activities (MedDRA). The primary system organ class (SOC), preferred term (PT), verbatim 
term, start date, and stop date or indication of ongoing, will be collected on the eCRF. 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.  


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Each subject’s medical history will be listed by MedDRA SOC and verbatim term using the 
Safety Set. 
7.0 
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. 
For the Healing Phase, prior medications are those with the start and stop dates prior to the first 
dose of Healing Phase study drug. Concomitant medications are those with start dates prior to the 
first dose of Healing Phase and continuing after the first dose of Healing Phase or with start dates 
between the first dose of Healing Phase and the first dose of Maintenance Phase.  
For the Maintenance Phase, concomitant medications are those with start dates prior to the first 
dose of Maintenance Phase and continuing after the first dose of Maintenance Phase or with start 
dates on or after the first dose of Maintenance Phase. 
See Figure 2 for details on the categorization of prior and concomitant medications. 
Figure 2 
Prior and Concomitant Medications 
 
 


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For the Healing Phase, the prior medications and concomitant medications will be summarized 
separately by treatment group and overall. For subjects who did not enter the Maintenance Phase, 
concomitant medications with start dates after the last dose of treatment in the Healing Phase 
will be summarized by treatment group and overall.  
For the Maintenance Phase, the concomitant medications with start dates on or after the first dose 
of the Maintenance Phase will be summarized by treatment group and overall. The concomitant 
medications that are ongoing at the end of the Healing Phase, i.e. with start dates before the first 
dose of the Maintenance Phase, will be summarized by treatment group and overall. All 
concomitant medications, including those with start dates before, on or after the first dose of the 
Maintenance Phase, will also be summarized by treatment group and overall. 
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 Section 13.2.  
For each phase, all prior and concomitant medications will be listed by treatment and subject for 
the Safety Set.   
7.2 
 Study Treatments 
7.2.1 
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.  
For the Healing Phase, treatment duration of exposure will be categorized and summarized as 
follows: ≥1 to ≤14 days, >15 to ≤28 days, >28 to ≤56 days, >56 days. For the Maintenance 
Phase, treatment duration of exposure will be categorized and summarized as follows: ≥1 to 
≤28 days, >29 to ≤56 days, >57 to ≤84 days, >85 to ≤112 days, >113 to ≤140 days, >141 to 
≤168 days and >169 days. 
Treatment exposure will be calculated as the number of days from first to last dose date of each 
phase: 
 
Exposure = Date of last dose – Date of first dose + 1 


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The date of last dose for each phase is recorded on the End of Treatment (EOT) page of that 
phase on the eCRF. If the date of last dose of the Healing Phase is missing, it will be imputed as 
follows: 
If a subject entered the Maintenance Phase, 
• Imputed date of last dose = the date of Maintenance Phase randomization – 1  
if a subject did not enter the Maintenance Phase, 
• Imputed date of last dose = the date of first dose of the Healing Phase + 27 for subjects if 
the latest available kit was dispensed on Day -1.  
• Imputed date of last dose = the latest kit dispense date + 27 for subjects if the latest 
available kit was dispensed after date of first dose.  
 
If the date of last dose of the Maintenance Phase is missing, it will be imputed as the latest kit 
dispense date + 83. The date of first dose for each phase is recorded on the Drug Accountability 
page on the eCRF. If the date of first dose for the Healing Phase is missing, it will be imputed 
using the date of randomization + 1. If the date of first dose for the Maintenance Phase is 
missing, it will be imputed using the date of last available visit during the Healing Phase + 1. All 
summaries for the treatment period will be performed using the Safety Set.  
The exposure summary, including person-time (overall total exposure in years), will also be 
presented for the treatment types across the two phases: 
• Vonoprazan to vonoprazan 
• Vonoprazan to lansoprazole 
• Lansoprazole to vonoprazan 
• Lansoprazole to lansoprazole 
All data for treatment exposure during the treatment period will be listed using the Safety Set.  
7.2.2 
Treatment Compliance 
For each phase, treatment compliance will be calculated as: 
Compliance (%) = (total actual capsules taken / total expected capsules) × 100, where 
total expected capsules = (date of last dose of this phase – date of first dose of this 
phase + 1) and  
total actual capsules taken = total number of capsules dispensed for this phase – total 
number of capsules returned for this phase  
 
For subjects with at least one kit not returned, the compliance will be imputed using the 
following rules for each phase: 


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• If no kits are returned among the kits dispensed during a phase, the compliance is 
imputed as 100% for this phase. 
• If only partial kits are returned among the kits dispensed during a phase, the returned 
amount for kits not returned will be imputed as 7 capsules, so that the taken amount is 35-
7=28 capsules for each kit that is not returned. 
• If a subject has returned amount imputed for at least one kit, which results in a treatment 
compliance of >120%, the treatment compliance will be set to 100% for this phase. 
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 80% and less than or equal to 120%. 
Treatment compliance for the treatment period will be summarized for the Safety Set. Summary 
statistics for treatment compliance percentages and compliance categories (<80, 80 - ≤100, 100 - 
≤120, >120) will be summarized for each treatment group and overall. Individual subject 
compliance information will be listed using the Safety Set. 
8.0 
EFFICACY ANALYSIS  
Healing Phase: 
The hypothesis-testing of the primary and secondary endpoints in the Healing Phase will be 
adjusted for multiple comparisons using a fixed-sequence testing procedure to control the Type 1 
error rate at the 0.05 level. The statistical tests will be performed at α =0.05 in the sequential 
order shown in Figure 3 until a test is not significant. If the primary hypothesis for the 
comparison between the treatment groups is statistically significant (α=0.05) in the MITT 
Population, then the primary objective of the trial will have been achieved and the next 
hypothesis can be tested; otherwise, testing will stop. The testing of each subsequent hypothesis 
is conditioned upon all the previous hypotheses being rejected at the 0.05 level of significance. If 
a hypothesis is not rejected at the 0.05 level of significance, then all remaining hypotheses are 
deemed not statistically significant. Only p-values that are significant according to this sequential 
order in Figure 3 are inferential and statistically significant. All the other p-values are 
descriptive. 
 
 


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Maintenance Phase: 
The hypothesis-testing of the primary endpoint of the Maintenance Phase will be adjusted using 
Hochberg’s multiple comparisons method to control the overall 0.05 level of significance to test 
the non-inferiority of each dose group of vonoprazan to lansoprazole. If both vonoprazan dose 
groups have p-value ≤0.05, both dose groups are found to be non-inferior to lansoprazole 15 mg. 
Otherwise, if one dose group has p-value > 0.05 and the other dose group has p-value ≤0.025, the 
dose group with p-value ≤0.025 is found to be non-inferior to lansoprazole 15 mg.  
If non-inferiority is declared for both vonoprazan dose groups from the primary efficacy 
analysis, the comparisons to lansoprazole 15 mg for the secondary efficacy endpoints will be 
performed using a fixed-sequence testing procedure shown in Figure 3 to control the Type 1 error 
rate at the 0.05 level until a test is not significant.  
If non-inferiority is not declared for either vonoprazan dose group from the primary efficacy 
analysis, the testing procedure will end. 
During the Maintenance Phase, additional comparisons will be made between the two 
vonoprazan dose groups for each primary and secondary efficacy endpoint with no adjustment 
for multiple comparisons. 
 
 
 
 
 
 
 
 
 
 


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Figure 3 
Testing Hierarchy 
Healing Phase 
 
 
 
Primary Endpoint 
Noninferiority: The % of subjects who have complete healing of EE by Week 8 
 
Noninferiority: The % of 24-hour heartburn-free days over the Healing Period 
 
Superiority: The % of Grades C/D subjects who have healing at Week 2 
 
Superiority: The % of subjects with onset of sustained resolution of heartburn by Day 3  
 
Superiority: The % of Grades C/D subjects who have healing by Week 8 
 
Superiority: The % of subjects (All Grades) who have healing at Week 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Maintenance Phase 
 
 
 
Primary Endpoint – Hochberg 10 mg and 20 mg 
Noninferiority: The % of subjects who maintain healing through Week 24 
 
Vonoprazan 20 mg 
Superiority: The % Grades C/D who maintain healing through Week 24 
 
Vonoprazan 20 mg 
Superiority: The % of subjects who maintain healing through Week 24 
 
Vonoprazan 20 mg 
Noninferiority: The % of 24-hour heartburn-free days through Week 24 
 
Vonoprazan 10 mg 
Superiority: The % Grades C/D who maintain healing through Week 24 
 
Vonoprazan 10 mg 
Superiority: The % of subjects who maintain healing through Week 24 
 
Vonoprazan 10 mg 
Noninferiority: The % of 24-hour heartburn-free days through Week 24 
 
 


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8.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint of the Estimand 1 (primary) of Healing Phase is the percentage of 
subjects who have complete healing of EE by Week 8 as assessed by endoscopy. 
The primary efficacy endpoint of the Estimand 1 (primary) Maintenance Phase is the percentage 
of subjects who maintain complete healing of EE after 24 weeks as assessed by endoscopy. 
See Section 13.6 for the primary endpoints of the additional estimands defined for the Healing 
Phase and Maintenance Phase. 
8.1.1 
Primary Analysis 
Healing Phase:  
For the Healing Phase, the frequency of EE healing rate by Week 8 will be summarized for each 
treatment group. A subject will be considered to have “complete healing of EE by Week 8” if the 
subject demonstrates healing at the Week 2, an unscheduled visit between Week 2 and Week 8 or 
Week 8 endoscopy. 
Non-inferiority of vonoprazan 20 mg to lansoprazole 30 mg will be evaluated with a Farrington 
and Manning test with a non-inferiority margin of 10% for the difference in EE rates by Week 8 
between treatments (vonoprazan 20 mg - lansoprazole 30 mg). The point estimate and 2-sided 
95% CI of the difference in endoscopic healing rate between vonoprazan 20 mg and lansoprazole 
30 mg will be calculated via the Miettinen and Nurminen method. The primary analysis will be 
performed using the MITT Set.  
If non-inferiority is shown, superiority of vonoprazan 20 mg to lansoprazole 30 mg by Week 8 
will also be assessed via the Farrington and Manning test of the null hypothesis difference ≤0 
versus the alternative hypothesis difference >0 as an exploratory analysis.  
All efficacy data will be listed using the Randomized Set.  
The number of subjects who had endoscopies at each visit, including both scheduled and 
unscheduled visits, will be summarized by analysis visit for each treatment group.  
Efficacy endpoints assessed by results from endoscopy will be based on the assessment from the 
central adjudication. The differences between central adjudication and investigators assessments 
of healing/not healed and LA Grade will be summarized in a table. 


