Clinical trial NCT04799158
Conditions: Non-Erosive Gastro-Esophageal Reflux Disease Heartburn
Keywords: Symptomatic Non-Erosive Gastroesophageal Reflux Disease NERD Vonoprazan Heartburn
Sponsor: Phathom Pharmaceuticals, Inc.
Start date: 2021-03-25; Completion date: 2022-01-17
Enrollment: 458 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to assess the efficacy of vonoprazan (10 mg, 20 mg, and 40 mg On-Demand) compared to placebo (On-Demand) in relief of episodic heartburn over 6 weeks in participants with symptomatic non-erosive gastroesophageal reflux disease (NERD), and to assess the safety of vonoprazan (10 mg, 20 mg, and 40 mg On-Demand) compared to placebo (On-Demand) in participants with symptomatic NERD.

Detailed description:

Arms: arm 1: Participants will receive vonoprazan 20 mg once daily for up to 4 weeks. arm 2: Participants who have stable disease (no heartburn on the last 7 days of the Run-In Period) will take vonoprazan 10 mg when heartburn occurs during the 6 week On-Demand Treatment Period. Participants can take no more than one dose in a 24 hour period. arm 3: Participants who have stable disease (no heartburn on the last 7 days of the Run-In Period) will take vonoprazan 20 mg when heartburn occurs during the 6 week On-Demand Treatment Period. Participants can take no more than one dose in a 24 hour period. arm 4: Participants who have stable disease (no heartburn on the last 7 days of the Run-In Period) will take vonoprazan 40 mg when heartburn occurs during the 6 week On-Demand Treatment Period. Participants can take no more than one dose in a 24 hour period. arm 5: Participants who have stable disease (no heartburn on the last 7 days of the Run-In Period) will take a placebo when heartburn occurs during the 6 week On-Demand Treatment Period. Participants can take no more than one dose in a 24 hour period.
Interventions: intervention 1: Vonoprazan intervention 2: Placebo
Intervention descriptions: intervention 1: Orally via capsules intervention 2: Orally via capsules

Protocol documents:
Prot_000.pdf: 
Protocol Number: NERD-201 
Official Title: A Phase 2, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and 
Safety of Vonoprazan 10 mg, 20 mg, and 40 mg Compared to Placebo for Relief of Episodic 
Heartburn in Subjects with Symptomatic Non-Erosive Gastroesophageal Reflux Disease  
Document Date: 16 July 2021 
NCT Number: NCT04799158 
 




Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
16 July 2021 
Page 2 
Protocol Approval – Sponsor Signatory 
Study Title 
A Phase 2, Randomized, Double-Blind, Multicenter Study to Evaluate 
the Efficacy and Safety of Vonoprazan 10 mg, 20 mg, and 40 mg 
Compared to Placebo for Relief of Episodic Heartburn in Subjects 
with Symptomatic Non-Erosive Gastroesophageal Reflux Disease 
Protocol Number NERD-201 
Protocol Version 
and Date 
Version 2.0, Amendment 1 
16 July 2021 
Protocol accepted and approved by: 
Vice President Clinical and Patient Safety 
 
 
 
 
 
 
 
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Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
16 July 2021 
Page 3 
Protocol Approval – Sponsor Signatory 
Study Title 
A Phase 2, Randomized, Double-Blind, Multicenter Study to Evaluate 
the Efficacy and Safety of Vonoprazan 10 mg, 20 mg, and 40 mg 
Compared to Placebo for Relief of Episodic Heartburn in Subjects 
with Symptomatic Non-Erosive Gastroesophageal Reflux Disease 
Protocol Number NERD-201 
Protocol Version 
and Date 
Version 2.0, Amendment 1 
16 July 2021 
Protocol accepted and approved by: 
Chief Operating Officer 
 
 
 
 
 
 
 
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Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
16 July 2021 
Page 4 
Protocol Approval – Sponsor Signatory 
Study Title 
A Phase 2, Randomized, Double-Blind, Multicenter Study to Evaluate 
the Efficacy and Safety of Vonoprazan 10 mg, 20 mg, and 40 mg 
Compared to Placebo for Relief of Episodic Heartburn in Subjects 
with Symptomatic Non-Erosive Gastroesophageal Reflux Disease 
Protocol Number NERD-201 
Protocol Version 
and Date 
Version 2.0, Amendment 1 
16 July 2021 
Protocol accepted and approved by: 
Chief Medical Officer 
 
 
 
 
 
 
 
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Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
16 July 2021 
Page 5 
Protocol Approval – Lead Statistician 
Study Title 
A Phase 2, Randomized, Double-Blind, Multicenter Study to Evaluate 
the Efficacy and Safety of Vonoprazan 10 mg, 20 mg, and 40 mg 
Compared to Placebo for Relief of Episodic Heartburn in Subjects 
with Symptomatic Non-Erosive Gastroesophageal Reflux Disease 
Protocol Number NERD-201 
Protocol Version 
and Date 
Version 2.0, Amendment 1 
16 July2021 
Protocol accepted and approved by:
Lead Statistician 
 
 
 
 
 
 
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	




Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
16 July 2021 
Page 7 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 2, Randomized, 
Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Vonoprazan 10 mg, 
20 mg, and 40 mg Compared to Placebo for Relief of Episodic Heartburn in Subjects with 
Symptomatic Non-Erosive Gastroesophageal Reflux Disease” 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 2.0, Amendment 1, dated 16 July 2021, 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 
 
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
14 Jul2021 
Page 8 
Table of Contents 
Table of Contents .......................................................................................................................8 
List of Tables ............................................................................................................................12 
List of Figures ..........................................................................................................................13 
Protocol Synopsis.....................................................................................................................14 
List of Abbreviations................................................................................................................20 
Summary of Changes ...............................................................................................................22 
1 
Introduction ......................................................................................................................23 
1.1 
Study Rationale .......................................................................................................23 
1.2 
Background .............................................................................................................23 
1.3 
Justification for Dose ..............................................................................................25 
2 
Study Objectives and Endpoints ......................................................................................27 
2.1 
Primary Objectives and Endpoints..........................................................................27 
2.2 
Secondary Objectives and Endpoints......................................................................27 
3 
Investigational Plan ..........................................................................................................30 
3.1 
Study Design ...........................................................................................................30 
3.1.1 
Rationale of Study Design .......................................................................33 
3.1.1.1 
Rationale for the Run-In Period ...............................................................33 
3.1.1.2 
Rationale for the On-Demand Treatment Period .....................................33 
4 
Subject Selection and Withdrawal Criteria ......................................................................34 
4.1 
Selection of Study Population .................................................................................34 
4.1.1 
Selection for Run-In Period .....................................................................34 
4.1.1.1 
Inclusion Criteria for Run-In Period ........................................................34 
4.1.1.2 
Exclusion Criteria for Run-In Period .......................................................35 
4.1.1.3 
Screen Failures .........................................................................................38 
4.1.2 
Selection for On-Demand Treatment Period ...........................................38 
4.1.2.1 
Inclusion Criteria for On-Demand Treatment Period ..............................38 
4.1.2.2 
Run-In Failures ........................................................................................39 
4.1.3 
Lifestyle Considerations ..........................................................................39 
4.2 
Withdrawal of Subjects From Study Drug and/or the Study ..................................39 


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vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
14 Jul2021 
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4.2.1 
Reasons for Withdrawal/Discontinuation ................................................39 
4.2.2 
Handling of Withdrawals .........................................................................41 
4.2.3 
Lost to Follow-up.....................................................................................42 
4.2.4 
Replacements ...........................................................................................42 
5 
Study Drugs ......................................................................................................................43 
5.1 
Method of Assigning Subjects to Treatment Groups ..............................................43 
5.2 
Treatments Administered ........................................................................................43 
5.2.1 
Run-In Period ...........................................................................................43 
5.2.2 
On-Demand Treatment Period .................................................................43 
5.3 
Rescue Antacid........................................................................................................44 
5.4 
Identity of Investigational Product and Rescue Antacid .........................................44 
5.4.1 
Vonoprazan and Placebo ..........................................................................44 
5.4.2 
Rescue Antacid ........................................................................................44 
5.5 
Management of Clinical Supplies ...........................................................................45 
5.5.1 
Study Drug Packaging and Storage .........................................................45 
5.5.2 
Test Article and Rescue Antacid Accountability ......................................45 
5.6 
Overdose Management ...........................................................................................45 
5.6.1 
Treatment of Overdose ............................................................................46 
5.7 
Blinding...................................................................................................................46 
5.7.1 
Breaking the Blind ...................................................................................46 
5.8 
Study Compliance ...................................................................................................47 
5.8.1 
Treatment Compliance .............................................................................47 
5.8.2 
Diary Compliance ....................................................................................47 
5.9 
Prior and Concomitant Therapy ..............................................................................47 
5.9.1 
Background Medications .........................................................................48 
5.9.2 
Excluded Medications..............................................................................49 
6 
Study Assessments and Procedures ..................................................................................50 
6.1 
Endoscopy ...............................................................................................................50 
6.2 
Efficacy Assessments ..............................................................................................50 
6.2.1 
Electronic Diary .......................................................................................50 
6.2.1.1 
Morning and Evening Heartburn Diary ...................................................51 
6.2.1.2 
Rescue Antacid Diary ..............................................................................51 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
14 Jul2021 
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6.2.1.3 
On-Demand Heartburn Episode Diary ....................................................51 
6.2.1.4 
On-Demand Heartburn Timed Assessments ............................................51 
6.2.1.5 
Severity Definitions .................................................................................51 
6.2.2 
PAGI-SYM Questionnaire .......................................................................52 
6.2.3 
PAGI-QoL Questionnaire ........................................................................53 
6.2.4 
Patient Global Impression of Change Questionnaire ...............................53 
6.2.5 
Patient Global Impression of Severity Questionnaire ..............................53 
6.2.6 
Patient Preference Questionnaire .............................................................53 
6.3 
Safety Assessments .................................................................................................54 
6.3.1 
Pretreatment Events and Adverse Events ................................................54 
6.3.1.1 
Definitions ...............................................................................................54 
6.3.1.2 
Documenting Adverse Events ..................................................................60 
6.3.1.3 
Time Period and Frequency for Collecting AE and SAE Information ....62 
6.3.1.4 
Regulatory Reporting Requirements for SAEs ........................................65 
6.3.2 
Pregnancy.................................................................................................66 
6.3.3 
Laboratory Analyses ................................................................................67 
6.3.4 
Physical Examinations .............................................................................69 
6.3.5 
Vital Signs ................................................................................................69 
6.3.6 
Electrocardiograms ..................................................................................70 
6.4 
Safety Monitoring Committee ................................................................................70 
7 
Statistical and Analytical Plan ..........................................................................................71 
7.1 
Sample Size Calculations ........................................................................................71 
7.2 
Analysis Sets ...........................................................................................................72 
7.2.1 
All Subjects Set ........................................................................................72 
7.2.2 
Safety Sets................................................................................................72 
7.2.3 
Intent-to-Treat Set ....................................................................................72 
7.3 
Description of Subgroups .......................................................................................73 
7.4 
Statistical Analysis Methodology ...........................................................................73 
7.4.1 
Efficacy Analyses ....................................................................................74 
7.4.1.1 
Primary Efficacy Endpoint ......................................................................74 
7.4.1.2 
Secondary Efficacy Endpoint ..................................................................74 
7.4.1.3 
Exploratory Endpoints On-Demand Treatment Period ............................75 
7.4.1.4 
Exploratory Endpoints Run-In Period .....................................................76 
7.4.2 
Safety Analyses ........................................................................................77 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
14 Jul2021 
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7.4.3 
Other Analyses .........................................................................................78 
7.4.4 
Interim Analyses ......................................................................................78 
8 
Data Quality Assurance ....................................................................................................79 
8.1 
Data Management ...................................................................................................79 
9 
Ethics ................................................................................................................................80 
9.1 
Independent Ethics Committee or Institutional Review Board ..............................80 
9.2 
Ethical Conduct of the Study ..................................................................................80 
9.3 
Subject Information and Consent............................................................................80 
10 Investigator’s Obligations ................................................................................................82 
10.1 Confidentiality ........................................................................................................82 
10.2 Financial Disclosure and Obligations .....................................................................82 
10.3 Investigator Documentation ....................................................................................83 
10.4 Study Conduct .........................................................................................................83 
10.5 Adherence to Protocol.............................................................................................83 
10.6 Adverse Events and Study Report Requirements ...................................................84 
10.7 Investigator’s Final Report .....................................................................................84 
10.8 Records Retention ...................................................................................................84 
10.9 Publications .............................................................................................................84 
11 Study Management ...........................................................................................................85 
11.1 Monitoring ..............................................................................................................85 
11.1.1 
External Data Monitoring Committee .....................................................85 
11.1.2 
Monitoring of the Study ...........................................................................85 
11.1.3 
Inspection of Records ..............................................................................85 
11.2 Management of Protocol Amendments and Deviations..........................................86 
11.2.1 
Modification of the Protocol ....................................................................86 
11.2.2 
Protocol Deviations..................................................................................86 
11.3 Study Termination ...................................................................................................86 
11.4 Final Report ............................................................................................................87 
12 Reference List...................................................................................................................88 
13 Appendices .......................................................................................................................91 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
14 Jul2021 
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13.1 Appendix 1: Schedule of Events .............................................................................91 
13.2 Appendix 2: Contraceptive Guidance .....................................................................95 
13.3 Appendix 3: Liver Function Tests ...........................................................................97 
13.3.1 
Liver Function Test Monitoring ...............................................................97 
13.3.2 
Considerations for Temporary Discontinuation of Study Drug ...............97 
13.3.3 
Permanent Discontinuation of Study Drug ..............................................98 
13.3.4 
Re-initiation of Study Drug .....................................................................99 
13.4 Appendix 4: Rome IV Criteria for Functional Heartburn and Functional Dyspepsia
 .......................................................................................................................100 
13.4.1 
Functional Heartburn .............................................................................100 
13.4.2 
Functional Dyspepsia .............................................................................100 
13.4.2.1 Postprandial Distress Syndrome ............................................................101 
13.4.2.2 Epigastric Pain Syndrome ......................................................................101 
13.5 Appendix 5: Protocol Amendments ......................................................................103 
13.5.1 
Protocol Amendment 1 ..........................................................................103 
 