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Maintenance Phase:  
For the Maintenance Phase, the frequency of subjects who maintain complete healing will be 
summarized for Week 24 for each treatment group. The maintenance of healing during the 
24-week Maintenance Phase will be calculated along with 2-sided 95% CIs for each treatment 
group. Non-inferiority of each dose group of vonoprazan to lansoprazole (i.e. vonoprazan 10 mg 
to lansoprazole 15 mg and vonoprazan 20 mg to lansoprazole 15 mg) will be evaluated with a 
Farrington and Manning test with a non-inferiority margin of 10% for the difference in 
maintenance of healing rates between treatments (each dose group of vonoprazan – lansoprazole 
15 mg) at Week 24. The point estimate and 2-sided 95% CI of the difference in the maintenance 
of healing rate between each dose group of vonoprazan and lansoprazole 15 mg will be 
calculated via the Miettinen and Nurminen method. The primary analysis will be performed 
using the MITT Set.  
If non-inferiority is shown for a vonoprazan dose group (vonoprazan 10 mg or vonoprazan 20 
mg), superiority compared to lansoprazole 15 mg will also be assessed following the testing 
hierarchy in Section 8.0 via the Farrington and Manning test of the null hypothesis difference ≤0 
versus the alternative hypothesis difference >0.  
All efficacy data will be listed using the Randomized Set.  
The number of subjects who had endoscopies at each visit, including both scheduled and 
unscheduled visits, will be summarized by analysis visit for each treatment group.  
Efficacy endpoints assessed by results from endoscopy will be based on the assessment from the 
central adjudication. The differences between central adjudication and investigators assessments 
of healing/not healed and LA Grade will be summarized in a table. 
8.1.2 
Assumption Testing 
Given the large sample sizes for both phases, 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 
To explore how intercurrent events affect the robustness of each estimand, the following 
sensitivity and supportive analyses will be performed. See Section 13.6 for more details on 
estimands, intercurrent event types, and associated analyses for the Healing Phase and 
Maintenance Phase. 


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Data summaries will parallel those described for the primary analysis of the primary efficacy 
endpoints for all sensitivity and supportive analyses. 
8.1.3.1 
Tipping Point Analysis 
To explore how missing data affects the robustness of the primary analysis, a missing data 
sensitivity analysis using a tipping point method will be performed for non-inferiority for both 
Healing and Maintenance Phases using different missing data strategies for Estimand 1. The 
tipping point analysis begins with most conservative imputation for missing data (i.e., most 
heavily slanted against the active treatment non-inferior to active control).  
Implementation of the tipping point approach for the Healing Phase will involve the following 
steps: 
1. The missing data for lansoprazole 30 mg subjects is assumed to be responders (ie, 
healed). Missing data for vonoprazan 20 mg subjects is assumed to be non-responders (ie, 
not healed). 
2. The data set is analyzed using the same Farrington and Manning method as the primary 
analysis to see if the p-value is ≤0.05; and if so, the tipping point analysis will be stopped 
at this point.  
3. Repeat step #1 switching an imputed responder for one lansoprazole 30 mg subject to an 
imputed non-responder.  
4. Repeat step #2 to obtain the p-value to see if the p-value is ≤0.05. 
Repeat steps #3 and #4 increasing the number of imputed lansoprazole 30 mg non-responders 
one at a time until the p-value is ≤0.05 or all missing data has been switched from an imputed 
responder to a non-responder for all lansoprazole 30 mg subjects with an imputed result. The 
number of non-responders that achieves this p-value will be considered the “tipping point.” 
Implementation of the tipping point approach for the Maintenance Phase will follow the same 
steps as above, starting with considering all missing data for lansoprazole 15 mg subjects as 
responders (ie, maintained healing) and missing data for each dose group of vonoprazan as non-
responders (ie, did not maintain healing).  
8.1.3.2 
Sensitivity Analysis on Observed Data Only 
For each phase, the primary analysis will be repeated for Estimand 1 on observed data only. 
Subjects without post-baseline endoscopy results will be excluded from these analyses. 


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8.1.3.3 
Multiple Imputation Analyses 
For each phase, 3 types of multiple imputation analyses will be performed for each estimand. 
The details of multiple imputation methods are summarized in Table 9 for the Healing Phase, and 
Table 13 for the Maintenance Phase. 
8.1.3.4 
Sensitivity Analysis on Prohibited Medications 
To explore how use of the prohibited medications of proton pump inhibitors or H2 receptor 
antagonists affects the robustness of the primary analysis, a sensitivity analysis will be performed 
for non-inferiority for both Healing and Maintenance Phases for Estimand 1 considering subjects 
as non-responders at timepoints after any PPI/H2RA use. 
8.1.3.5 
Supportive Analysis Using PP Set 
Supportive analyses will be repeated using PP Set for Estimand 1, on the primary efficacy 
endpoints for non-inferiority (for both Healing and Maintenance Phases) and superiority (for 
Maintenance Phase if shown).  
8.1.4 
Subgroup Analysis 
For both phases, the primary efficacy endpoints will be analyzed separately for the following 
subgroups using the same method as the primary: 
• Age group at Screening (<45, ≥45 - <65, ≥65 - <75, ≥75) 
• Sex (Male, Female) 
• 
Baseline BMI category (<25, ≥25 - <30, ≥30) 
• Region (United States, Europe) 
• Baseline Adjudicated EE grade (A, B, C, D) 
• Baseline Adjudicated EE grade category (A/B, C/D) 
• 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) 
• Race (white, black or African American, Asian, American Indian or Alaska native, native 
Hawaiian or other Pacific islander, other) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino) 


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In addition, for the Maintenance Phase, the primary efficacy endpoint will be analyzed separately 
for the following subgroups: 
• Healing Phase treatment (vonoprazan 20 mg, lansoprazole 30 mg) 
• Healing Phase treatment duration (Week 2, Week 8) 
The subgroup analyses will be performed using the MITT Set. 
8.2 
Secondary Efficacy Endpoint 
Healing Phase 
For the Healing Phase, the following secondary endpoints will be analyzed for superiority of 
vonoprazan 20 mg compared to lansoprazole 30 mg  
1. The percentage of subjects who have complete healing of EE at Week 2 as assessed by 
endoscopy 
2. The percentage of subjects who have complete healing of EE at Week 2 as assessed by 
endoscopy for subjects with baseline LA Classification Grades C or D 
3. The percentage of subjects who have complete healing of EE by Week 8 as assessed by 
endoscopy for subjects with baseline LA Classification Grades C or D 
4. The percentage of subjects with onset of sustained resolution of heartburn by Day 3 
(sustained resolution is defined as at least 7 consecutive days with no daytime or 
nighttime heartburn as assessed by the daily diary) 
 
Superiority of vonoprazan 20 mg to lansoprazole 30 mg will be assessed via the Farrington and 
Manning test of the null hypothesis difference ≤0 versus the alternative hypothesis difference >0.  
For the Healing Phase, the following secondary endpoint will be analyzed for non-inferiority of 
vonoprazan 20 mg compared to lansoprazole 30 mg. 
5. The percentage of 24-hour heartburn–free days over the Healing Phase as assessed by the 
daily diary 
 
A 2-sided 95% CI will be calculated for the difference between the treatment groups in the mean 
percentage of 24-hour heartburn–free days (each dose group of vonoprazan minus lansoprazole). 
The 95% confidence interval will be computed from Welch’s t-test. The difference in the means 
will be compared from Welch’s t-test as an exploratory analysis. If the lower bound of this CI is 
greater than -15%, noninferiority will be concluded. If noninferiority is shown, the percentage of 
24-hour heartburn–free days will also be compared between treatment groups using a Wilcoxon 
rank-sum test as an exploratory analysis.  


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A fixed noninferiority margin of -15% is justified based on results from a randomized, double-
blind study in 1284 subjects that evaluated EE healing with placebo, lansoprazole 15 mg, 
lansoprazole 30 mg, or omeprazole 20 mg (Castell et al 1996). In this study, a twice daily patient 
diary was used to collect daytime and nighttime heartburn symptoms. The diary was very similar 
to the diary being used in the current study, except that it used a 4-point severity scale (none, 
mild, moderate, severe) rather than a 5-point severity scale (none, mild, moderate, severe, very 
severe). Given that the secondary endpoint is based on presence or absence of any degree of 
heartburn, these minor scale differences are not relevant for the purpose of establishing the 
noninferiority margin. The difference in the mean percentage of 24-hour heartburn–free days 
between lansoprazole 30 mg (72.6%) and placebo (31.6%) was 41.0%; the lower limit of the 
2-sided 95% CI was 35.8%. Hence, even with a conservative assumption of this lower bound as 
the true treatment effect of lansoprazole 30 mg, a noninferiority margin of -15% assures that 
vonoprazan retains at least 58% of the treatment effect of lansoprazole 30 mg compared with 
placebo. 
Endpoints #4 and #5 will use data collected from the subject symptom diary. For each subject, 
the percentage of 24-hour heartburn-free days over the Healing Phase will be calculated using all 
days with at least 1 morning or evening diary entry during the Healing Phase. 
See Section 13.4.1 for data handling details for the subject daily diary and Section 13.4.3 for data 
handling details on sustained resolution of heartburn.  
Maintenance Phase 
For the Maintenance Phase, the following secondary endpoint will be analyzed for superiority of 
each dose group of vonoprazan compared to lansoprazole 15 mg. 
1. The percentage of subjects who maintain complete healing of EE after 24 weeks as 
assessed by endoscopy for subjects with baseline LA Classification Grades C or D 
 
Superiority compared to lansoprazole 15 mg will be assessed via the Farrington and Manning 
test of the null hypothesis difference ≤0 versus the alternative hypothesis difference >0.  
For the Maintenance Phase, the following secondary endpoint will be analyzed for non-
inferiority of each dose group of vonoprazan compared to lansoprazole 15 mg. 
2. The percentage of 24-hour heartburn–free days over the Maintenance Phase as assessed 
by the daily diary 
 