List of Tables 
Table 2-1 
Primary Objectives and Endpoints.................................................................. 27 
Table 2-2 
Secondary Objectives and Endpoints.............................................................. 27 
Table 5-1 
Excluded Medications and Treatments ........................................................... 49 
Table 6-1 
Definitions of Heartburn Severity (Daytime/Nighttime) for the Screening, 
Run-In, and Safety Follow-up Periods............................................................ 52 
Table 6-2 
Medically Significant Adverse Event List ...................................................... 55 
Table 6-3 
Adverse Events of Special Interest List .......................................................... 56 
Table 6-4 Protocol-Required Safety Laboratory Assessments ................................................ 68 
Table 13-1 
Schedule of Events .......................................................................................... 92 
Table 13-2 
Abnormal Liver Function Criteria For Permanent Discontinuation of Study 
Drug ................................................................................................................ 98 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
14 Jul2021 
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List of Figures 
Figure 3-1 
Study Scheme.................................................................................................. 31 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
14 Jul2021 
Page 14 
Protocol Synopsis 
Protocol 
Number: 
NERD-201 
Title: 
A Phase 2, Randomized, Double-Blind, Multicenter Study to Evaluate the 
Efficacy and Safety of Vonoprazan 10 mg, 20 mg, and 40 mg Compared 
to Placebo for Relief of Episodic Heartburn in Subjects with Symptomatic 
Non-Erosive Gastroesophageal Reflux Disease 
Sponsor: 
Phathom Pharmaceuticals, Inc. 
2150 East Lake Cook Road, Suite 800 
Buffalo Grove, IL 60089 USA 
Study Phase: 
2 
Study Sites: 
Approximately 65 sites in the United States 
Indication: 
Patients with symptomatic NERD 
Rationale: 
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. 
The term GERD covers a spectrum of conditions, including non-erosive 
gastroesophageal reflux disease (NERD), erosive esophagitis (EE), and 
Barrett’s esophagus. When defining GERD as the presence of at least 
weekly heartburn and/or regurgitation, epidemiological studies reported 
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. 
Vonoprazan belongs to a new class of acid-inhibitory agents called 
“potassium-competitive acid blockers” and is being developed in the 
United States and Europe for healing of all grades of EE and relief of 
heartburn, maintenance of healing of all grades of EE and relief of 
heartburn, and treatment of Helicobacter pylori infection.  
Vonoprazan at doses from 10 mg to 40 mg has been shown in both single 
and multiple repeat-dosing studies to have a rapid onset of action after the 
first dose and near maximal effect on pH holding time within 24 hours of 
dosing, which is maintained with multiple dosing. It is believed that this 
pharmacologic profile may make it an optimum agent for the treatment of 
NERD utilizing an “On-Demand” dosing scheme. This study will evaluate 
the safety and effectiveness of vonoprazan 10 mg, 20 mg, and 40 mg to 
treat episodic heartburn in patients with symptomatic NERD after an 
initial 20 mg vonoprazan dose in an open-label Run-In Period. 
 
 
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
14 Jul2021 
Page 15 
Objectives: 
Primary 
• To assess the efficacy of vonoprazan (10 mg, 20 mg, and 40 mg 
On-Demand) compared to placebo (On-Demand) in relief of episodic 
heartburn over 6 weeks in subjects with symptomatic NERD. 
• To assess the safety of vonoprazan (10 mg, 20 mg, and 40 mg 
On-Demand) compared to placebo (On-Demand) in subjects with 
symptomatic NERD. 
Secondary 
• To assess the use of study medication and rescue antacid in subjects 
treated with vonoprazan (10 mg, 20 mg, and 40 mg On-Demand) 
compared to placebo (On-Demand) over the On-Demand Treatment 
Period. 
Study 
Population: 
Subjects aged 18 years of age or older with symptomatic NERD 
confirmed by endoscopy. 
Key Inclusion and Exclusion Criteria 
Run-In Period 
Main Inclusion Criteria: 
• The subject identified their main symptom as heartburn, a burning 
sensation in the retrosternal area (behind the breastbone). 
• History of episodes of heartburn for 6 months or longer prior to 
screening. 
• Heartburn reported on 4 or more days during any 7 consecutive 
days in the Screening Period as recorded in the electronic diary. 
Main Exclusion Criteria: 
• Endoscopically confirmed EE.  
• The subject has active irritable bowel syndrome or had a flare of 
IBS requiring therapy within the prior 6 months. 
• The subject has a history of, or is suspected of having, functional 
upper gastrointestinal disorders such as functional dyspepsia or 
functional heartburn diagnosed by the Rome IV criteria. 
On-Demand Treatment Period 
Main Inclusion Criteria: 
• The subject has stable disease, ie, no heartburn in the last 7 days of 
the Run-In Period. 
• The subject completes the Run-In Period and continues to fulfill 
all eligibility criteria for the Run-In Period (except heartburn 
inclusion criteria). 


Phathom Pharmaceuticals, Inc. 
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Protocol: NERD-201 Version 2.0, Amendment 1 
14 Jul2021 
Page 16 
• Subject completes at least 80% of diary entries over the Run-In 
Period, including 80% of the entries for the last 7 days.  
Study 
Design: 
This is a Phase 2, multicenter, double-blind study of vonoprazan versus 
placebo assessing the relief of episodic heartburn. Subjects with 
symptomatic NERD (as confirmed by endoscopy) and heartburn 
symptoms will receive open-label vonoprazan 20 mg once daily (QD) for 
4 weeks. Subjects with stable disease (ie, no heartburn on the last 7 days 
of the Run-In Period) will be randomized to receive vonoprazan 10 mg, 
20 mg, 40 mg or placebo On-Demand for 6 weeks. Subjects will complete 
an electronic diary to assess presence and severity of heartburn symptoms 
and use of rescue antacid (if needed) in all periods. During the 
On-Demand Treatment Period, a more detailed diary will also document 
time of study drug administration and when heartburn relief occurs.  
The study will include 4 periods: 
Screening Period: Subjects will provide informed consent and undergo 
screening assessments to determine study eligibility (including endoscopy 
to confirm absence of EE). Subject will have to discontinue proton pump 
inhibitors and histamine-2 receptor antagonists during this period. 
Study-supplied rescue antacid will be allowed if needed. Subjects will 
complete an electronic diary to assess presence and severity of heartburn 
symptoms and use of rescue antacid. If all eligibility criteria are met, the 
subject will enter the Run-In Period.  
Run-In Period: Subjects with symptomatic NERD whose eligibility is 
confirmed will receive open-label vonoprazan 20 mg QD for 4 weeks to 
treat heartburn. Study-supplied rescue antacid will be allowed if needed. 
Subjects will complete an electronic diary to assess presence and severity 
of heartburn symptoms and use of rescue antacid.  
On-Demand Treatment Period: Subjects who have stable disease (ie, no 
heartburn on the last 7 days of the Run-In Period) and are compliant with 
the diary and study medication will be randomized to receive either 
vonoprazan 10 mg, 20 mg, or 40 mg or placebo On-Demand (but no more 
than 1 dose within 24 hours) for 6 weeks to treat episodic heartburn. 
Study-supplied rescue antacid will be allowed 3 hours after taking study 
medication if needed. Subjects will complete an electronic diary to assess 
presence and severity of heartburn symptoms and use of rescue antacid. In 
addition, a more detailed diary will also document time of study drug 
administration and when heartburn relief occurs. Subjects will be 
contacted by phone weekly during the first 3 weeks to assess their 
understanding of diary instructions and On-Demand dosing and to 
emphasize the importance of completing the diary assessments. 
Follow-up Period: A safety follow-up visit will occur 1 week after 
completing the On-Demand Treatment Period to assess adverse events 


Phathom Pharmaceuticals, Inc. 
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Protocol: NERD-201 Version 2.0, Amendment 1 
14 Jul2021 
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(AEs) and serum gastrin. Study-supplied rescue antacid will be allowed if 
needed. Subjects will complete an electronic diary to assess presence and 
severity of heartburn symptoms and use of rescue antacid. 
Estimated 
Study 
Duration: 
The total duration of the study is up to 16 weeks. Screening Period is up 
to 5 weeks, the Run-In Period is 4 weeks, and the On-Demand Treatment 
Period is 6 weeks. A follow-up visit will occur 1 week after completing 
the On-Demand Treatment Period. 
Efficacy 
Assessments: 
Primary Endpoints 
• The percentage of evaluable(a) heartburn episodes completely relieved 
within 3 hours and with no further heartburn reported for 24 hours 
after taking study drug (b) 
 
(a) An evaluable heartburn episode is an episode for which study drug 
was taken and for which the subject completed at least one entry in 
the heartburn episode diary. 
(b) For a heartburn episode to be considered completely relieved, a 
subject must not have taken rescue antacid within 3 hours of taking 
study drug. 
Secondary Endpoints 
• The percentage of evaluable heartburn episodes completely relieved 
within 3 hours after taking study drug 
• The percentage of evaluable heartburn episodes for each subject that 
are completely relieved within 3 hours and with no further heartburn 
reported for 24 hours after taking study drug 
• The mean number of tablets of rescue antacid taken per day over the 
On-Demand Treatment Period 
• The percentage of subjects with complete relief of heartburn within 
3 hours after the first episode and with no further heartburn reported 
for 24 hours after taking study drug 
• The percentage of days study drug was taken over the On-Demand 
Treatment Period 
• The percentage of 24-hour heartburn-free days over the On-Demand 
Treatment Period 
Safety 
Assessments: 
Safety will be assessed by the following: 
• AEs 
• Laboratory test values (hematology, serum chemistry, urinalysis); 
serum gastrin and pepsinogen I/II levels 
• Electrocardiograms (ECGs) 
• Vital signs 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-201 Version 2.0, Amendment 1 
14 Jul2021 
Page 18 
Study Drug, 
Dosage, and 
Route of 
Administra-
tion: 
Open-label vonoprazan 20 mg QD will be taken during the 4-week 
Run-In Period. Blinded study drug (vonoprazan 10 mg, 20 mg, or 40 mg 
or placebo) will be taken for the treatment of an On-Demand heartburn 
episode (only once in a 24-hour period) during the 6-week On-Demand 
Treatment Period. Study drug will be taken orally with approximately 
240 mL (8 oz) water. Rescue antacid will be provided.  
Sample Size: 
The sample size for the On-Demand Treatment Period is calculated based 
on the following assumptions: 
• Subjects will be randomized to receive either vonoprazan 10 mg, 
20 mg, or 40 mg or placebo with a randomization ratio of 1:1:1:1. 
• Each subject experiences at least 4 evaluable heartburn episodes.  
• Comparison between each dose of vonoprazan to placebo will be 
performed using the Fisher’s Exact test. 
• A clinically relevant difference of 15% between each dose of 
vonoprazan and placebo in the proportion of evaluable heartburn 
episodes completely relieved within 3 hours and with no further 
heartburn reported for 24 hours after taking study drug. 
Based on these assumptions, a sample size of 200 heartburn episodes per 
treatment group (or 50 subjects with at least 4 heartburn episodes per 
treatment group) provides at least 80% statistical power at the 0.05 
significance level. During the study if less than 200 subjects are projected 
to enroll into the On-Demand Treatment Period, additional subjects may 
be enrolled into the Run-In Period to ensure that a sufficient number of 
subjects enroll into the On-Demand Treatment Period. 
Assuming 60% of subjects at the end of the Run-In Period do not meet the 
eligibility criteria for the On-Demand Treatment Period, approximately 
500 subjects will be enrolled into the Run-In Period to achieve 
200 subjects for the On-Demand Treatment Period.  
Statistical 
Methods: 
Efficacy Analyses 
Primary Efficacy Endpoint 
The percentage of evaluable heartburn episodes completely relieved 
within 3 hours and with no further heartburn reported for 24 hours after 
taking study drug will be compared between each dose of vonoprazan and 
placebo using Fisher’s Exact test for the Intent-to-Treat (ITT) On-Demand 
set. 
 
Secondary Efficacy Endpoint 
All secondary endpoints will be analyzed for the ITT On-Demand set. 


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The following secondary endpoints will be compared for each dose of 
vonoprazan to placebo using Fisher’s Exact test: 
• The percentage of evaluable heartburn episodes completely relieved 
within 3 hours after taking study drug. 
• The percentage of subjects with complete relief of heartburn within 
3 hours after the first episode and with no further heartburn reported 
for 24 hours after taking study drug. 
The following secondary endpoints will be compared for each dose of 
vonoprazan to placebo using a Wilcoxon rank-sum test: 
• The percentage of evaluable heartburn episodes for each subject that 
are completely relieved within 3 hours and with no further heartburn 
reported for 24 hours after taking study drug. 
• The percentage of days study drug was taken over the On-Demand 
Treatment Period. 
• The mean number of tablets of rescue antacid taken per day over the 
On-Demand Treatment Period. 
• The percentage of 24-hour heartburn-free days during the On-Demand 
Treatment Period. 
Safety Analyses 
Safety will be summarized separately for the Run-In Period and the 
On-Demand Treatment Period. For each period, safety will be assessed by 
summarizing the incidence of AEs and changes in clinical laboratory tests, 
gastrin and pepsinogen I/II levels, ECGs, and vital signs. 
 
Version and 
Date of 
Protocol: 
Version 2.0, Amendment 1; 16 July 2021 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EE 
erosive esophagitis 
EMA 
European Medicines Agency 
EPS 
epigastric pain syndrome 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
GGT 
gamma-glutamyl transferase 
H2RA 
histamine-2 receptor antagonist 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IBS 
irritable bowel syndrome 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NERD 
non-erosive gastroesophageal reflux disease 


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Abbreviation 
Definition 
PAGI-QoL 
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life 
PAGI-SYM 
Patient Assessment of Gastrointestinal Disorders-Symptom Severity 
Index  
PD 
pharmacodynamic(s) 
PDS 
postprandial distress syndrome 
PPI 
proton pump inhibitor 
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 reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 


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Summary of Changes 
Protocol Amendment History and Reasons for Amendment 
Version 
Date 
Reasons for Amendment 
Version 1.0 
25 Jan 2021 
Original Protocol 
Version 2.0 
(Protocol 
Amendment 1) 
16 July 2021 
• To update the IBS exclusion criterion to exclude 
active IBS or a flare requiring therapy within prior 
6 months 
• To add 2 telephone contacts at Week 1 and Week 2 
of the On-Demand Treatment Period. 
• To clarify that compliance with diary and study 
medication is required for entry into the On-Demand 
Treatment Period. 
• To change baseline serum gastrin level to be 
unblinded during the study. 
• To increase the number of subjects expected to be 
enrolled into the Run-In Period to 500 subjects to 
ensure that a sufficient number of subjects enroll 
into the On-Demand Treatment Period. 
• To clarify that use of prescription 
cannabinoids/tetrahydrocannabinol is exclusionary. 
• To clarify that Run-In failures should undergo 
assessments from the Week 4 Run-In Period. 
 
 


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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, maintenance of healing of all grades of EE and relief of heartburn, 
treatment of Helicobacter pylori infection, and treatment of heartburn in patients with 
symptomatic non-erosive gastroesophageal reflux disease (NERD). 
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 
Vonoprazan at doses from 10 mg to 40 mg has been shown in both single and multiple 
repeat-dosing studies to have a rapid onset of action after the first dose and near maximal 
effect on pH holding time within 24 hours of dosing, which is maintained with multiple 
doses. It is believed that this pharmacologic profile may make it an optimum agent for the 
treatment of NERD utilizing an “on-demand” dosing scheme. This study will evaluate the 
safety and effectiveness of vonoprazan 10 mg, 20 mg, and 40 mg to treat episodic heartburn 
in patients with symptomatic NERD who have stable disease after treatment with vonoprazan 
20 mg in an open-label Run-In Period. 
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 
NERD, EE, and Barrett’s esophagus. When defining GERD as the presence of at least weekly 
heartburn and/or regurgitation, epidemiological studies reported 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). 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). 


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The 2013 American College of Gastroenterology “Guidelines for the Diagnosis and 
Management of Gastroesophageal Reflux Disease” recommends that for patients who require 
long-term PPI therapy, PPIs should be administered in the lowest effective dose, including 
on‑demand or intermittent therapy (Katz et al 2013). On-demand therapy is a self-managed 
therapeutic strategy in which patients take acid-suppressing medications as needed based on 
symptoms of heartburn. Proton pump inhibitors are recommended for treatment of 
symptomatic NERD for 4 to 8 weeks. None of the PPIs are approved for on-demand therapy 
in the United States. While esomeprazole and rabeprazole are approved for on-demand 
treatment of symptomatic GERD in Europe, the primary endpoints of these studies that 
support this were based on subject satisfaction with treatment and study discontinuation 
rates, rather than directly measuring relief of active heartburn episodes (Talley et al 2001; 
Talley et al 2002; Bytzer et al 2004). Studies with PPIs have shown that in NERD patients 
the median time to first report of symptom relief takes 2 days and for sustained symptom 
relief 10 to 13 days. This finding is consistent with the known mechanism of action of PPIs, 
in which there is a build-up effect on the inhibition of acid output after repeated daily dosing. 
Nevertheless, PPIs are still recommended as needed or On-Demand for the treatment of 
GERD (Katz et al 2013). Published systematic reviews and meta‑analysis show that the 
on-demand management of NERD with PPIs has been reported to be a favorable approach 
for patients as maintenance treatment for NERD (Pace et al 2007; Khan et al 2018). 
Moreover, patient adherence and satisfaction with on-demand treatment is greater than with 
continuous PPI treatment with the potential to limit the concerns of adverse events (AEs) and 
reduce the pill burden for patients.  
To date, only over-the-counter histamine-2 receptor antagonists (H2RAs) are approved in the 
US for on-demand treatment of heartburn; however, these agents have their own limitations 
related to having to dose more than once a day, dosing with food, and the development of 
tachyphylaxis upon continued use (Colin‑Jones 1995). 
In contrast to EE, NERD is mostly viewed as a non-progressive disease and the treatment 
approach is symptom-driven (Savarino et al 2017). Reflux symptoms do not occur on a daily 
basis in NERD patients, so continuous dosing may not be warranted in these patients. There 
are limited data evaluating vonoprazan on-demand in NERD. The available data suggest 
on-demand therapy is potentially an effective alternative to continuous treatment. In a study 
published by Hoshikawa et al evaluating vonoprazan 20 mg on-demand for NERD, the 
authors concluded that on-demand therapy is as effective as continuous PPI maintenance 


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therapy in terms of patient satisfaction and the majority of the patients preferred the 
on-demand approach over continuous maintenance treatment (Hoshikawa et al 2019). Similar 
results are reported with PPI treatment, where on-demand therapy was non-inferior to 
continuous, but on-demand also reduced medication usage (Bayerdörffer et al 2016). 
The pharmacokinetic and pharmacodynamic (PD) profiles of vonoprazan were assessed in 
multiple studies, including Study TAK-438_107, which showed a rapid rise in pH and a dose 
response for percent time above pH 4. The mean percentage of time above pH 4 on Day 1 for 
vonoprazan 10 mg, 20 mg, and 40 mg was 43%, 63%, and 86%, respectively, and by Day 7 
was 60%, 85%, and 93%, respectively.  
 conducted 2 studies in Japan to evaluate the treatment of heartburn in subjects with 
NERD (TAK-438/CCT-201 [Kinoshita et al 2016] and Vonoprazan-3001 [Kinoshita et al 
2019]). Although there was a trend in favor of vonoprazan for the proportion of 
heartburn-free days (primary endpoint) between treatment groups, the difference did not 
reach statistical significance. The learnings from these studies are being applied in the current 
NERD study. Phathom plans to add measures to select an appropriate NERD population and 
reduce inclusion of functional heartburn patients. Phathom plans to use an electronic diary 
data collection tool to allow timely and accurate capture of patient symptoms. In addition, a 
wider dose range of vonoprazan is being explored than what has been studied in the 
 