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The secondary endpoint will use data collected from the subject symptom diary. A 2-sided 95% 
CI will be calculated for the difference between the treatment groups in the mean percentage of 
24-hour heartburn–free days (each dose group of vonoprazan minus lansoprazole). The 95% 
confidence interval will be computed from Welch’s t-test. The difference in the means will be 
compared from Welch’s t-test as an exploratory analysis. If the lower bound of this CI is greater 
than -15%, noninferiority will be concluded. If noninferiority is shown, the percentage of 
24-hour heartburn–free days will also be compared between treatment groups using a Wilcoxon 
rank-sum test as an exploratory analysis. 
A fixed noninferiority margin of -15% is justified based on results from a randomized, double-
blind study that evaluated maintenance of EE healing over 6 months with placebo, 
dexlansoprazole 30 mg QD, and dexlansoprazole 60 mg QD (Metz et al 2009). This study used 
the same twice daily patient diary to collect daytime and nighttime heartburn symptoms that will 
be used in the current study. 
Data for the relief of heartburn based on a daily patient diary from a maintenance of EE healing 
study that compared the efficacy of lansoprazole 15 mg QD to placebo are not available, as the 
maintenance of EE healing studies for lansoprazole demonstrated superior relief of symptoms 
including heartburn based on the investigator’s assessment. However, data are available from a 
study comparing dexlansoprazole, the R-enantiomer of lansoprazole, to placebo, and results for 
the approved dexlansoprazole maintenance dose of 30 mg are considered relevant to inform the 
noninferiority margin for the approved lansoprazole maintenance dose of 15 mg. 
The difference in the mean percentage of 24-hour heartburn–free days between dexlansoprazole 
30 mg (83.3%) and placebo (36.0%) was 47.3%; the lower limit of the 2-sided 95% CI was 
40.3%. Hence, even with a conservative assumption of this lower bound as the true treatment 
effect of lansoprazole 15 mg, a noninferiority margin of -15% assures that vonoprazan retains at 
least 62% of the treatment effect of lansoprazole 15 mg compared with placebo. 
All secondary endpoints will be analyzed using the MITT Set. 
8.2.1 
Subgroup Analysis 
For both phases, the percentage of 24-hour heartburn–free days will be analyzed separately for 
subjects with Baseline Adjudicated EE grade category A/B and C/D using the same method as 
the secondary endpoint. 
8.2.2 
Sensitivity Analysis 
To explore how missing data affects the robustness of the secondary analysis on the percentage 
of 24-hour heartburn–free days over each phase, a sensitivity analysis will be performed for each 


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phase, in which the days after a subject discontinues treatment will be imputed as non-
responders, i.e. having heartburn on those days. The percentage will be calculated from the 
number of planned days in the treatment period of each phase: 
• Healing Phase: the treatment duration or 56 days, whichever is greater 
• Maintenance Phase, the treatment duration in this phase, or 168 days, whichever is 
greater. 
A summary of the percentage of missing diaries during each phase will be summarized by 
treatment group. A study day with no diary will be counted as 2 missing diaries, a study day with 
only either daytime or nighttime diary will be counted as 1 missing diary. The percentage will be 
calculated from the number of planned days in the treatment period of each phase. 
8.3 
Exploratory Endpoints  
For the exploratory efficacy endpoints, all comparisons between treatment groups will be 
performed with no adjustment to the alpha level. 
Healing Phase 
For the Healing Phase, the following exploratory endpoints will be compared between treatment 
groups using a Wilcoxon rank-sum test. 
• The percentage of days without daytime heartburn over the Healing Phase as assessed by 
the daily diary 
• The percentage of days without nighttime heartburn over the Healing Phase as assessed 
by the daily diary 
• The mean severity of daytime and nighttime heartburn over the Healing Phase as 
assessed by the daily diary 
• The mean severity of daytime heartburn over the Healing Phase as assessed by the daily 
diary 
• The mean severity of nighttime heartburn over the Healing Phase as assessed by the daily 
diary 
• The percentage of 24-hour heartburn–free days over the first 14 days of the Healing 
Phase as assessed by the daily diary 
• The percentage of days without daytime heartburn over the first 14 days of the Healing 
Phase as assessed by the daily diary 
• The percentage of days without nighttime heartburn over the first 14 days of the Healing 
Phase as assessed by the daily diary 
• The mean severity of daytime and nighttime heartburn over the first 14 days of the 
Healing Phase as assessed by the daily diary 


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• The mean severity of daytime heartburn over the first 14 days of the Healing Phase as 
assessed by the daily diary 
• The mean severity of nighttime heartburn over the first 14 days of the Healing Phase as 
assessed by the daily diary 
• The change from baseline to the end of the Healing Phase for each subscale and the total 
score of the PAGI-SYM questionnaire 
• The change from baseline to the end of the Healing Phase for each subscale and the total 
score of the PAGI-QoL questionnaire 
• The change from baseline to the end of the Healing Phase for the EQ-5D-5L index and 
visual analogue scale (VAS) scores 
 
For the following endpoint, cumulative incidences of events will be estimated using the Kaplan-
Meier method. Standard errors (SE) and 2-sided 95% CIs will be calculated using the 
Greenwood’s formula. Log-rank tests will be performed. The median and its 2-sided 95% CIs, 
the mean, and the SE will be calculated for the number of days to events. See Section 13.4.3 for 
details on the definitions of events and censoring. 
• The time to sustained resolution of heartburn  
Maintenance Phase 
For the Maintenance Phase, the following exploratory endpoints will be compared between each 
two treatment groups (i.e. vonoprazan 10 mg vs. lansoprazole 15 mg, vonoprazan 20 mg vs. 
lansoprazole 15 mg, vonoprazan 10 mg vs vonoprazan 20 mg) using a Wilcoxon rank-sum test. 
The maintenance baseline is defined as the last visit during the Healing Phase prior to the first 
dose of the study drug in the Maintenance Phase. 
• The percentage of days without daytime heartburn over the Maintenance Phase as 
assessed by the daily diary 
• The percentage of days without nighttime heartburn over the Maintenance Phase as 
assessed by the daily diary 
• The mean severity of daytime and nighttime heartburn over the Maintenance Phase as 
assessed by the daily diary 
• The mean severity of daytime heartburn over the Maintenance Phase as assessed by the 
daily diary 
• The mean severity of nighttime heartburn over the Maintenance Phase as assessed by the 
daily diary 
• The percentage of 24-hour heartburn–free days, the percentage of days without daytime 
heartburn, and the percentage of days without nighttime heartburn during each month of 
the Maintenance Phase as assessed by the daily diary 


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• The mean severity of daytime and nighttime heartburn, the mean severity of daytime 
heartburn, and the mean severity of nighttime heartburn during each month of the 
Maintenance Phase as assessed by the daily diary 
• The change from maintenance baseline to the end of the Maintenance Phase for each 
subscale and the total score of the PAGI-SYM questionnaire 
• The change from maintenance baseline to the end of the Maintenance Phase for each 
subscale and the total score of the PAGI-QoL questionnaire 
• The change from maintenance baseline to the end of the Maintenance Phase for the 
EQ-5D-5L index and visual analogue scale (VAS) scores 
The following endpoints will be summarized by treatment group for all Maintenance Phase 
subjects who enter the Follow-up Phase. 
• Percentage of 24-hour heartburn-free days over the Follow-up Phase as assessed by the 
daily diary 
• Percentage of days with use of antacids over the Follow-up Phase as assessed by the daily 
diary 
• Percentage of days with use of H2-receptor antagonists over the Follow-up Phase as 
assessed by the daily diary 
• Percentage of days with use of either antacids or H2-receptor antagonists over the 
Follow-up Phase as assessed by the daily diary 
 
All exploratory endpoints will be analyzed using the MITT Set. Refer to Section 13.4 for data 
handling details on symptom diary, PAGI-SYM, PAGI-QoL and EQ-5D-5L.  
9.0 
SAFETY ANALYSIS 
For each phase, safety will be assessed by summarizing the incidence of AEs and changes in 
clinical laboratory tests, gastrin and pepsinogen I/II levels, and vital signs. In addition, ECG and 
gastric biopsy will be summarized in the Maintenance Phase. For all safety analyses, baseline for 
the Healing Phase will be the last visit prior to the first dose of study drug in the Healing Phase. 
Baseline for the Maintenance Phase will be the last visit during the Healing Phase prior to the 
first dose of study drug in the Maintenance Phase.  
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 Version 23 of the Medical Dictionary for Regulatory 
Activities (MedDRA). A treatment-emergent AE (TEAE) is defined as any event that occurs after 
the first dose of study drug in that phase or any event at baseline that worsens in either intensity 
or frequency after the first dose of study drug in that phase. For subjects who did not enter the 
Maintenance Phase, an AE that starts after more than 30 days of the last dose of study drug in the 


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Healing Phase will not be counted as a TEAE of the Healing Phase. For subjects who entered the 
Maintenance Phase, an AE that starts after more than 30 days of the last dose of study drug in the 
Maintenance Phase will not be counted as a TEAE of the Maintenance Phase. 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’.  
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 
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 
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 TEAEs (>5% of subjects in any treatment group) will be 
presented by primary system organ class, preferred term and treatment group along with the 
number and proportion of subjects reporting at least one of these most frequent non-serious 
TEAEs. 
The number and proportion of subjects as well as the number of events (except deaths) with the 
following types of events will be summarized by primary system organ class, preferred term and 
treatment: 
• Adverse events leading to treatment discontinuation 


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• Serious Adverse Events (SAEs) 
• Deaths 
• Adverse events of special interest (AESI) 
In the Maintenance Phase, TEAEs, TEAEs related to study drug, SAEs and AEs leading to 
treatment discontinuation will also be presented by primary system organ class and preferred 
term for the treatment types across the two phases: 
• Vonoprazan to vonoprazan 
• Vonoprazan to lansoprazole 
• Lansoprazole to vonoprazan 
• Lansoprazole to lansoprazole 
All adverse events in the Healing Phase will be included in a listing using the Screened Set. All 
adverse events in the Maintenance Phase will be included in a listing using the Randomized Set. 
All adverse events over the Follow-Up Phase will be included in a listing using the Safety Set. In 
addition, the following select adverse events will be displayed in separate listings for each phase: 
• Deaths 
• Serious adverse events 
• Adverse events leading to treatment discontinuation 
• Adverse events related to study drug 
• Adverse events of special interest 
9.1.1 
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 2 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 2 
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 
Greenstick fracture  
Hand fracture  
Hip fracture  
Humerus fracture  
Ilium fracture  
Impacted fracture  
Jaw fracture  
Limb fracture  
Lower limb 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 
MedDRA: Medical Dictionary for Regulatory Activities; PT: preferred term; SMQ: Standardized MedDRA Queries. 
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) and serum gastrin and pepsinogen I/II 


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levels will be presented by treatment group and overall for each phase. Changes from baseline 
will also be presented for quantitative variables by treatment group and overall for each phase. 
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.  
For each period, the number and percentage of subjects with at least one post-baseline serum 
gastrin value >500 pg/mL and >1000 pg/mL and with the test value higher than baseline value, if 
available, will be presented. A supportive listing of subjects with such post-baseline elevations 
will be provided including the subject ID, baseline, and post-baseline values. 
Abnormal liver function tests are defined as liver test values that meet at least one of the criteria 
listed below. For each phase, the number and percentage of subjects with at least one post-
baseline abnormal liver function test and with the test 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. 
• 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 


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• ALT > 3xULN and Alkaline phosphatase > 1.5xULN 
• AST > 3xULN and Alkaline phosphatase > 1.5xULN 
 
• Alkaline phosphatase > 3xULN 
• ALT > 3xULN and Alkaline phosphatase > 3xULN 
• AST > 3xULN and Alkaline phosphatase > 3xULN 
9.3 
Vital Signs 
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 for each 
phase. Changes from baseline will also be presented by treatment group and overall for each 
phase. 
Abnormal vital sign values are defined as vital sign values that meet one of the criteria listed 
below. For each phase, the number and percentage of subjects with at least one post-baseline 
abnormal vital sign value and with the value worse 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 
ECG parameters, including heart rate, RR interval, PR interval, QRS interval, QT interval, QTc 
Fridericia (QTcF) will be collected on eCRF. Descriptive statistics for these ECG parameters will 
be presented by treatment group and overall for the Maintenance Phase only. Changes from 
baseline will also be presented for quantitative variables by treatment group and overall for the 
Maintenance Phase. For ECG interpretations (within normal limits, abnormal but not clinically 


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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 in the Maintenance Phase. 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  
9.6 
Gastric Biopsy 
A shift table showing the change in gastric biopsy results from baseline to the final visit will be 
produced for each biopsy by treatment group. 
10.0 
INTERIM ANALYSIS/OTHER ANALYSES 
10.1 
Interim Analysis 
No interim analysis is planned. 
10.2 
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.     
The following adjustments will be made to the efficacy analysis: Missing data for subjects 
without a post-baseline endoscopy at a visit due to COVID-19 related reasons will be imputed 
using a missing at random assumption (Section 4.5).  


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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.  
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. 
11.0 
CHANGES IN THE PLANNED ANALYSIS 
The following changes to the analysis specified in Protocol Amendment 2, dated 01Oct2019 
have been made. 
The definition of the Per Protocol Set was updated to exclude subjects with major protocol 
deviations regardless of study outcome (healed or not healed during the Healing Phase and 
remained healed or recurred during the Maintenance Phase). 
The protocol includes description of a potential analysis of the Healing Phase data to be  
performed after all subjects have completed the Healing Phase. It has been decided not to 
conduct this analysis so reference to this potential analysis was removed in Amendment 1 to the 
SAP. 
 
 


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12.0 
REFERENCES 
Castell DO, Richter JE, Robinson M, et al. Efficacy and safety of lansoprazole in the treatment 
of erosive reflux esophagitis. The Lansoprazole Group. Am J Gastroenterol. 1996;91(9):1749-57. 
Earnest DL, Dorsch E, Jones J, et al. A placebo-controlled dose-ranging study of lansoprazole in 
the management of reflux esophagitis. Am J Gastroenterol. 1998;93(2):238-43. 
Metz DC, Howden CW, Perez MC, et al. Clinical trial: dexlansoprazole MR, a proton pump 
inhibitor with dual delayed-release technology, effectively controls symptoms and prevents 
relapse in patients with healed erosive oesophagitis. Aliment Pharmacol Ther. 
2009;29(7):742-54. 
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. 
13.0 
APPENDICES 
 
 


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13.1 
Schedule of Events 
 
Table 3 
Schedule of Events 
Screening 
Period (a) 
Healing Phase 
Maintenance Phase 
Safety 
F/U 
(e) 
Un-
sched-
uled 
Visit (f) 
Timing 
Healing 
Day -1 
(b) 
Healing 
Day 1(b) 
Week 2 
(c) 
Healing 
Day 15 
Week 8 
(c,m) 
Healing 
Day 57 
Main 
Week 4 
Main Day 
29 
Main 
Week 12 
Main Day 
85 
Main 
Week 16 
Main Day 
113 
Main 
Week 20 
Main 
Day 141 
Main 
Week 24 
Main Day 169 
Final Visit/ET 
(d) 
Visit Windows (Days) 
Day-35 
to -2 
- 
 
12 to 18 
54 to 60 
26 to 36 
82 to 92 
110 to 120 
138 to 
148 
166 to 176 
- 
- 
Visit Number: 
1 
2 
 
3 
4 
M1 
M2 
M3 
M4 
M5 
F/U 
- 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic and medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and Alcohol history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination(g) 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
Vital signs  
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
Concurrent medical conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FSH(h) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C; HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory test including 
hematology, serum chemistry, and 
urinalysis(i) 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
 
 
13C-UBT Breath Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CYP2C19 genotyping test 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Serum gastrin/pepsinogen I/II 
levels(j) 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
Pregnancy test (serum HCG)(k) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine HCG)(k) 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
Guidance on avoidance of 
pregnancy 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
 


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Screening 
Period (a) 
Healing Phase 
Maintenance Phase 
Safety 
F/U 
(e) 
Un-
sched-
uled 
Visit (f) 
Timing 
Healing 
Day -1 
(b) 
Healing 
Day 1(b) 
Week 2 
(c) 
Healing 
Day 15 
Week 8 
(c,m) 
Healing 
Day 57 
Main 
Week 4 
Main Day 
29 
Main 
Week 12 
Main Day 
85 
Main 
Week 16 
Main Day 
113 
Main 
Week 20 
Main 
Day 141 
Main 
Week 24 
Main Day 169 
Final Visit/ET 
(d) 
Visit Windows (Days) 
Day-35 
to -2 
- 
 
12 to 18 
54 to 60 
26 to 36 
82 to 92 
110 to 120 
138 to 
148 
166 to 176 
- 
- 
Visit Number: 
1 
2 
 
3 
4 
M1 
M2 
M3 
M4 
M5 
F/U 
- 
Subject's diary; distribute and/or 
review(l) 
X(r) 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
 
PAGI-SYM 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
PAGI-QoL 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
EQ-5D-5L 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
Endoscopy 
X 
 
 
X 
X 
 
 
 
 
 
X 
 
 
Gastric biopsy(n) 
X 
 
 
 
X(s) 
 
 
 
 
 
X 
 
 
Randomization  
 
X 
 
X(o) 
X(o) 
 
 
 
 
 
 
 
 
Dispense study drug 
 
X(p) 
 
X(q) 
X(q) 
 
 
X 
 
 
 
 
 
First day of study drug 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Drug return/accountability/ review 
treatment compliance(q) 
 
 
 
X 
X 
 
X 
X 
 
 
X 
 
 
Phone call to subject 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
AE/pretreatment event assessment 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE, adverse events; CYP2C19, cytochrome P450 2C19; ECG, electrocardiogram; EQ-5D-5L, EuroQol-5 Dimensions-5 Levels; FSH, follicle-stimulating 
hormone; F/U, follow-up; HCG, human chorionic gonadotropin; HIV, human immunodeficiency virus; Main, maintenance; PAGI-SYM, Patient Assessment of 
Gastrointestinal Disorders-Symptoms Severity Index; PAGI-QoL, Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life; UBT, urea breath test 
(a)  Visit window is Day -35 to Day -2 for assessment of Helicobacter pylori, serum gastrin and pepsinogen I/II values, ECG, and endoscopy in the Screening Period. 
However, given the invasive nature of an endoscopy, any endoscopic confirmation performed in a routine clinical setting before informed consent signing which 
would have included standard of care gastric mucosa sampling, endoscopy images available for adjudication and done within 7 days of randomization/dosing is 
acceptable to use for the purpose of fulfilling the Screening requirement, and repeat endoscopic examination during the Screening Period will not be required. 
(b)  The date of randomization is defined as Day -1. The date of first dosing day is defined as Day 1 for both the Healing and Maintenance Phases. 
(c)  If the subject is confirmed as healed and rerandomized to the Maintenance Phase, this visit is considered the baseline visit for the Maintenance Phase, and subjects 
who prematurely discontinue from the Healing Phase or who are not healed at Week 8 should undergo Maintenance Phase Week 24/Final Visit/ET procedures 
(including gastric biopsy). 
(d)  For early discontinuations, the assessments mentioned for Week 24 are required to be performed. 
(e)  A safety follow-up visit is to be scheduled 4 weeks after the last dose of study drug administration. Subjects whose healing is not confirmed after Week 8 and who 
discontinued the study after the Healing Phase will undergo a safety follow-up visit 4 weeks after the last dose of study drug administration. 


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(f)  At an unscheduled visit, the following procedures are to be completed with additional procedures at the investigator’s discretion: a brief physical examination, vital 
sign measurements, concomitant medication assessment, and adverse event assessment. If the visit results in premature termination, then all procedures outlined for 
Maintenance Phase Week 24 /Final visit should be performed. 
(g)  Full physical examination is performed at baseline; a brief physical examination is performed at all other visits. 
(h)  If menopause is suspected. 
(i)  See Protocol Section 6.6 for all protocol-required laboratory assessments. 
(j)  Gastrin and pepsinogen I and II results will not be reported to investigative sites or other blinded personnel until the study blind is broken. 
(k)  Only female subjects with childbearing potential. 
(l)  Subjects should be instructed to complete the electronic diary every morning upon waking (for nighttime symptoms) and every evening before bedtime (for daytime 
symptoms) on each day of the study.  
(m)  Visit to be performed if not healed at Week 2. 
(n)  Four gastric mucosal biopsies (1 each from the greater and lesser curvature of the body and 1 each from the greater and lesser curvature of the antrum) should be 
obtained at each time point a gastric biopsy is done. 
(o)  Subjects with confirmed endoscopic healing at Week 2 or Week 8 will be rerandomized to the Maintenance Phase. 
(p)  Subjects are to start dose administration from Day 1. 
(q)  Subjects are to visit the study site without taking the study drug at Week 2 and Week 8 visits. For subjects without confirmed endoscopic healing of erosive 
esophagitis at Week 2, the daily dose of the study drug is to be administered after completion of assessments scheduled on that day. Subjects may need to return to 
the site a few days after Week 2 and Week 8 visits to receive a new allotment of study drug. No study procedures will be performed. 
(r)  Complete at least 7 days of diary during screening period. 
(s)  Only if EE not healed (follow Week 24 Final Visit/ET procedures). 
 
 


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13.2 
Imputation Rules for Missing Date Information 
13.2.1 
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 double-blind study drug, then the day and month of the date of the first dose of 
double-blind 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 
double-blind 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 
double-blind 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 double-blind study drug, then the day of the date of the first 
dose of double-blind 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 double-blind study drug 
or if both years are the same but the month is before the month of the date of the first 
dose of double-blind 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 double-blind study drug 
or if both years are the same but the month is after the month of the date of the first dose 
of double-blind study drug, then the first day of the month will be assigned to the missing 
day. 
 