Japan program. 
Overall, with vonoprazan’s pharmacological profile of rapid, potent, and sustained elevations 
of gastric pH, vonoprazan offers the potential to be a highly effective treatment option for 
both continuous dosing and on-demand use for the treatment of heartburn in patients with 
symptomatic NERD. 
1.3 Justification for Dose 
Selection of the vonoprazan 20 mg dose for the Run-In Period and the vonoprazan 10 mg, 
20 mg, and 40 mg doses for the On-Demand Treatment Period of Study NERD-201 is based 
on the following studies: 
• 
 conducted a 7-day multiple repeat-dose study in healthy subjects administered 
with vonoprazan 10 mg, 20 mg, 30 mg, and 40 mg. In this study, intragastric pH was 
measured for 24 hours before and after receiving the first dose of vonoprazan. On 


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Day 1, vonoprazan quickly raised intragastric pH in a dose-dependent manner with 
10 mg, 20 mg, and 40 mg doses achieving a mean pH of 4 between 2 to 4 hours after 
dosing. The vonoprazan 40 mg dose maintains pH above 4 for 24 hours after a single 
dose. 
• A recent study compared vonoprazan 20 mg to lansoprazole 30 mg and famotidine 
20 mg (Ohkuma et al 2018). Gastric pH was measured for 6 hours after dosing. Over 
this period, the mean pH was similar between vonoprazan (4.30) and famotidine 
(4.45) and both were higher than lansoprazole (2.65).  
Based on the PD profile, vonoprazan 20 mg and 40 mg are more likely to be suitable for 
on-demand dosing; however, Phathom proposes to also assess vonoprazan 10 mg to confirm 
the lowest effective dose.  
To date, the vonoprazan 40 mg once-daily (QD) dose has been evaluated in 248 subjects with 
a maximum duration of 8 weeks. In Phase 2, 3, and 4 studies, the safety of vonoprazan 20 mg 
and 40 mg are comparable. 
The 20 mg dose for the vonoprazan Run-In Period was selected based on the historical data 
from Japan where vonoprazan 20 mg is the recommended daily dose in the healing of EE and 
has also shown to relieve heartburn in these patients (Ashida et al 2018). While this dose has 
not yet been shown to be effective in NERD as a daily dose, it is considered a safe and 
logical dose to be selected for the Run-In Period of this study. 
Overall, the proposed doses of vonoprazan 10 mg, 20 mg, and 40 mg are appropriate for this 
Phase 2 study to explore the on-demand use. 
 


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2 
Study Objectives and Endpoints 
2.1 Primary Objectives and Endpoints 
Table 2-1 
Primary Objectives and Endpoints 
Objectives 
Endpoints 
• To assess the efficacy of vonoprazan (10 mg, 
20 mg, and 40 mg On-Demand) compared to 
placebo (On-Demand) in relief of episodic 
heartburn over 6 weeks in subjects with 
symptomatic NERD.  
• 
The percentage of evaluable(a) heartburn episodes 
completely relieved within 3 hours and with no 
further heartburn reported for 24 hours after 
taking study drug(b) 
• To assess the safety of vonoprazan (10 mg, 20 mg, 
and 40 mg On-Demand) compared to placebo 
(On-Demand) in subjects with symptomatic 
NERD. 
• 
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 ECGs 
o Vital signs 
Abbreviations: AEs, adverse events; ECGs, electrocardiograms; NERD, non-erosive gastroesophageal reflux 
disease. 
(a)  An evaluable heartburn episode is an episode for which study drug was taken and for which the subject 
completed at least one entry in the heartburn episode diary. 
(b)  For a heartburn episode to be considered completely relieved, a subject must not have taken rescue antacid 
within 3 hours of taking study drug. 
 
2.2 Secondary Objectives and Endpoints 
Table 2-2 
Secondary Objectives and Endpoints 
Objectives 
Endpoints 
• To assess the use of study 
medication and rescue antacid in 
subjects treated with vonoprazan 
(10 mg, 20 mg, and 40 mg 
On-Demand) compared to placebo 
(On-Demand) over the On-Demand 
Treatment Period. 
Secondary: 
• 
The percentage of evaluable(a) heartburn episodes completely 
relieved within 3 hours after taking study drug(b) 
• 
The percentage of evaluable(a) heartburn episodes for each 
subject that are completely relieved within 3 hours and with no 
further heartburn reported for 24 hours after taking study drug 
• 
The mean number of tablets of rescue antacid taken per day 
over the On-Demand Treatment Period 
• 
The percentage of subjects with complete relief of heartburn 
within 3 hours after the first episode and with no further 
heartburn reported for 24 hours after taking study drug 
• 
The percentage of days study drug was taken over the On-
Demand Treatment Period 
• 
The percentage of 24-hour heartburn-free days over the On-
Demand Treatment Period 


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Objectives 
Endpoints 
 
Exploratory: 
 
On-Demand Treatment Period  
• 
The percentage of evaluable(a) heartburn episodes completely 
relieved within 30 minutes or 1, 1.5, or 2 hours and with no 
further heartburn reported for 24 hours after taking study 
drug(b) 
• 
The percentage of evaluable(a) heartburn episodes that are 
completely relieved within 30 minutes or 1, 1.5, or 2 hours 
after taking study drug(b)  
• 
The percentage of evaluable(a) heartburn episodes that 
improved at 30 minutes or 1, 1.5, 2, or 3 hours after taking 
study drug(b)  
• 
The percentage of episodes for which subjects continue to be 
heartburn-free after 24 or 48 hours of taking study drug 
• 
The percentage of subjects with at least 50%, at least 75%, and 
100% of their evaluable heartburn episodes completely 
relieved within 3 hours with no further heartburn reported for 
24 hours after taking study drug(b) 
• 
The percentage of subjects with at least 50%, at least 75%, and 
100% of their evaluable heartburn episodes completely 
relieved within 3 hours after taking study drug(b) 
• 
The percentage of subjects with complete relief of the first 
episode of heartburn within 3 hours after taking study drug  
• 
The mean number of days between heartburn episodes(b) 
• 
The percentage of days without daytime heartburn over the 
On-Demand Treatment Period  
• 
The percentage of days without nighttime heartburn over the 
On-Demand Treatment Period  
• 
The mean severity of daytime and nighttime heartburn over the 
On-Demand Treatment Period  
• 
The mean severity of nighttime heartburn over On-Demand 
Treatment Period  
• 
The mean severity of daytime heartburn over the On-Demand 
Treatment Period  
• 
The percentage of days without rescue antacid use over the 
On-Demand Treatment Period  
• 
The change from baseline to the end of the On-Demand 
Treatment Period for each subscale and the total score of the 
PAGI-SYM questionnaire 
• 
The change from baseline to the end of the On-Demand 
Treatment Period for each subscale and the total score of the 
PAGI-QoL questionnaire 
• 
The patient global impression of change in GERD symptoms 
at the end of the On-Demand Treatment Period 
• 
The patient global impression of severity in GERD symptoms 
over the last 7 days of the On-Demand Treatment Period 
• 
The percentage of subjects with each dosing preference 


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Objectives 
Endpoints 
 
Run-In Period  
• 
The percentage of 24-hour heartburn-free days over the Run-In 
Period  
• 
The percentage of days without daytime heartburn over the 
Run-In Period  
• 
The percentage of days without nighttime heartburn over the 
Run-In Period  
• 
The mean severity of daytime and nighttime heartburn over the 
Run-In Period  
• 
The mean severity of nighttime heartburn over the Run-In 
Period  
• 
The mean severity of daytime heartburn over the Run-In 
Period  
• 
The percentage of days without rescue antacid use over the 
Run-In Period  
• 
The change from baseline to the end of the Run-In Period for 
each subscale and the total score of the PAGI-SYM 
questionnaire 
• 
The change from baseline to the end of the Run-In Period for 
each subscale and the total score of the PAGI-QoL 
questionnaire 
• 
The patient global impression of change in GERD symptoms at 
the end of the Run-In Period  
• 
The patient global impression of severity in GERD symptoms 
over the last 7 days of the Run-In Period 
Abbreviations: GERD, gastroesophageal reflux disease; PAGI-QoL, Patient Assessment of Upper 
Gastrointestinal Disorders-Quality of Life; PAGI-SYM, Patient Assessment of Gastrointestinal 
Disorders-Symptom Severity Index. 
(a) An evaluable heartburn episode is an episode for which study drug was taken and for which the subject 
completed at least one entry in the heartburn episode diary. 
(b)  For a heartburn episode to be considered completely relieved, a subject must not have taken rescue 
antacid within 3 hours of taking study drug. 
 


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3 
Investigational Plan 
3.1 Study Design 
This is a Phase 2, multicenter, double-blind study of vonoprazan versus placebo assessing the 
relief of episodic heartburn. Subjects with symptomatic NERD (as confirmed by endoscopy) 
and heartburn symptoms will receive open-label vonoprazan 20 mg QD for 4 weeks. Subjects 
with stable disease (ie, no heartburn on the last 7 days of the Run-In Period) will be 
randomized to receive either vonoprazan 10 mg, 20 mg, 40 mg or placebo On-Demand for 
6 weeks. Subjects will complete an electronic diary to assess presence and severity of 
heartburn symptoms and use of rescue antacid (if needed) in all periods. During the 
On-Demand Treatment Period, a more detailed diary will also document time of study drug 
administration and when heartburn relief occurs. 
A schematic diagram of the overall study design is presented in Figure 3-1. 


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Figure 3-1 
Study Scheme 
 
Abbreviations: QD, once daily 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The study will include 4 periods (see the schedule of events [SoE] in Appendix 1 
[Section 13.1] for details): 
1. Screening Period: Subjects will provide informed consent and undergo 
screening assessments to determine study eligibility (including endoscopy to 
confirm absence of EE). Study-supplied rescue antacid will be allowed if 
needed. Subjects will complete an electronic diary to assess presence and 
severity of heartburn symptoms and use of rescue antacid. If all eligibility 
criteria are met, the subject will be eligible to enter the Run-In Period.  
2. Run-In Period: Subjects with symptomatic NERD whose eligibility is 
confirmed will receive open-label vonoprazan 20 mg QD for 4 weeks. 
Study-supplied rescue antacid will be allowed if needed. Subjects will 
complete an electronic diary to assess presence and severity of heartburn 
symptoms and use of rescue antacid.  
3. On-Demand Treatment Period: Subjects who have stable disease (ie, no 
heartburn on the last 7 days of the Run-In Period) and are compliant with the 
Diary and study medication will be randomized to receive either vonoprazan 10 
mg, 20 mg, or 40 mg or placebo On-Demand for 6 weeks to treat episodic 
heartburn. Study drug should only be taken once in a 24-hour period. 
Study-supplied rescue antacid will be allowed 3 hours after taking study 
medication if needed. Subjects will complete an electronic diary to assess 
presence and severity of heartburn symptoms and use of rescue antacid. In 
addition, a more detailed diary will also document time of study drug 
administration and when heartburn relief occurs. Subjects will be contacted by 
phone weekly during the first 3 weeks to assess their understanding of diary 
instructions and On-Demand dosing and to emphasize the importance of 
completing the diary assessments. 
4. Follow-up Period: A safety follow-up visit will occur 1 week after completing 
the On-Demand Treatment Period to assess AEs and serum gastrin. 
Study-supplied rescue antacid will be allowed if needed. Subjects will 
complete an electronic diary to assess presence and severity of heartburn 
symptoms and use of rescue antacid.  


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End-of-study: 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 
3.1.1.1 Rationale for the Run-In Period 
The Run-In Period is designed: 
• To mimic clinical practice of first gaining control of the disease and heartburn 
episodes before transitioning to an “On-Demand” dosing scheme. 
• To minimize inclusion of potential functional heartburn patients who do not truly 
have acid-related NERD prior to randomization. 
• To emulate the future Phase 3 design that plans to have a Run-In Period for the 
reasons stated above. 
Four weeks of treatment is consistent with the duration of studies for the treatment of 
heartburn and an appropriate duration to identify patients with stable disease. 
3.1.1.2 Rationale for the On-Demand Treatment Period 
On-demand studies with H2RAs ranged from 2 to 4 weeks in duration. It is anticipated that 
after 4 weeks of continuous treatment with vonoprazan, it may take several days for 
symptoms to return. Therefore, an On-Demand Treatment Period of 6 weeks is deemed an 
appropriate duration for Study NERD-201 to observe a sufficient number of episodes of 
heartburn for this study. 


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4 
Subject Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
This study will be conducted at approximately 65 sites in the United States and will enroll 
approximately 500 subjects in the Run-In Period to allow randomization of approximately 
200 subjects (approximately 50 subjects per arm) in the On-Demand Treatment Period. 
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 
Selection for Run-In Period 
4.1.1.1 Inclusion Criteria for Run-In Period 
Subjects are eligible for enrollment in the Run-In Period of 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. 
4. The subject identified their main symptom as heartburn, a burning sensation in 
the retrosternal area (behind the breastbone). 
5. History of episodes of heartburn for 6 months or longer prior to screening. 
6. Heartburn reported on 4 or more days during any 7 consecutive days in the 
Screening Period as recorded in the electronic diary. 


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7. 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. 
4.1.1.2 Exclusion Criteria for Run-In Period 
Subjects are not eligible for study participation in the Run-In Period of the study if they meet 
any of the following exclusion criteria: 
1. Endoscopically confirmed EE during the Screening Period assessed by the 
investigator. Endoscopy should be performed after subjects meet Inclusion 
Criteria 6. Any endoscopic confirmation performed in a routine clinical setting 
within 7 days before signing the informed consent is acceptable to use for the 
purpose of fulfilling the screening requirement. 
2. The subject has active irritable bowel syndrome (IBS) or had a flare of IBS 
requiring therapy within the prior 6 months. 
3. The subject has a history of or is suspected of having functional heartburn 
diagnosed by the Rome IV criteria: (Appendix 4). 
4. The subject has a history of or is suspected of having functional dyspepsia 
diagnosed by the Rome IV criteria (Appendix 4).  
5. The subject has endoscopic Barrett’s esophagus (>1 cm of columnar-lined 
esophagus) and/or definite dysplastic changes in the esophagus. 
6. The subject has any other clinically significant 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) or hiatal hernia are eligible to participate. 
7. The subject has scleroderma (systemic sclerosis). 


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8. 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). 
9. The subject has an active gastric or duodenal ulcer within 4 weeks before the 
first dose of study drug. 
10. Use of prescription or non-prescription PPIs or H2RAs throughout the study. 
11. The subject has received vonoprazan in a clinical trial at any time or any other 
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. 
12. 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. 
13. The subject has cutaneous lupus erythematosus or systemic lupus 
erythematosus. 
14. The subject has had clinically significant upper or lower gastrointestinal 
bleeding within 4 weeks prior to Screening. 
15. The subject has Zollinger-Ellison syndrome or other gastric acid 
hypersecretory conditions. 
16. 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). Skin testing may be performed according to local standard practice to 
confirm hypersensitivity. 


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17. The subject has a history of alcohol abuse, illegal drug use, drug addiction, 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 within the 12 months prior to screening. Subjects must have a 
negative urine drug screen for cannabinoids/tetrahydrocannabinol and non-
prescribed medications at screening. Subjects taking prescription drugs (except 
prescription cannabinoids/tetrahydrocannabinol) will be allowed. 
18. The subject is taking any excluded medications or treatments listed in the 
protocol (Section 5.9.2). 
19. 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. 
20. 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. 
21. 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. 
22. 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 recovered 
from cutaneous basal cell carcinoma or cervical carcinoma in situ). 
23. The subject has 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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24. 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 (except 
subjects with Gilbert Syndrome)  
4.1.1.3 Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently entered in the Run-In Period of 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, pretreatment adverse event (PTE), AEs, and any 
serious adverse events (SAEs). 
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. 
Subjects may be allowed to be rescreened upon discussion with medical monitor.  
4.1.2 
Selection for On-Demand Treatment Period 
4.1.2.1 Inclusion Criteria for On-Demand Treatment Period 
Subjects are eligible for enrollment in the On-Demand Treatment Period of the study if they 
meet all of the following inclusion criteria: 
1. The subject completes the Run-In Period, during which the subject was at least 
80% compliant with open-label study drug. 
2. The subject has stable disease, ie, no heartburn the last 7 days of the Run-In 
Period. 
3. The subject continues to fulfill all eligibility criteria for the Run-In Period 
(except Inclusion Criteria 4). 


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4. Subject completes at least 80% of diary entries during Run-In Period, including 
80% of diary entries over the last 7 days. 
4.1.2.2 Run-In Failures 
Run-In failures refer to instances when subjects consent to participate in the clinical study, 
are subsequently entered in the Run-In Period of the study, and do not meet the eligibility 
criteria for the On-Demand Treatment Period. Run-In failures may also include those 
subjects who withdraw from the study drug or the study (Section 4.2) during the Run-In 
Period. Run-In failures who do not meet On-Demand entrance eligibility criteria are to 
undergo all applicable Week 4 Run-In Period assessments (Table 13-1-Schedule of Events). 
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. 
4.2 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 1 week after completing the 
On-Demand Treatment Period. 
4.2.1 Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time (eg, Run-In Period, On-Demand 
Treatment Period) 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 drug or 
the study should be recorded in the electronic case report form (eCRF). For screen failure 
subjects, refer to Section 4.1.1.3. For Run-In failure subjects, refer to Section 4.1.2.2. 


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A subject may be withdrawn from the study for any of the following reasons: 
1. Adverse event or SAE: The subject has experienced a 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 or stable. 
2. Liver function test (LFT) abnormalities: Appropriate clinical follow-up 
(including repeat laboratory tests) is to be done until a subject’s laboratory 
profile has returned to normal/baseline status. See Appendix 3 (Section 13.3) 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 (IRBs) 
/Independent Ethics Committees (IECs), 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 6.3.2 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 drug or the study 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 
discontinue from the Run-In Period will undergo all Week 4 Run-In Period 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 SoE in Appendix 1 (Section 13.1) for data to be collected at the time of 
discontinuation of study drug and follow-up and for any further evaluations that need to be 
completed. 
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 4.2.1. 


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4.2.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she signs the ICF, repeatedly fails to 
return for scheduled visits during the Run-In Period or On-Demand Treatment Period, and is 
unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter [or local equivalent methods] to the subject’s last known 
mailing address 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 and have 
symptomatic NERD will initially be dosed during an open-label Run-In Period with 
vonoprazan 20 mg QD for 4 weeks. 
Subjects with stable disease (as defined by those who have no heartburn on the last 
7 consecutive days of the Run-In Period) and are compliant with the diary and study 
medication will be randomized using a 1:1:1:1 allocation ratio to receive either vonoprazan 
10 mg, 20 mg, or 40 mg or placebo during the 6-week On-Demand Treatment Period. 
Subjects will be provided study medication on Day -1 of the On-Demand Treatment Period 
and instructed to take their first dose of study medication after experiencing the first 
heartburn episode. 
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 will 
also use an appropriate block size, which will not be revealed. 
5.2 Treatments Administered 
5.2.1 Run-In Period 
• Open-label study drug (vonoprazan 20 mg QD) to be taken orally for 4 weeks. 
• Subjects should be instructed as follows: 
To take study drugs with approximately 240 mL (8 oz) water at about the same time 
each day. 
5.2.2 On-Demand Treatment Period 
• Blinded study drug (vonoprazan 10 mg, vonoprazan 20 mg, vonoprazan 40 mg, or 
placebo) to be taken orally On-Demand for treatment of episodic heartburn. Study 
drug should only be taken once in a 24-hour period. The diary will confirm if 


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24 hours has elapsed since the last dose of study drug. The On-Demand Treatment 
Period will be 6 weeks. 
• Subjects should be instructed as follows: 
To take study drug On-Demand with approximately 240 mL (8 oz) water. 
5.3 Rescue Antacid 
• Up to 12 tablets of Gelusil® per day (not more than 4 tablets at one time) may be used 
as rescue antacid during the Screening Period, Run-In Period, On-Demand Treatment 
Period, and Safety Follow-up Period.  
• During the On-Demand Period, rescue antacid should not be taken until 3 hours after 
study drug administration.  
5.4 Identity of Investigational Product and Rescue Antacid 
5.4.1 Vonoprazan and Placebo 
Vonoprazan study medication will be supplied as 10-mg, 20-mg, and 40-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. The 40-mg capsule is composed of two 20-mg tablets in one Swedish 
Orange DB-AAel capsule. 
 
manufactures the vonoprazan drug substance and tablet drug product. 
The over-encapsulated vonoprazan 10-mg, 20-mg, and 40-mg dose strengths and placebo 
will be identical in appearance. They will be packaged in bottles. 
5.4.2 Rescue Antacid  
Sites will be provided with Gelusil as rescue antacid. The sites will dispense rescue antacid 
on the first day of the Screening Period, and as needed during the Run-In, On-Demand 
Treatment, and Safety Follow-up Periods.  


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5.5 Management of Clinical Supplies 
5.5.1 Study Drug Packaging and Storage 
Over-encapsulated vonoprazan and placebo will be distributed in bottles and shipped by 
. 
Study supplies must be stored in a secure area (eg, a locked cabinet), protected from 
moisture, and kept at a controlled room temperature (20°C to 25°C [68°F to 77°F]; 
excursions allowed between 15°C and 30°C [59°F to 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. 
Gelusil rescue antacid will be supplied in the original commercial package with a 
protocol-specific ancillary label and will be shipped by 
. Gelusil must be stored in a 
secure area (eg, a locked cabinet) under the conditions specified on the commercial label 
(below 30°C [86°F]) and remain in the original container until dispensed. 
5.5.2 Test Article and Rescue Antacid 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. 
The investigator will maintain accurate records of receipt of all rescue antacid, including 
dates of receipt. In addition, accurate records will be kept regarding when study drug is 
dispensed in the study.  
5.6 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 


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Section 6.3.1.3.1. The SAEs associated with overdose should be reported according to the 
procedure outlined in Section 6.3.1.3.2. 
5.6.1 Treatment of Overdose 
In the event of drug overdose, the subject should be treated symptomatically. 
5.7 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 On-Demand Treatment Period. 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, the database is locked, and the study is unblinded. 
5.7.1 Breaking the Blind 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. In 
the event of a medical emergency, the investigator will be able to access the IRT to determine 
the subject’s treatment group assignment. The investigator will, whenever possible, discuss 
options with the medical monitor before unblinding. The sponsor must be notified as soon as 
possible if the investigational drug blind is broken. The date, time, and reason the blind is 
broken must be recorded in the source documents, and the same information (except the 
time) must be recorded on the eCRF. If any site personnel are unblinded, administration of 
the investigational drug must be stopped immediately, and the subject must be withdrawn 
from the study. 