13.2.2 
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 double-blind study drug is missing, then replace it with the last visit date. If the imputed 


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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. 
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 double-blind study drug, then the day and month of the date of the last dose of 
double-blind 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 
double-blind 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 
double-blind 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 double-blind study drug, then the day of the date of the last 
dose of double-blind 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 double-blind study drug 
or if both years are the same but the month is before the month of the date of the last dose 
of double-blind 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 double-blind study drug or if both 
years are the same but the month is after the month of the date of the last dose of double-
blind study drug, then the first day of the month will be assigned to the missing day. 
 
13.2.3 
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 13.2.1. Incomplete stop dates will not be imputed. 


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13.3 
LA Classification of Esophagitis Grading 
Table 4 
LA Grade Classification 
Grade A 
One or more mucosal breaks with a length of no longer than 5 mm that does 
not extend between the tops of 2 mucosal folds 
Grade B 
One or more mucosal breaks with a length of longer than 5 mm that does not 
extend between the tops of 2 mucosal folds 
Grade C 
One or more mucosal breaks that are continuous between the tops of 2 or 
more mucosal folds, which involves less than 75% of the circumference 
Grade D 
One or more mucosal breaks, which involves at least 75% of the 
circumference 
A mucosal break is defined as “an area of slough or erythema with a sharp line of demarcation from adjacent normal 
mucosa” 
 
13.4 
Symptom Diary 
13.4.1 
Data Handling for Subject Daily Diary 
Subjects will document the presence (yes/no) and maximum severity (1=Mild, 2=Moderate, 
3=Severe, or 4=Very Severe) of daytime and nighttime heartburn symptoms in their diary two 
times per day, once in the morning for nighttime heartburn and once in the evening for daytime 
heartburn. If the presence of heartburn is answered as “no” in a diary, the question of maximum 
severity will not be answered. In this situation, the maximum severity will be considered as 0 
(0=None) in the analysis. See Table 5 for details on definitions of heartburn severity. 
Table 5 
Definitions of Heartburn Severity (Daytime/Nighttime) 
Definitions of Daytime Heartburn Severity (Daytime=Awake Time) 
None - No heartburn 
Mild - Occasional heartburn, can be ignored, does not influence daily routine 
Moderate - Heartburn cannot be ignored and/or occasionally influences daily routine 
Severe - Heartburn present most of day and/or regularly influences daily routine 
Very Severe - Constant heartburn and/or markedly influences daily routine 
Definitions of Nighttime Heartburn Severity (Nighttime=Sleep Time) 
None - No heartburn 
Mild - Occasional heartburn, can be ignored, does not influence sleep 
Moderate - Heartburn cannot be ignored and/or occasionally influences sleep 
Severe - Heartburn present most of night and/or regularly influences sleep 
Very Severe - Constant heartburn and/or markedly influences sleep 
 
For analysis purposes, diary entries will be assigned to a study day based on the day the 
collection interval started for that entry. For example, the Day 1 diary entries will include the 


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evening diary completed on Day 1 (the collection interval started when the subject awoke on 
Day 1) and the morning entry completed on Day 2 (the collection interval started when the 
subject went to bed on Day 1).  
For each subject, the percentage of days with neither daytime nor nighttime heartburn during 
treatment will be calculated using all days with at least 1 morning or evening diary entry during 
the treatment period (Day 1 to the day of the last dose of study drug during the phase). For 
example, if a subject completed at least 1 diary entry on 44 of 50 days, but missed both entries 
on 6 days, 44 days will be used as the denominator in the analysis. All entries on that day will 
need to be heartburn-free in order for the day to be counted as a day with neither daytime nor 
nighttime heartburn. This will also apply when more than 2 diary entries are assigned to the same 
study day. 
If a subject has only one diary entry on a day and that entry does not indicate heartburn, the day 
will be considered heartburn-free for the analysis.  
Only evening diary entries will be used for assessing daytime heartburn and only morning diary 
entries will be used for assessing nighttime heartburn. For each phase, the mean severity of 
daytime and nighttime heartburn during treatment for each subject will be calculated by taking 
the mean of the average severity on all days with at least 1 morning or evening diary entry. For 
each day, the highest recorded severity will be determined separately for all morning diary 
entries and all evening diary entries. The average severity for the day will be determined by 
taking the mean of the highest recorded morning and evening diary entries on that day. These 
daily averages will then be averaged for all days with at least 1 morning or evening diary entry to 
obtain the endpoint value for each subject. 
The mean severity of daytime heartburn during treatment for each subject will be calculated by 
determining the highest recorded severity for all evening diary entries per day, then taking the 
mean of all days with at least 1 evening diary entry during that phase.  
The mean severity of nighttime heartburn during treatment for each subject will be calculated by 
determining the highest recorded severity for all morning diary entries per day, then taking the 
mean of all days with at least 1 morning diary entry during that phase. 
13.4.2 
Baseline Summary of Subject Diary 
For the Healing Phase, the baseline diary variables will be summarized using diaries from the 
last 7 days prior to Day-1, ie, Days -8 to -2, inclusive. Only days with at least 1 morning or 
evening diary entry during the specified days will be included in these summaries. 


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Summary statistics (n, mean, SD, minimum, 25th percentile, median, 75th percentile, and 
maximum) will be generated for the mean severity of daytime and nighttime heartburn, mean 
severity of daytime heartburn, and mean severity of nighttime heartburn. The number of days 
with daytime or nighttime heartburn, number of days with daytime heartburn, and number of 
days with nighttime heartburn will be summarized by treatment group in categories of (≥0 - ≤3, 
>3 - ≤5, >5 - ≤7).  
13.4.3 
Sustained Resolution of Heartburn 
Sustained resolution of heartburn will be defined as the first occurrence of 7 consecutive days 
with neither daytime nor nighttime heartburn during treatment. The time to sustained resolution 
of heartburn will be defined as the time from the first dose of study drug to the first day of the 
7 consecutive days.  
Subjects included in the analysis who do not achieve sustained resolution of heartburn will be 
censored on the first day of the last grouping of 7 consecutive days. For example, a subject 
whose last diary entries for 7 consecutive days during treatment correspond to Study Days 22 to 
28 and who does not achieve sustained resolution by that time will be censored as of Study 
Day 22.  
For the secondary endpoint of the percentage of subjects with onset of sustained resolution of 
heartburn by Day 3, subjects who do not have sustained resolution of heartburn for 7 consecutive 
days due to missing diary data will be considered as not having sustained resolution of heartburn.  
13.5 
PAGI-QOL and PAGI-SYM Scoring 
13.5.1 
PAGI-QOL 
The PAGI-QOL questionnaire includes questions that ask about how some of the gastrointestinal 
problems the subject may be experiencing may have affected his quality of life. The final version 
of the questionnaire consists of 30 items, each with response options based on a 6-point Likert 
scale and with a recall period of the previous 2 weeks. The items are grouped into 5 subscales 
and a total score, as described in the following table. 


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PAGI-QOL Subscale 
Description 
Location on  
PAGI-QOL eCRF 
Daily Activities 
10 items related to avoiding or 
having difficulties with daily 
activities 
Questions 1-10 
Clothing 
2 items, 1 related to feeling 
constricted and 1 related to 
frustration felt about not being able 
to dress as wanted 
Questions 11-12 
Diet and Food Habits 
7 items related to restrictions made and 
induced frustrations 
Questions 13-19 
Relationship 
3 items describing the impact of the 
disease on relationships with their 
partner, relatives, and friends 
Questions 20-22 
Psychological Well-being and 
Distress 
8 items describing disease impact on 
feelings or emotional state 
Questions 23-30 
PAGI-QOL Total Score 
Mean of PAGI-QOL Subscales 
Not applicable 
Each item is scored by the subject on a 6-point Likert scale: 0=None of the time, 1=A little of the time,
2=Some of the time, 3 = A good bit of the time, 4=Most of the time, and 5=All of the time. 
 
The subscales scores will be calculated by taking the mean of the non-missing items in each 
subscale after reversing the item scores. The subscale scores will range from 0 (lowest QOL) to 5 
(highest QOL). Missing data for the subscales will be handled using the half-scale rule, ie, a 
subscale score will be calculated when ≤50% of the items within a subscale are missing; if >50% 
of the items within a subscale are missing, the score will be set to missing. The PAGI-QOL total 
score will be calculated by taking the mean of the corresponding subscales. If any subscale 
scores are missing, the total score will be set to missing. 
Positive changes indicate improved quality of life.  
13.5.2 
PAGI-SYM 
The PAGI-SYM questionnaire includes questions that ask about the severity of symptoms the 
subject may have related to his gastrointestinal problem. The final version of the questionnaire 
consists of 20 items, each with response options based on a 6-point Likert scale and with a recall 
period of the previous 2 weeks. The items are grouped into 6 subscales and a total score, as 
described in the following table. 


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PAGI-SYM Subscale 
Description 
Location on  
PAGI-SYM eCRF 
Nausea/Vomiting 
3 items related to severity of nausea, 
retching, and vomiting 
Questions 1-3 
Fullness/Early Satiety 
4 items related to severity of stomach 
fullness, ability to finish a meal, feeling 
full after meals, and loss of appetite 
Questions 4-7 
Bloating 
2 items related to severity of bloating and 
stomach size 
Questions 8-9 
Upper Abdominal Pain 
2 items related to severity of upper 
abdominal pain and discomfort 
Questions 10-11 
Lower Abdominal Pain 
2 items related to severity of lower 
abdominal pain and discomfort 
Questions 12-13 
Heartburn/Regurgitation 
7 items related to severity of heartburn 
during the day and when lying down, 
discomfort inside chest during the day and 
at night, regurgitation during the day and 
when lying down, and bitter taste in mouth 
Questions 14-20 
PAGI-SYM Total Score 
Mean of PAGI-SYM Subscales 
Not applicable 
Each item is scored by the subject on a 6-point Likert scale: 0=None, 1=Very Mild, 2=Mild, 
3=Moderate, 4=Severe, and 5=Very Severe. 
 
The subscales scores will be calculated by taking the mean of the non-missing items in each 
subscale. The items will not be reversed scored prior to calculating the subscale score. The 
subscale scores will range from 0 (None) to 5 (Very Severe). Missing data for the subscales will 
be handled using the half-scale rule, i.e., a subscale score will be calculated when ≤50% of the 
items within a subscale are missing; if >50% of the items within a subscale are missing, the score 
will be set to missing. The PAGI-SYM total score will be calculated by taking the mean of the 
corresponding subscales. If any subscale scores are missing, the total score will be set to missing. 
Negative changes indicate improvement (decreased severity). 
 


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13.5.3 
EQ-5D-5L 
EQ-5D-5L descriptive system, may be converted into a single index value. The index values, 
presented in country specific value sets, are a major feature of the EQ-5D instrument, facilitating 
the calculation of quality-adjusted life years (QALYs) that are used to inform economic 
evaluations of health care interventions. By using the crosswalk link function of US value set for 
subjects in US and UK value set for subjects in Europe, and the individual responses to the 
EQ-5D-5L descriptive system, index values for the EQ-5D-5L can be calculated. Documents 
containing information on the crosswalk project, tables of values for all 3125 health states and 
the ‘EQ-5D-5L Crosswalk Index Value Calculator’ can be downloaded from the EuroQol 
website. EQ-5D-5L Index score is on a scale from 0 (worst imaginable health state) to 1 (best 
imaginable health state).


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13.6 
Estimands and Sensitivity Analysis 
Estimands and Sensitivity Analysis for the Healing Phase and Maintenance Phase are summarized in the following tables. 
13.6.1 
Healing Phase 
13.6.1.1 
Intercurrent Event Types  
Table 6 
Intercurrent Event Types 
Label 
Intercurrent Event Type 
IcEv1 
(Discontinuation) 
Discontinuation of treatment prior to completing the Healing Phase[1]   
IcEv2 
(Prohibited EE Medication[2]) 
PPI or H2 receptor antagonist taken during the Healing Phase (whether taken directly for EE or a different 
condition) 
IcEv3 
(Treatment Non-compliance) 
Treatment compliance (%) is defined as (total actual capsules taken / total expected capsules) × 100 in range of 
80%-120% during the Healing Phase. Total expected tablets vary according to the timing of the endoscopy 
confirming the end of Healing Phase.  
IcEv4 
(COVID-19 Impacts) 
Unable to perform endoscopy assessment due to COVID-19 related reasons. 
Abbreviation: EE, Erosive Esophagitis; IcEv, intercurrent event; PPI, proton pump inhibitor 
Notes:  
[1] Healing Phase can be completed at Week 2 or Unscheduled Visit (prior to Week 8) if there is absence of EE in endoscopy (confirmed healed status) 
but otherwise completes at Week 8. 
[2] Other major protocol deviations that impact efficacy will be reviewed prior to breaking the blind and will be considered in the same manner as 
prohibited EE medication.  
 


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13.6.1.2 
Estimand Specification 
Table 7 
Objectives, Endpoints, and Estimands 
Objective 
Estimand Label 
Endpoint 
Estimand Description 
To assess the efficacy of 
vonoprazan (20 mg QD) 
compared to lansoprazole 
(30 mg QD) in healing 
of EE over 8 weeks in 
subjects with 
endoscopically proven EE. 
Estimand 1 
(Primary) 
The percentage of subjects who have 
complete healing of EE by Week 8 as 
assessed by endoscopy 
Difference between treatments (vonoprazan 20 mg – 
lansoprazole 30 mg) in rates of EE healing by Week 8 in patients 
with endoscopically proven EE irrespective of whether they fully 
adhere to the treatment schedule or take prohibited EE 
medications (PPIs and H2 receptor antagonists). 
 
As above with further detail 
given in estimand 
description. 
Estimand 2 
(Composite - 
Supportive) 
Percentage of subjects with effective 
treatment defined as complete healing of 
EE by Week 8 as assessed by endoscopy 
and completed treatment with 80% -120% 
compliance and without intake of 
prohibited EE medications during the 
Healing Phase. 
Difference between treatments (vonoprazan 20 mg – 
lansoprazole 30 mg) in the effectiveness rates of treatment by 
Week 8 in patients with endoscopically proven EE where 
treatment effectiveness for EE healing requires that the patient 
has  
• 
EE healed by Week 8; and 
• 
completed treatment with 80%-120% compliance; and 
• 
no intake of prohibited EE medications (PPIs and H2 
receptor antagonists). 
Otherwise, the treatment effectiveness for EE healing failed.  
As above with further detail 
given in estimand 
description. 
Estimand 3 
(Hypothetical-
Supplementary) 
Percentage of subjects who have complete 
healing of EE by Week 8 as assessed by 
endoscopy 
Difference between treatments (vonoprazan 20 mg – 
lansoprazole 30 mg) in rates of EE healing by Week 8 in patients 
with endoscopically proven EE assuming the hypothetical 
situation that they complete treatment during the Healing Phase 
with 80%-120% compliance and no intake of prohibited EE 
medications (PPIs and H2 receptor antagonists). 
Abbreviations: EE, Erosive Esophagitis; PPI, proton pump inhibitor. 
 
 


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Table 8 
Summary of Estimands and Strategies for Managing Intercurrent Events 
Estimand Label 
Estimand 1 (Primary) 
Estimand 2 (Composite - Supportive) 
Estimand 3 (Hypothetical-
Supplementary) 
Estimand Description 
Difference between treatments (vonoprazan 
20 mg – lansoprazole 30 mg) in rates of EE 
healing by Week 8 in patients with 
endoscopically proven EE irrespective of 
whether they fully adhere to the treatment 
schedule or take prohibited EE medications 
(PPIs and H2 receptor antagonists). 
 
Difference between treatments 
(vonoprazan 20 mg – lansoprazole 
30 mg) in the effectiveness rates of 
treatment by Week 8 in patients with 
endoscopically proven EE where 
treatment effectiveness for EE healing 
requires that the patient has  
• 
EE healed by Week 8; and 
• 
completed treatment with 80%-
120% compliance; and 
• 
no intake of prohibited EE 
medications (PPIs and H2 
receptor antagonists).  
Otherwise, the treatment effectiveness for 
EE healing failed. 
Difference between treatments 
(vonoprazan 20 mg – lansoprazole 
30 mg) in rates of EE healing by Week 8 
in patients with endoscopically proven 
EE assuming the hypothetical situation 
that they complete treatment during the 
Healing Phase with 80%-120% 
compliance and no intake of prohibited 
EE medications (PPIs and H2 receptor 
antagonists). 
Target Population 
Patients with endoscopically proven EE (all 
Grades A-D) who would meet the 
inclusion/exclusion criteria of the study.   
Patients with endoscopically proven EE 
(all Grades A-D) who would meet the 
inclusion/exclusion criteria of the study.   
Patients with endoscopically proven EE 
(all Grades A-D) who would meet the 
inclusion/exclusion criteria of the study.   
 
 
 


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Table 8 
Summary of Estimands and Strategies for Managing Intercurrent Events (continued) 
Estimand Label 
Estimand 1 (Primary) 
Estimand 2 (Composite - Supportive) 
Estimand 3 (Hypothetical-
Supplementary) 
Variable (measured on 
individual and defined as 
endpoint in ICH E9[R1]) 
EE Healing status (“healed” or “not 
healed”); taken as “healed” if there is an 
absence of EE in a centrally adjudicated 
endoscopy at Week 2, an unscheduled visit 
between Week 2 and Week 8, or at Week 
8.   
Treatment effectiveness for EE healing 
(success/failure) where failure is defined 
if  
• 
EE present at Week 8 as 
assessed by central adjudication 
of endoscopy; or 
• 
Healing Phase treatment 
discontinued; or 
• 
Healing Phase treatment 
compliance < 80% or >120%; or 
• 
Intake of prohibited EE 
medications (PPIs and H2 
receptor antagonists).   
Conversely, success requires EE healing 
status result of healed, completed 
treatment with 80% -120% compliance 
and without intake of prohibited EE 
medications during the Healing Phase. 
EE Healing status (“healed” or “not 
healed”); taken as “healed” if there is an 
absence of EE in a centrally adjudicated 
endoscopy at Week 2, an unscheduled 
visit between Week 2 and Week 8, or at 
Week 8.   
Endpoint  
 
Percentage of subjects who have complete 
healing of EE by Week 8 as assessed by 
endoscopy. 
Percentage of subjects with effective 
treatment defined as complete healing of 
EE by Week 8 as assessed by endoscopy 
and completed treatment with 80% -
120% compliance and without intake of 
prohibited EE medications during the 
Healing Phase. 
Percentage of subjects who have 
complete healing of EE by Week 8 as 
assessed by endoscopy. 
Treatment Condition(s) 
Experimental: Vonoprazan 20 mg 
Reference: Lansoprazole 30 mg 
Experimental: Vonoprazan 20 mg 
Reference: Lansoprazole 30 mg 
Experimental: Vonoprazan 20 mg 
Reference: Lansoprazole 30 mg 
Population-Level 
Summary 
Difference in EE healing rates. 
Difference in treatment effectiveness for 
EE healing rates 
Difference in EE healing rates. 


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Table 8 
Summary of Estimands and Strategies for Managing Intercurrent Events (continued) 
Estimand Label 
Estimand 1 (Primary) 
Estimand 2 (Composite - Supportive) 
Estimand 3 (Hypothetical-
Supplementary) 
Intercurrent Event 
Strategy  
 
 
 
IcEv1 (Discontinuation) 
Composite 
Composite  
Hypothetical  
IcEv2 (Prohibited EE 
Medication) 
Treatment policy 
Composite  
Hypothetical  
IcEv3 (Treatment Non-
compliance) 
Treatment policy 
Composite 
Hypothetical  
IcEv4 (COVID-10 
Impacts) 
Hypothetical 
Hypothetical 
Hypothetical 
Rationale for Strategies 
Treatment policy strategy is used to understand the treatment effect in the Healing Phase irrespective of all intercurrent events in 
Table 6 as this reflects what might happen in clinical practice. Every attempt is taken to measure the healing status by Week 8 
(regardless of prior treatment discontinuation or use of prohibited EE medications).  
 
Composite policy is used to understand treatment effectiveness where the decision of the patient to not comply with the treatment 
schedule or feel the need for additional (prohibited) EE medication is taken as failure.   
 
Hypothetical policy is used to estimate a treatment effect that is attributable to the difference between the treatments when taken as 
indicated without interference from prohibited EE medications. Given the non-inferiority hypothesis this approach has generally 
higher sensitivity to pick up an inferior treatment.  
 
Abbreviation: EE, Erosive Esophagitis; IcEv, intercurrent event; PPI, proton pump inhibitor 
Non-compliance is defined as <80% or >120% of expected doses administered during the Healing Phase where expected number of doses is dependent 
on time of progression to the Maintenance Phase. 
Note that on completing the Healing Phase (up to Week 8), patients may progress to the Maintenance Phase. 
 
 


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13.6.1.3 
Statistical Methods and Sensitivity Analyses 
Table 9 
Summary of Statistical Methods and Sensitivity Analyses 
Estimand Label 
Estimand Description 
Main Estimation 
Sensitivity/Supportive Analyses 
Analysis 
Set 
Imputation/Data/Censoring 
Rules 
Analysis Model/Method 
Estimand 1 
(Primary) 
Difference between 
treatments (vonoprazan 
20 mg – lansoprazole 30 mg) 
in rates of EE healing by 
Week 8 in patients with 
endoscopically proven EE 
irrespective of whether they 
fully adhere to the treatment 
schedule or take prohibited 
EE medications (PPIs and 
H2 receptor antagonists). 
 