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5.8 Study Compliance 
5.8.1 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.  
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 will be recorded in the eCRF. 
Noncompliance during the Run-In Period 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. 
5.8.2 Diary Compliance 
Diary noncompliance during the Run-In Period or On-Demand Treatment Period is defined 
as completing less than 80% of study diary entries. Subjects exhibiting poor compliance as 
assessed by diary entries should be counseled on the importance of good compliance to the 
study assessments. 
5.9 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 


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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, 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. 
Prior use of H2RAs or PPIs should be documented. The dose and duration and whether or not 
symptoms were relieved by the medication should be collected.  
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
5.9.1 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 4.1.1.2) 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 who 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. 


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5.9.2 Excluded Medications 
A list of excluded medications is provided in Table 5-1 
Table 5-1 
Excluded Medications and Treatments 
Excluded Medications and Treatments 
Beginning of 
Exclusion 
End of 
Exclusion 
Other investigational drugs or drugs administered 
due to participation in another clinical trial 
30 days prior to start of 
Screening Period 
Follow-up Visit 
Antacids (except study-supplied Gelusil) 
Screening Period 
Follow-up Visit 
H2RAs 
Screening Period 
Follow-up Visit 
PPIs 
Screening Period 
Follow-up Visit 
Strong inhibitors or inducers of CYP3A4 (eg, 
itraconazole, ketoconazole, indinavir, nelfinavir, 
ritonavir, saquinavir, telithromycin) 
14 days prior to Run-In 
Period Day 1 
End of On-
Demand 
treatment 
CYP3A4 substrates with a narrow therapeutic index 
14 days prior to Run-In 
Period Day 1 
End of On-
Demand 
treatment 
Surgical procedures that could affect gastric acid 
secretion (eg, any form of partial gastrectomy, 
vagotomy) 
30 days prior to Run-In 
Period Day 1 
Follow-up Visit 
Other agents affecting digestive organs, including 
muscarinic antagonists (eg, hyoscyamine), 
prokinetics, oral anticholinergic agents, 
prostaglandins, bismuth, sucralfate 
30 days prior to Run-In 
Period Day 1 
Follow-up Visit 
Atazanavir sulfates; rilpivirine hydrochloride 
(contraindicated with vonoprazan) 
5 days prior to Run-In 
Period Day 1 
Follow-up Visit 
Abbreviations: CYP, cytochrome P450 isoenzyme; H2RA, histamine-2 receptor antagonist; PPI, proton pump 
inhibitor. 


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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 Endoscopy 
During the Screening Period, an endoscopy will be performed on all subjects to document the 
absence of EE. The screening endoscopy should be performed after the subject has fulfilled 
all other admission criteria (including diary) and will be assessed by the investigator. Any 
endoscopic confirmation performed in a routine clinical setting within 7 days before signing 
the informed consent is acceptable to use for the purpose of fulfilling the screening 
requirement. 
6.2 Efficacy Assessments  
6.2.1 Electronic Diary 
Subjects will be given an electronic diary on the first day of the Screening Period. During the 
Screening, Run-In, and Safety Follow-up Periods subjects will complete the morning and 
evening Heartburn Diary and Rescue Antacid Diary. During the On-Demand Treatment 
Period, subjects will complete the heartburn episode diary, including the Timed Heartburn 
Assessments and Rescue Antacid Diary. Subjects must bring the electronic diary device to 
each site visit for the investigator to verify Run-In and On-Demand diary eligibility criteria 
and to move the subject to the appropriate period within the electronic diary device, as noted 


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in the eDiary Vendor User Manual. Subjects must return the devices that have been assigned 
to them upon completion/termination from the study. 
6.2.1.1 Morning and Evening Heartburn Diary  
During the Screening Period, Run-In Period, and Safety Follow-up Period, subjects will 
document the presence and 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 episode and severity rating) and every 
evening before bedtime (to record that day's heartburn episode and severity rating). 
6.2.1.2 Rescue Antacid Diary  
During all periods of the study, subjects will record the use of rescue antacid, including the 
time and number of tablets taken.  
6.2.1.3 On-Demand Heartburn Episode Diary 
During the On-Demand Treatment Period, subjects will document episodes of heartburn 
experienced and the use of On-Demand study medication as they occur. On days that a 
subject has not reported an episode of heartburn, subjects will also be reminded every 
morning and every evening to record any unrecorded heartburn episodes (no longer than the 
prior day) OR to document that they have not had any heartburn episodes. 
6.2.1.4 On-Demand Heartburn Timed Assessments  
Once heartburn is reported and the subject is eligible to take study medication (ie, 24 hours 
since the last administration), the diary will be programmed to collect the heartburn episode 
assessments for 3 hours in order to assess when heartburn relief occurs. The diary will 
prompt responses 30 minutes after study drug administration is reported and then 1, 1.5, 2, 
and 3 hours after study drug treatment. On rare occasions, when required, subjects may opt 
out of the timed assessments. 
6.2.1.5 Severity Definitions 
The severity of heartburn will be graded by the subject according to the definitions outlined 
in Table 6-1 for the Screening, Run-In, and Safety Follow-up Periods. 


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Table 6-1 
Definitions of Heartburn Severity (Daytime/Nighttime) for the 
Screening, Run-In, and Safety Follow-up Periods 
Definitions of Daytime Heartburn Severity (Daytime=Awake Time) 
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) 
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 
 
The severity of heartburn will be graded by the subject according to the definitions outlined 
in Table 6-2 for the On-Demand Treatment Period. 
Table 6-2 
Definitions of Heartburn Severity for the On-Demand Treatment 
Period 
Mild - Heartburn is present but can be ignored, does not influence daily routine or sleep 
Moderate - Heartburn cannot be ignored and/or occasionally influences daily routine or sleep  
Severe - Heartburn regularly influences daily routine or sleep  
Very Severe - Heartburn markedly influences daily routine or sleep 
 
6.2.2 PAGI-SYM Questionnaire 
During the start of the Run-In Period (Day -1), at the end of the Run-In Period, and at the end 
of the On-Demand Treatment Period, each subject will self-administer a paper version of the 
Patient Assessment of Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM) 
questionnaire. 
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. 


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6.2.3 PAGI-QoL Questionnaire 
During the start of the Run-In Period (Day -1), at the end of the Run-In Period, and at the end 
of the On-Demand Treatment Period, each subject will self-administer a paper version of the 
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-QoL) 
questionnaire. 
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.  
6.2.4 Patient Global Impression of Change Questionnaire 
At the end of the Run-In Period and at the end of the On-Demand Treatment Period, each 
subject will self-administer a paper version of the Patient Global Impression of Change. 
Subjects will record their responses directly on each questionnaire. The data from the 
questionnaire will be entered into the eCRF, and the originals will remain at the site as source 
documentation.  
6.2.5 Patient Global Impression of Severity Questionnaire 
At the end of the Run-In Period and at the end of the On-Demand Treatment Period, each 
subject will self-administer a paper version of the Patient Global Impression of Severity. 
Subjects will record their responses directly on each questionnaire. The data from the 
questionnaire will be entered into the eCRF, and the originals will remain at the site as source 
documentation. 
6.2.6 Patient Preference Questionnaire 
At the end of the On-Demand Treatment Period, each subject will self-administer a paper 
version of the Patient Preference Questionnaire. 
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. 


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6.3 Safety Assessments 
6.3.1 Pretreatment Events and Adverse Events 
6.3.1.1 Definitions  
6.3.1.1.1 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. 
6.3.1.1.2 
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 adverse event (TEAE) is defined as any event that occurs after the first 
dose of study drug or any event at baseline that worsens in either intensity or frequency after 
the first dose of study drug in that period. 
6.3.1.1.3 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence at any dose for which the following 
occurs:  
1. Results in DEATH.  
2. Is LIFE-THREATENING. The term “life-threatening” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe.  
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.  
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Is CONGENITAL ANOMALY/BIRTH DEFECT.  
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:  


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• May require intervention to prevent items 1 through 5 above 
• May include any event or symptoms described in the medically significant AE list 
(Table 6-2) 
• Exposes the subject to danger, even though the event is not immediately 
life-threatening or fatal or does not result in hospitalization 
Table 6-2 
Medically Significant Adverse Event List 
Term 
Acute respiratory failure / acute respiratory distress syndrome 
Torsade de pointes / ventricular fibrillation / ventricular tachycardia 
Malignant hypertension 
Convulsive seizure agranulocytosis  
Aplastic anemia  
Toxic epidermal necrolysis/Stevens-Johnson syndrome  
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis 
Confirmed or suspected endotoxin shock 
Confirmed or suspected transmission of infectious agent by a medicinal product 
Neuroleptic malignant syndrome / malignant hyperthermia 
Spontaneous abortion / stillbirth and fetal death 
 
The PTEs that fulfill one or more of the serious criteria above are also to be considered SAEs 
and should be reported and followed up in the same manner (see Section 6.3.1.3.2 and 
Section 6.3.1.3.3). 
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 6.3.1.3.2. 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 6.3.3 


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must also be performed. In addition, if the LFT increases are SAEs, a Liver Function Test 
Increase Form must be completed and transmitted (see Appendix 3, Section 13.3). 
6.3.1.1.4 
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 Table 6-3. 
Table 6-3 
Adverse Events of Special Interest List 
Term 
Hepatotoxicity  
Severe cutaneous adverse reactions 
Clostridium difficile infections and pseudomembranous colitis 
Hypergastrinemia 
Bone fracture 
 
For additional details on liver function monitoring see Section 13.3. 
6.3.1.1.5 
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.  


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• Is caused by a study procedure (eg, a bruise after blood collection); 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. Abnormal 
findings identified at baseline evaluations and screening assessments (eg, laboratory tests, 
ECG, endoscopy, 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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6.3.1.2 Documenting Adverse Events 
6.3.1.2.1 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. 
6.3.1.2.2 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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6.3.1.2.3 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. 
6.3.1.2.4 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. 
6.3.1.2.5 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. 
6.3.1.2.6 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. 
6.3.1.2.7 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. 


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6.3.1.2.8 Outcome 
• Recovered/resolved: Subject returned to baseline status with respect to the AE/PTE. 
• Recovering/resolving: The intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms have lessened/improved; 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 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. 
6.3.1.3 Time Period and Frequency for Collecting AE and SAE 
Information 
6.3.1.3.1 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 the study 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 


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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 be 
followed up for the purposes of the protocol. All subjects experiencing AEs, whether 
considered associated with the use of the study drug or not, must be monitored until the 
symptoms subside and any clinically relevant changes in laboratory values have returned to 
baseline or until there is a satisfactory explanation for the changes observed. 
All PTEs and AEs will be documented in the PTE/AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event: 
1. Event term 
2. Start and stop date 
3. Severity 
4. Investigator’s opinion of the causal relationship between the event and administration 
of study drug(s) (related or not related) (not completed for PTEs) 
5. Investigator’s opinion of the causal relationship to study procedure(s), including the 
details of the suspected procedure 
6. Action concerning study drug (not applicable for PTEs) 
7. Outcome of event 
8. Seriousness 
6.3.1.3.2 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 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 


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• Investigator’s name 
• Name of the study drug(s) 
• Causality assessment 
If the Medidata Rave system is not functioning for any reason, a paper SAE case report form 
must be completed (in English), signed by the investigator, and faxed to the contact listed 
below. 
The SAE 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. 
6.3.1.3.3 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 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. 


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All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
6.3.1.3.4 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. 
6.3.1.4 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 toward 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 SUSARs according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 


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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it and will notify the IRB/IEC, if appropriate according to local requirements. 
If there is an increase in unexpected SAEs or if there is a change in the frequency and 
character of expected SAEs based on the known safety profile of vonoprazan, further 
evaluation will be conducted to characterize these events and any impact on benefit/risk. 
Health Authorities will be consulted to agree upon the appropriate action to be taken 
regarding the conduct of the study, including no change to the protocol, revision of the safety 
monitoring plan, suspension of enrollment, or discontinuation of the study. 
6.3.2 Pregnancy 
If any subject is found to be pregnant during the study, she should be withdrawn, and any 
sponsor-supplied drug (vonoprazan active) should be immediately discontinued. If the 
pregnancy occurs during administration of active study drug, eg, after Visit 2 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 6.3.1.3.2. 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 (whether subjects on active study drug 
or placebo) will be reported using the pregnancy form and will be followed up to final 
outcome. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted. 


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6.3.3 Laboratory Analyses 
See Table 6-4 for the list of clinical laboratory tests to be performed and the SoE 
(Section 13.1) for the timing and frequency. 
• The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Abnormal laboratory findings 
that are expected with the underlying disease should not be considered clinically 
significant unless judged by the investigator to be more severe than expected for the 
subject’s condition. 
• All laboratory tests with abnormal values considered clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor 
notified. 
o All protocol-required laboratory assessments, as defined in Table 6-4, 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 6-4 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)(e) 
• 
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 
• 
Serum hCG pregnancy test(c) at Screening Visit 1 
• 
Urine hCG pregnancy test(c) at Run-In Period Visit 2, randomization Visit 3, and final 
visit for On-Demand Treatment Period Visit 5 
• 
Serology (HIV antibody, HBsAg, and HCV antibody; hepatitis C, viral load RNA(d) 
[qualitative]) 
• 
Serum gastrin (fasting 12 hours) and serum pepsinogen I and II levels will also be 
evaluated as safety/PD biomarkers at Day -1 of Run-In Period; Week 4 of Run-In 
Period; Week 6 of On-Demand Treatment Period; and safety follow-up visit. Day -1 
baseline gastrin levels will not be blinded. Gastrin at the Week 4 Run-In, Week 6 
On-Demand treatment, and Safety Follow-up visits  and all pepsinogen I and II results 
will be blinded and will not be reported to investigative sites or other blinded 
personnel until after 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; HCV, hepatitis C virus; HIV, human immunodeficiency virus; MCH, mean 
corpuscular hemoglobin; MCV, mean corpuscular volume; PD, pharmacodynamics; RBC, red blood cell; 
SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase; WBC, 
white blood cell. 
(a)  See Section 13.3 for the appropriate guidance on reporting of abnormal liver function tests. For liver 
function test monitoring, see Section 13.3.1. For temporary and permanent discontinuation of study 
drugs due to abnormal liver function tests, see Section 13.3.2 and Section 13.3.3, respectively. 
(b) Required only for confirmation of postmenopausal females as defined in Section 13.2 (Appendix 2). 
Women whose duration of (consecutive) amenorrhea is borderline or open to doubt and where the 
investigator believes the subject to be menopausal by history should have confirmatory FSH drawn. 
(c)  As needed for women of childbearing potential. During the Run-In Period and On-Demand Treatment 
Period, serum pregnancy test will be performed if the urine pregnancy test is positive. 
(d)  Reflex - if hepatitis C positive. 
(e) 8 hours fasting at Screening Visit 1. 
 
Investigators must document their review of each laboratory safety report. 
6.3.4 Physical Examinations 
Refer to the SoE (Section 13.1) for the timing and frequency for full and brief physical 
examinations, as well as height and weight.  
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. 
6.3.5 Vital Signs 
Refer to the SoE (Section 13.1) for the timing and frequency of vital sign assessments.  
Vital signs will include body temperature (oral, temporal, or tympanic measurement), sitting 
blood pressure (resting more than 5 minutes), and heart rate (beats per minute).  


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6.3.6 Electrocardiograms 
Refer to the SoE (Section 13.1) for the timing and frequency of ECG assessments.  
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using one of the following categories: within 
normal limits, abnormal but not clinically significant, or abnormal and clinically significant. 
The following parameters will be recorded on the eCRF from the subject’s ECG trace: heart 
rate, PR interval, RR interval, QT interval, QTcF (derived) 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. 
6.4 Safety Monitoring Committee 
Not applicable. 
 


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7 
Statistical and Analytical Plan 
This section 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 endpoints. To preserve the integrity of the statistical 
analysis and study conclusions, the SAP will be finalized before database lock. 
7.1 Sample Size Calculations 
The sample size for the On-Demand Treatment Period is calculated based on the following 
assumptions: 
• Subjects will be randomized to receive either vonoprazan 10 mg, 20 mg, or 40 mg or 
placebo with a randomization ratio of 1:1:1:1. 
• Each subject experiences at least 4 evaluable heartburn episodes.  
• Comparison between each dose of vonoprazan to placebo will be performed using the 
Fisher’s Exact test.  
• A clinically relevant difference of 15% between each dose of vonoprazan and placebo 
in the proportion of evaluable heartburn episodes completely relieved within 3 hours 
and with no further heartburn reported for 24 hours after taking study drug.  
Based on these assumptions, a sample size of 200 heartburn episodes per treatment group (or 
50 subjects with at least 4 heartburn episodes per treatment group) provides at least 80% 
statistical power at the significance level of 0.05. During the study if less than 200 subjects 
are projected to enroll into the On-Demand Treatment Period, additional subjects may be 
enrolled into the Run-In Period to ensure that a sufficient number of subjects enroll into the 
On-Demand Treatment Period. 
Assuming 60% of subjects at the end of the Run-In Period do not meet the eligibility criteria 
for the On-Demand Treatment Period, a total of  approximately 500 subjects will be enrolled 
into the Run-In Period to achieve 200 subjects for the On-Demand Treatment Period.  


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The hypothesis testing is as follows: 
Null Hypothesis  
H0: Pvono = Pplacebo 
Alternative Hypothesis 
Ha: Pvono ≠ Pplacebo 
where P is the proportion of heartburn episodes. 
7.2 Analysis Sets 
The following analysis sets will be used in the statistical analysis. 
7.2.1 All Subjects Set 
All Subjects set consists of all eligible subjects who enrolled into the Run-In Period. 
7.2.2 Safety Sets 
All safety endpoints will be reported for the Run-In and On-Demand Treatment Periods 
separately using the Safety set of each period. For the Run-In Period, the primary and 
secondary endpoints will be reported for the Safety Run-In set. 
Safety Run-In Set 
The Safety Run-In set includes subjects in the All Subjects set who received at least one dose 
of study drug (vonoprazan 20 mg) during the Run-In Period. 
Safety On-Demand Set  
The Safety On-Demand set includes all subjects in the Safety Run-In set who were 
randomized and treated at least one heartburn episode with randomized treatment during the 
On-Demand Treatment Period. 
7.2.3 Intent-to-Treat Set 
All efficacy endpoints (primary, secondary, and exploratory) will be analyzed for the 
On-Demand Treatment Period for the Intent-to-Treat (ITT) On-Demand set. 


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Intent-to-Treat On-Demand Set 
The ITT On-Demand set includes all subjects in the Safety Run-In set who were randomized 
and completed at least one heartburn episode diary during the On-Demand Treatment Period. 
7.3 Description of Subgroups  
The primary endpoint, the percentage of evaluable heartburn episodes completely relieved 
within 3 hours and with no further heartburn reported for 24 hours after taking study drug, 
will be analyzed by subgroup using the primary analysis method.  
The subgroups are: 
• age category, years (<45, ≥45 - <65, ≥65 - <75, ≥75) 
• sex (male, female)  
• baseline body mass index (BMI) category, kg/m2 (<25, ≥25 - <30, ≥30)  
• mean heartburn severity during the Screening Period (mild, moderate, severe, very 
severe) 
7.4 Statistical Analysis Methodology 
For the On-Demand Treatment Period, each treatment comparison of vonoprazan 10 mg, 
20 mg, and 40 mg to placebo will be tested at the 0.05 significance level. 
An evaluable heartburn episode is an episode for which study drug was taken and for which 
the subject completed at least one entry in the heartburn episode diary. For a heartburn 
episode to be considered completely relieved, a subject must not have taken rescue antacid 
within 3 hours of taking study drug. 
Continuous variables will be summarized using the mean, standard deviation, median, 
minimum value, and maximum value. Categorical variables will be summarized using 
frequency counts and percentages. Statistical analysis of all endpoints, primary, secondary, 
and exploratory, will be described in detail in the SAP. Statistical analysis will be performed 
using SAS software Version 9.4 or later. 


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No adjustments will be made for multiple comparisons given the exploratory nature of this 
study. 
7.4.1 Efficacy Analyses 
7.4.1.1 
Primary Efficacy Endpoint 
The primary endpoint of the percentage of evaluable heartburn episodes completely relieved 
within 3 hours and with no further heartburn reported for 24 hours after taking study drug 
will be compared between each dose of vonoprazan and placebo using Fisher’s Exact test for 
the ITT On-Demand set. 
A sensitivity analysis of the primary endpoint will be performed by including heartburn 
episodes with rescue antacid use within 3 hours after taking study drug as completely 
relieved.  
7.4.1.2 Secondary Efficacy Endpoint 
All secondary endpoints will be analyzed for the ITT On-Demand set and compared for each 
dose of vonoprazan to placebo.  
The following secondary endpoints will be compared for each dose of vonoprazan to placebo 
using Fisher’s Exact test. 
• The percentage of evaluable heartburn episodes completely relieved within 3 hours 
after taking study drug. 
• The percentage of subjects with complete relief of heartburn within 3 hours after the 
first episode and with no further heartburn reported for 24 hours after taking study 
drug. 
The following secondary endpoints will be compared for each dose of vonoprazan to placebo 
using a Wilcoxon rank-sum test. 
• The percentage of evaluable heartburn episodes for each subject that are completely 
relieved within 3 hours and with no further heartburn reported for 24 hours after 
taking study drug. 