MITT[1] 
Where subjects have missing EE 
healing data due to reasons not 
related to COVID-19 (perhaps 
due to loss to follow up or 
withdrawing consent for 
endoscopy), the healing status 
will be imputed as “non-
responder” (single imputation 
method known as non-responder 
imputation [NRI]). 
Where subjects have missing EE 
healing data due to reasons 
related to COVID-19, multiple 
imputation (MI) under missing 
at random (MAR) assumption 
will be utilized. The multiply 
imputed values of LA 
classification grade at Week 2 or 
8 will be used to derive the 
missing EE healing status. 
 
Farrington and Manning test 
with a non-inferiority margin 
of 10% for the difference in 
EE healing rates by Week 8 
between treatments 
(vonoprazan 20 mg - 
lansoprazole 30 mg). The 
point estimate and 2-sided 
95% CI of the difference in 
EE healing rate between 
vonoprazan 20 mg and 
lansoprazole 30 mg will be 
calculated via the Miettinen 
and Nurminen method. 
1. 
Tipping point for NRI (Sensitivity). 
2. 
Same as primary analysis on observed 
data only (Sensitivity). 
3. 
Multiple imputation (MI) under 
missing at random (MAR) assumption 
followed by calculation of difference 
in EE healing rate with 95% 
CI(Sensitivity) using Rubin’s Method.  
 
Healing Phase treatment and the LA 
classification grade at screening 
(A/B/C/D), Week 2 (Healed/A/B/C/D) 
will be used as variables in the 
multiple imputation model. The 
multiply imputed values of LA 
classification grade at Week 2 or 8 will 
be used to derive the missing EE 
healing status. 
4. 
Per-protocol analysis per the SAP 
(Supportive).  
 


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Table 9 
Summary of Statistical Methods and Sensitivity Analyses (continued) 
Estimand Label 
Estimand Description 
Main Estimation 
Sensitivity/Supportive Analyses 
Analysis 
Set 
Imputation/Data/Censoring 
Rules 
Analysis Model/Method 
Estimand 2 
(Composite - 
Supportive) 
Difference between 
treatments (vonoprazan 20 
mg – lansoprazole 30 mg) in 
the effectiveness rates of 
treatment by Week 8 in 
patients with endoscopically 
proven EE where treatment 
effectiveness for EE healing 
requires that the patient has  
• 
EE healed by Week 
8; and 
• 
completed 
treatment with 80% 
-120% compliance; 
and 
• 
no intake of 
prohibited EE 
medications (PPIs 
and H2 receptor 
antagonists). 
Otherwise, the treatment 
effectiveness for EE healing 
failed.  
Subjects who do not have 
endoscopy performed by 
Week 8 due to COVID-19 
related reasons will be 
imputed. 
MITT[1] 
The same MI model output 
generated above for Estimand 1 
will be utilized. The multiply 
imputed values of LA 
classification grade at Week 2 or 
8 will be used to derive the 
missing EE healing status. LA 
classification grade combined 
with treatment discontinuation, 
compliance and prohibited EE 
medication data will generate the 
composite treatment 
effectiveness endpoint. 
 
The same analysis as for 
Estimand 1. 
Not required as this is itself a supportive 
analysis and due to the composite definition, 
there should be only minimal missing data 
for this treatment effectiveness endpoint with 
the main reason being subjects withdrawing 
consent for endoscopy. Thus, the missing at 
random (MAR) assumption should be 
reasonable.  
 
 


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Table 9 
Summary of Statistical Methods and Sensitivity Analyses (continued) 
Estimand Label 
Estimand Description 
Main Estimation 
Sensitivity/Supportive Analyses 
Analysis 
Set 
Imputation/Data/Censoring 
Rules 
Analysis Model/Method 
Estimand 3 
(Hypothetical - 
Supplementary) 
Difference between 
treatments (vonoprazan 
20 mg – lansoprazole 30 mg) 
in rates of EE healing by 
Week 8 in patients with 
endoscopically proven EE 
assuming the hypothetical 
situation that they complete 
treatment during the Healing 
Phase with 80%-120% 
compliance and no intake of 
prohibited EE medications 
(PPIs and H2 receptor 
antagonists). 
MITT[1] 
Create a flag to exclude data 
after intercurrent events. 
Then, using the same type of MI 
model as used in Estimand 1 
sensitivity analysis, impute 
missing values of LA 
classification grade at Week 2 or 
8 which will be used to derive 
the missing EE healing status. 
Same as primary analysis on 
the MI imputed data. 
 
 
Abbreviations: ITT, intent-to-treat; NRI, non-responder imputation; MI, multiple imputation; MAR, missing at random; MITT, modified intent-to-treat.  
[1] The MITT set for the Healing Phase will be defined as all subjects randomized into the Healing Phase who have documented EE at baseline and 
receive at least 1 dose of study drug during the Healing Phase. All analyses using the MITT set will group subjects according to the randomized 
treatment. 
 
 


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13.6.2 
Maintenance Phase 
13.6.2.1 
Intercurrent Event Types  
Table 10 
Intercurrent Event Types 
Label 
Intercurrent Event Type 
IcEv1 
(Discontinuation) 
Discontinuation of maintenance treatment prior to completing 24 weeks Maintenance Phase.  
IcEv2 
(Prohibited EE Medication[1]) 
PPI or H2 receptor antagonist taken during the Maintenance Phase (whether taken directly for EE or a different 
condition) 
IcEv3 
(Treatment Non-compliance) 
Treatment compliance (%) is defined as (total actual capsules taken / total expected capsules) × 100 in range of 
80%-120% during the Maintenance Phase.   
IcEv4 
(COVID-19 Impacts) 
Unable to perform endoscopy assessment due to COVID-19 related reasons. 
Abbreviation: EE, Erosive Esophagitis; IcEv, intercurrent event; PPI, proton pump inhibitor 
Notes:  
 [1] Other major protocol deviations that impact efficacy will be reviewed prior to breaking the blind and will be considered in the same manner as 
prohibited EE medication.  
 
 


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13.6.2.2 
Estimand Specification 
Table 11 
Objectives, Endpoints, and Estimands 
Objective 
Estimand Label 
Endpoint 
Estimand Description 
To assess the efficacy of 
vonoprazan (10 or 20 mg 
QD) compared to 
lansoprazole (15 mg QD) in 
maintenance of healing 
of EE over 24 weeks in 
subjects with 
endoscopically proven EE. 
Estimand 1 
(Primary) 
Percentage of subjects who maintain 
complete healing of EE after24 Weeks as 
assessed by endoscopy 
Difference between maintenance treatments (vonoprazan 10 or 
20 mg – lansoprazole 15 mg) in rates of maintained EE healing 
up to Week 24 in patients healed from an episode of 
endoscopically proven EE irrespective of whether they fully 
adhere to the maintenance treatment schedule or take prohibited 
EE medications (PPIs and H2 receptor antagonists). 
 
As above with further detail 
given in estimand 
description. 
Estimand 2 
(Composite - 
Supportive) 
Percentage of subjects with effective 
maintenance treatment defined as 
maintenance of complete healing of EE up 
to Week 24 as assessed by endoscopy and 
completed maintenance treatment with 
80% -120% compliance and without intake 
of prohibited EE medications during the 
Maintenance Phase. 
Difference between maintenance treatments (vonoprazan 10 or 
20 mg – lansoprazole 15 mg) in the effectiveness rates of 
maintenance treatment up to Week 24 in patients healed from an 
episode of endoscopically proven EE where maintenance 
treatment effectiveness requires that the patient has  
• 
Maintained complete EE healing up to Week 24; and 
• 
completed 24 weeks of maintenance treatment with 
80%-120% compliance; and 
• 
no intake of prohibited EE medications (PPIs and H2 
receptor antagonists). 
Otherwise, the maintenance treatment effectiveness failed.  
As above with further detail 
given in estimand 
description. 
Estimand 3 
(Hypothetical-
Supplementary) 
Percentage of subjects who maintain 
complete healing of EE after 24 Weeks as 
assessed by endoscopy 
 
Difference between maintenance treatments (vonoprazan 10 or 
20 mg – lansoprazole 15 mg) in rates of maintained EE healing 
up to Week 24 in patients healed from an episode of 
endoscopically proven EE assuming the hypothetical situation 
that they complete 24 weeks of maintenance treatment with 80%-
120% compliance and no intake of prohibited EE medications 
(PPIs and H2 receptor antagonists). 
Abbreviations: EE, Erosive Esophagitis; PPI, proton pump inhibitor. 
 


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Table 12 
Summary of Estimands and Strategies for Managing Intercurrent Events 
Estimand Label 
Estimand 1 (Primary) 
Estimand 2 (Composite - 
Supportive) 
Estimand 3 (Hypothetical-
Supplementary) 
Estimand Description 
Difference between maintenance 
treatments (vonoprazan 10 or 20 mg 
– lansoprazole 15 mg) in rates of 
maintained EE healing up to Week 24 
in patients who have healed from an 
episode of endoscopically proven EE 
irrespective of whether they fully 
adhere to the maintenance treatment 
schedule or take prohibited EE 
medications (PPIs and H2 receptor 
antagonists). 
 
Difference between maintenance 
treatments (vonoprazan 10 or 20 mg 
– lansoprazole 15 mg) in the 
effectiveness rates of maintenance 
treatment up to Week 24 in patients 
healed from an episode of 
endoscopically proven EE where 
maintenance treatment effectiveness 
requires that the patient has  
• 
maintained complete EE 
healing up to Week 24; and 
• 
completed 24 weeks of 
maintenance treatment with 
80%-120% compliance; and 
• 
no intake of prohibited EE 
medications (PPIs and H2 
receptor antagonists).  
Otherwise, the maintenance treatment 
effectiveness failed. 
Difference between maintenance 
treatments (vonoprazan 10 or 20 mg 
– lansoprazole 15 mg) in rates of 
maintained EE healing up to Week 24 
in patients healed from an episode of 
endoscopically proven EE assuming 
the hypothetical situation that they 
complete 24 weeks of maintenance 
treatment with 80%-120% 
compliance and no intake of 
prohibited EE medications (PPIs and 
H2 receptor antagonists). 
Target Population 
Patients who have a confirmed 
absence of EE having been healed 
from an episode of endoscopically 
proven EE (all Grades A-D) and 
would meet the inclusion/exclusion 
criteria of the study and be willing to 
continue directly from healing 
therapy to maintenance therapy.   
Patients who have a confirmed 
absence of EE having been healed 
from an episode of endoscopically 
proven EE (all Grades A-D) who 
would meet the inclusion/exclusion 
criteria of the study and be willing to 
continue directly from healing 
therapy to maintenance therapy.   
Patients who have a confirmed 
absence of EE having been healed 
from an episode of endoscopically 
proven EE (all Grades A-D) who 
would meet the inclusion/exclusion 
criteria of the study and be willing to 
continue directly from healing 
therapy to maintenance therapy.   
 
 


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Table 12 
Summary of Estimands and Strategies for Managing Intercurrent Events (continued) 
Estimand Label 
Estimand 1 (Primary) 
Estimand 2 (Composite - 
Supportive) 
Estimand 3 (Hypothetical-
Supplementary) 
Variable (measured on 
individual and defined as 
endpoint in ICH E9[R1]) 
Maintenance of EE healing up to 
Week 24 status (“healing maintained” 
or “recurrence”); taken as “healing 
maintained” if there is an absence of 
EE in a centrally adjudicated 
endoscopy at Week 24.  
Maintenance of EE healing treatment 
effectiveness (success/failure) where 
failure is defined if  
• 
EE recurrence is present by 
Week 24 as assessed by 
endoscopy; or 
• 
Maintenance Phase 
treatment discontinued; or 
• 
Maintenance Phase 
treatment compliance < 80% 
or >120%; or 
• 
Intake of prohibited EE 
medications (PPIs and H2 
receptor antagonists).   
Conversely, success requires EE 
healing maintained up to Week 24, 
completed 24 weeks of maintenance 
treatment with 80% -120% 
compliance and without intake of 
prohibited EE medications during the 
Maintenance Phase. 
Maintenance of EE healing up to 
Week 24 status (“healing maintained” 
or “recurrence”); taken as “healing 
maintained” if there is an absence of 
EE in a centrally adjudicated 
endoscopy at Week 24.  
Endpoint  
 
Percentage of subjects who maintain 
complete healing of EE after 24 
weeks as assessed by endoscopy 
 
Percentage of subjects with effective 
maintenance treatment defined as 
maintenance of complete healing of 
EE up to Week 24 as assessed by 
endoscopy and completed 
maintenance treatment with 80% -
120% compliance and without intake 
of prohibited EE medications during 
the Maintenance Phase. 
Percentage of subjects who maintain 
complete healing of EE after 24 
weeks as assessed by endoscopy 
 


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Table 12 
Summary of Estimands and Strategies for Managing Intercurrent Events (continued) 
Estimand Label 
Estimand 1 (Primary) 
Estimand 2 (Composite - 
Supportive) 
Estimand 3 (Hypothetical-
Supplementary) 
Treatment Condition(s) 
Experimental: Vonoprazan 10 mg, 
Vonoprazan 20 mg 
Reference: Lansoprazole 15 mg 
Experimental: Vonoprazan 10, 
Vonoprazan 20 mg 
Reference: Lansoprazole 15 mg 
Experimental: Vonoprazan 10 mg, 
Vonoprazan 20 mg 
Reference: Lansoprazole 15 mg 
Population-Level 
Summary 
Difference in maintained EE healing 
rates. 
Difference in maintenance treatment 
effectiveness rates 
Difference in maintained EE healing 
rates. 
Intercurrent Event 
Strategy  
 
 
 
IcEv1 (Discontinuation) 
Composite 
Composite  
Hypothetical  
IcEv2 (Prohibited EE 
Medication) 
Treatment policy 
Composite  
Hypothetical  
IcEv3 (Treatment Non-
compliance) 
Treatment policy 
Composite 
Hypothetical  
IcEv4 (COVID-10 
Impacts) 
Hypothetical 
Hypothetical 
Hypothetical 
Rationale for Strategies 
Treatment policy strategy is used to understand the treatment effect in the Maintenance Phase irrespective of all intercurrent events 
in Table 10 as this reflects what might happen in clinical practice. Every attempt is taken to measure the healing status at Week 24 
(regardless of maintenance treatment discontinuation or use of prohibited EE medications).  
 
Composite policy is used to understand maintenance treatment effectiveness where the decision of the patient to not comply with the 
maintenance treatment schedule or feel the need for additional (prohibited) EE medication is taken as failure.   
 
Hypothetical policy is used to estimate a treatment effect that is attributable to the difference between the maintenance treatments 
when taken as indicated without interference from prohibited EE medications. Given the non-inferiority hypothesis this approach 
has generally higher sensitivity to pick up an inferior treatment.  
 
 
Abbreviation: EE, Erosive Esophagitis; IcEv, intercurrent event; PPI, proton pump inhibitor 
Non-compliance is defined as <80% or >120% of expected doses administered during the maintenance phase. 


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13.6.2.3 
Statistical Methods and Sensitivity Analyses 
Table 13 
Summary of Statistical Methods and Sensitivity Analyses 
Estimand Label 
Estimand Description 
Main Estimation 
Sensitivity/Supportive Analyses 
Analysis 
Set 
Imputation/Data/Censoring 
Rules 
Analysis 
Model/Method 
Estimand 1 
(Primary) 
Difference between 
maintenance treatments 
(vonoprazan 10 or 20 mg – 
lansoprazole 15 mg) in 
rates of maintained EE 
healing up to Week 24 in 
patients healed from an 
episode of endoscopically 
proven EE irrespective of 
whether they fully adhere 
to the treatment schedule 
or take prohibited EE 
medications (PPIs and H2 
receptor antagonists). 
 
MITT[1] 
Where subjects have missing 
EE healing data due to 
reasons not related to 
COVID-19 (perhaps due to 
loss to follow up or 
withdrawing consent for 
endoscopy), the EE healing 
maintenance will be imputed 
as “non-
responder/recurrence” (single 
imputation method known as 
non-responder imputation 
[NRI]). 
Where subjects have missing 
EE healing data due to 
reasons related to COVID-19, 
multiple imputation (MI) 
under missing at random 
(MAR) assumption will be 
utilized. The multiply 
imputed values of LA 
classification grade at Week 
24 will be used to derive the 
missing EE maintenance 
status. 
 
Farrington and 
Manning test with a 
non-inferiority margin 
of 10% for the 
difference in 
maintenance of EE 
healing rates up to 
Week 24 between 
treatments [each dose 
of vonoprazan (10 or 
20 mg) - lansoprazole 
15 mg)]. The point 
estimates and 2-sided 
95% CI of the 
differences in 
maintenance of EE 
healing rates between 
each dose of 
vonoprazan (10 or 
20 mg) and 
lansoprazole 15 mg 
will be calculated via 
the Miettinen and 
Nurminen method. 
1. Tipping point for NRI 
(Sensitivity). 
2. Same as primary analysis on 
observed data only (Sensitivity). 
3. Multiple imputation (MI) under 
missing at random (MAR) 
assumption followed by 
calculation of difference in 
maintenance of EE healing rate 
with 95% CI (Sensitivity) using 
Rubin’s Method.  
Maintenance Phase treatment and 
the LA classification grade at 
screening (A/B/C/D) will be used 
as variables in the multiple 
imputation model. The multiply 
imputed values of LA 
classification grade at Week 24 
will be used to derive the missing 
maintenance of EE healing status.  
4. Per-protocol analysis per the SAP 
(Supportive).  
 
 


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Table 13 
Summary of Statistical Methods and Sensitivity Analyses (continued) 
Estimand Label 
Estimand Description 
Main Estimation 
Sensitivity/Supportive Analyses 
Analysis 
Set 
Imputation/Data/Censoring 
Rules 
Analysis 
Model/Method 
Estimand 2 
(Composite - 
Supportive) 
Difference between 
maintenance treatments 
(vonoprazan 10 or 20 mg – 
lansoprazole 15 mg) in the 
effectiveness rates of 
maintenance treatment up to 
Week 24 in patients healed 
from an episode of 
endoscopically proven EE 
where maintenance treatment 
effectiveness requires that the 
patient has  
• Maintained EE healing 
up to Week 24; and 
• completed 24 weeks of 
maintenance treatment 
with 80% -120% 
compliance; and 
• no intake of prohibited 
EE medications (PPIs 
and H2 receptor 
antagonists). 
Otherwise, the maintenance 
treatment effectiveness failed. 
Subjects who do not have 
endoscopy performed by 
Week 24 due to COVID-19 
related reasons will be 
imputed. 
MITT[1] 
The same MI model output 
generated above for Estimand 1 
will be utilized. The multiply 
imputed values of LA 
classification grade at Week 24 
will be used to derive the missing 
EE healing maintenance. LA 
classification grade combined 
with maintenance treatment 
discontinuation, compliance and 
prohibited EE medication data 
will generate the composite 
maintenance treatment 
effectiveness endpoint. 
 
The same analysis as for 
Estimand 1. 
Not required as this is itself a supportive 
analysis and due to the composite definition, 
there should be only minimal missing data for 
this treatment effectiveness endpoint with the 
main reason being subjects withdrawing consent 
for endoscopy. Thus, the missing at random 
(MAR) assumption should be reasonable.  
 
 
 


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Table 13 
Summary of Statistical Methods and Sensitivity Analyses (continued) 
Estimand Label 
Estimand Description 
Main Estimation 
Sensitivity/Supportive Analyses 
Analysis 
Set 
Imputation/Data/Censoring 
Rules 
Analysis 
Model/Method 
Estimand 3 
(Hypothetical - 
Supplementary) 
Difference between 
maintenance treatments 
(vonoprazan 10 or 20 mg – 
lansoprazole 15 mg) in 
rates of maintained EE 
healing up to Week 24 in 
patients   healed from an 
episode of endoscopically 
proven EE assuming the 
hypothetical situation that 
they complete 24 weeks of 
maintenance treatment 
with 80%-120% 
compliance and no intake 
of prohibited EE 
medications (PPIs and H2 
receptor antagonists). 
MITT[1] 
Create a flag to exclude data 
after intercurrent events. 
Then, using the same type of 
MI model as used in 
Estimand 1 sensitivity 
analysis, impute missing 
values of LA classification 
grade at Week 24 which will 
be used to derive the missing 
maintenance of EE healing 
status. 
Same as primary 
analysis on the MI 
imputed data. 
 
 
 
Abbreviations: ITT, intent-to-treat; NRI, non-responder imputation; MI, multiple imputation; MAR, missing at random; MITT, modified intent-to-treat.  
[1] The MITT set for the Maintenance Phase will be defined as all subjects randomized into the Maintenance Phase who have healed EE at the end of 
the Healing Phase and receive at least 1 dose of study drug during the Maintenance Phase. All analyses using the MITT set will group subjects 
according to the randomized treatment.