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• The percentage of days study drug was taken over the On-Demand Treatment Period. 
• The mean number of tablets of rescue antacid taken per day over the On-Demand 
Treatment Period. 
• The percentage of 24-hour heartburn-free days over the On-Demand Treatment 
Period. 
7.4.1.3 Exploratory Endpoints On-Demand Treatment Period 
The exploratory endpoints will be analyzed for the ITT On-Demand set. The analysis of 
exploratory endpoints will be described in detail in the SAP. These endpoints are: 
• The percentage of evaluable heartburn episodes completely relieved within 
30 minutes or 1, 1.5, or 2 hours and with no further heartburn reported for 24 hours 
after taking study drug. 
• The percentage of evaluable heartburn episodes that are completely relieved within 
30 minutes or 1, 1.5, or 2 hours after taking study drug.  
• The percentage of evaluable heartburn episodes that improved at 30 minutes or 1, 1.5, 
2, or 3 hours after taking study drug. 
• The percentage of episodes for which subjects continue to be heartburn-free after 24 
or 48 hours of taking study drug. 
• The percentage of subjects with at least 50%, at least 75%, and 100% of their 
evaluable heartburn episodes completely relieved within 3 hours with no further 
heartburn reported for 24 hours after taking study drug. 
• The percentage of subjects with at least 50%, at least 75%, and 100% of their 
evaluable heartburn episodes completely relieved within 3 hours after taking study 
drug. 
• The percentage of subjects with complete relief of the first episode of heartburn 
within 3 hours after taking study drug. 
• The mean number of days between heartburn episodes. 


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• The percentage of days without daytime heartburn over the On-Demand Treatment 
Period.  
• The percentage of days without nighttime heartburn over the On-Demand Treatment 
Period.  
• The mean severity of daytime and nighttime heartburn over the On-Demand 
Treatment Period.  
• The mean severity of nighttime heartburn over On-Demand Treatment Period.  
• The mean severity of daytime heartburn over the On-Demand Treatment Period.  
• The percentage of days without rescue antacid use over the On-Demand Treatment 
Period.  
• The change from baseline to the end of the On-Demand Treatment Period for each 
subscale and the total score of the PAGI-SYM questionnaire. 
• The change from baseline to the end of the On-Demand Treatment Period for each 
subscale and the total score of the PAGI-QoL questionnaire. 
• The patient global impression of change in GERD symptoms at the end of the 
On-Demand Treatment Period. 
• The patient global impression of severity in GERD symptoms over the last 7 days of 
the On-Demand Treatment Period. 
• The percentage of subjects with each dosing preference. 
7.4.1.4 Exploratory Endpoints Run-In Period 
The exploratory endpoints will be analyzed for the Safety Run-In set. The analysis of 
exploratory endpoints will be described in detail in the SAP. These endpoints are: 
• The percentage of 24-hour heartburn-free days over the Run-In Period.  
• The percentage of days without daytime heartburn over the Run-In Period.  


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• The percentage of days without nighttime heartburn over the Run-In Period.  
• The mean severity of daytime and nighttime heartburn over the Run-In Period.  
• The mean severity of nighttime heartburn over the Run-In Period.  
• The mean severity of daytime heartburn over the Run-In Period.  
• The percentage of days without rescue antacid use over the Run-In Period.  
• The change from baseline to the end of the Run-In Period for each subscale and the 
total score of the PAGI-SYM questionnaire. 
• The change from baseline to the end of the Run-In Period for each subscale and the 
total score of the PAGI-QoL questionnaire. 
• The patient global impression of change in GERD symptoms at the end of the Run-In 
Period.  
• The patient global impression of severity in GERD symptoms over the last 7 days of 
the Run-In Period. 
7.4.2 Safety Analyses 
Safety will be summarized separately for the Run-In Period and the On-Demand Treatment 
Period. For each period, safety will be assessed by summarizing the incidence of AEs and 
changes in clinical laboratory tests, gastrin and pepsinogen I/II levels, ECGs and vital signs. 
For the Run-In Period, baseline will be the last assessment on or before the date of first dose 
of study drug in the Run-In Period. For the On-Demand Treatment Period, baseline will be 
the last assessment on or before the date of randomization.  
Adverse Events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of subjects experiencing TEAEs (see definition in 
Section 6.3.1.1.2) will be summarized by MedDRA system organ class (SOC) and preferred 
term (PT) overall, by severity, and by relationship to study drug for the Run-In and 
On-Demand Treatment Periods for each treatment group. Separate summaries will also be 
generated for treatment-related AEs overall and by severity. 


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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 an SOC, the subject will be counted only once for that SOC. In the 
tabulation of TEAE frequency by maximum intensity, a subject will be counted only once 
using the highest severity for each PT and SOC. 
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. 
7.4.3 Other Analyses 
For the Run-In Period, demographics and other baseline characteristics will be summarized 
overall and by treatment group using the Safety Run-In set. For the On-Demand Treatment 
Period, demographics and other baseline characteristics will be summarized overall and by 
treatment group using the ITT On-Demand and Safety On-Demand 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, race). 
7.4.4 Interim Analyses 
No interim analyses will be performed. 


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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 (DHHS 2018). The 
sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). 
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 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 subinvestigator listed on Form FDA 1572 
or equivalent form for non-US sites 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, the 
investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
• IRB/IEC-approved informed consent, samples of site advertisements for recruitment for 
this study, and any other written information regarding this study that is to be provided to 
the subject 
• Laboratory certifications and normal ranges for any local laboratories used by the site, in 
accordance with 42 CFR 493 
10.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6. The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of subjects begins. 
10.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6 and all applicable guidelines and regulations. 


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


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11 Study Management 
11.1 Monitoring 
11.1.1 External Data Monitoring Committee 
Not applicable. 
11.1.2 Monitoring of the Study 
The clinical monitor, 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. 


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


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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 
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 
Ashida K, Iwakiri K, Hiramatsu N, Sakurai Y, Hori T, Kudou K, et al. Maintenance for 
healed erosive esophagitis: Phase III comparison of vonoprazan with lansoprazole. World 
J Gastroenterol. 2018;24(14):1550-61. 
Bayerdörffer E, Bigard MA, Weiss W, Mearin F, Rodrigo L, Dominguez Muñoz JE, et al. 
Randomized, multicenter study: on-demand versus continuous maintenance treatment 
with esomeprazole in patients with non-erosive gastroesophageal reflux disease. BMC 
Gastroenterol. 2016;16:48.  
Bytzer P, Blum A, De Herdt D, Dubois D; Trial Investigators. Six-month trial of 
on-demand rabeprazole 10 mg maintains symptom relief in patients with non-erosive 
reflux disease. Aliment Pharmacol Ther. 2004;20(2):181-8.  
Colin-Jones DG. The role and limitations of H2-receptor antagonists in the treatment of 
gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 1995;9(suppl 1):9-14. 
Department of Health and Human Services (DHHS), Food and Drug Administration 
(FDA), Center for Drug Evaluation and Research (CDER), Center for Biologics 
Evaluation and Research (CBER). Guidance for industry: E6(R2) Good Clinical Practice: 
Integrated Addendum to E6(R1) March 2018. [cited 2021 Jan 12] Available from: 
https://www.fda.gov/media/93884/download  
El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of 
gastro-oesophageal reflux disease: a systematic review. Gut. 2014;63(6):871-80. 
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. 
Hoshikawa Y, Kawami N, Hoshino S, Tanabe T, Umezawa M, Kaise M, et al. Efficacy of 
on-demand therapy using 20-mg vonoprazan for non-erosive reflux disease. Esophagus. 
2019;16(2):201-6.  
Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of 
gastroesophageal reflux disease. Am J Gastroenterol. 2013;108(3):308-29. 


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Khan Z, Alastal Y, Khan MA, Khan MS, Khalil B, Shrestha S, et al. On-demand therapy 
with proton pump inhibitors for maintenance treatment of nonerosive reflux disease or 
mild erosive esophagitis: a systematic review and meta-analysis. Gastroenterol Res Pract. 
2018;2018:6417526. 
Kinoshita Y, Sakurai Y, Shiino M, Kudou K, Nishimura A, Miyagi T, et al. Evaluation of 
the efficacy and safety of vonoprazan in patients with nonerosive gastroesophageal reflux 
disease: a Phase III, randomized, double-blind, placebo-controlled, multicenter study. 
Curr Ther Res Clin Exp. 2016;81-82:1-7.  
Kinoshita Y, Sakurai Y, Takabayashi N, Kudou K, Araki T, Miyagi T, et al. Efficacy and 
safety of vonoprazan in patients with nonerosive gastroesophageal reflux disease: a 
randomized, placebo-controlled, Phase 3 study. Clin Transl Gastroenterol. 
2019;10(11):e00101.  
Ohkuma K, Iida H, Inoh Y, Kanoshima K, Ohkubo H, Nonaka T, et al. Comparison of the 
early effects of vonoprazan, lansoprazole and famotidine on intragastric pH: a three-way 
crossover study. J Clin Biochem Nutr. 2018;63(1):80-3. 
Pace F, Tonini M, Pallotta S, Molteni P, Porro GB. Systematic review: maintenance 
treatment of gastro-oesophageal reflux disease with proton pump inhibitors taken 
'on-demand'. Aliment Pharmacol Ther. 2007;26(2):195-204. 
Rome IV Criteria page. Rome Foundation web site. Available at: 
https://theromefoundation.org/rome-iv/rome-iv-criteria/. Accessed January 14, 2021. 
Savarino E, de Bortoli N, De Cassan C, Della Coletta M, Bartolo O, Furnari M, et al. The 
natural history of gastro-esophageal reflux disease: a comprehensive review. Dis 
Esophagus. 2017;30(2):1-9. 
Talley NJ, Lauritsen K, Tunturi-Hihnala H, Lind T, Moum B, Bang C, et al. 
Esomeprazole 20 mg maintains symptom control in endoscopy-negative 
gastro-oesophageal reflux disease: a controlled trial of 'on-demand' therapy for 6 months. 
Aliment Pharmacol Ther. 2001;15(3):347-54.  


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Talley NJ, Venables TL, Green JR, Armstrong D, O’Kane KP, Giaffer M, et al. 
Esomeprazole 40 mg and 20 mg is efficacious in the long-term management of patients 
with endoscopy-negative gastro-oesophageal reflux disease: a placebo-controlled trial of 
on-demand therapy for 6 months. Eur J Gastroenterol Hepatol. 2002;14(8):857-63.  
Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group. 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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(c)  The date of first dosing day is defined as Day 1 in both Run-In Period and On-Demand Treatment Period. The date of randomization is defined as Day -1 
of On-Demand Treatment Period. 
(d)  Subjects should continue to meet inclusion criteria (Section 4.1.1.1) and exclusion criteria (Section 4.1.1.2), except Inclusion Criterion 4. 
(e) Full physical examination is performed at Screening; a brief physical examination is performed at all other visits. 
(f) Required only for confirmation of postmenopausal females as described in Section 13.2 (Appendix 2). Women whose duration of (consecutive) 
amenorrhea is borderline or open to doubt and where the investigator believes the subject to be menopausal by history should have confirmatory FSH 
drawn. 
(g)  See Section 6.3.3 and Table 6-4 for all required laboratory assessments.  
(h)  Gastrin Week 4 Run-In, Week 6 On-Demand treatment and Safety follow-up visits and pepsinogen I and II results will be blinded and will not be reported 
to investigative sites or other blinded personnel until the study blind is broken. 
(i)  Only female subjects with childbearing potential. Serum hCG at screening and urine hCG at all subsequent visits.  
(j)  The screening endoscopy can be performed any time during that period; however, it should be performed after the subject has fulfilled all other admission 
criteria. Any endoscopic confirmation performed in a routine clinical setting within 7 days before signing the informed consent is acceptable to use for the 
purpose of fulfilling the screening requirement. 
(k)  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 Screening, Run-In and Follow-up Period. During the On-Demand Treatment Period, subjects will be 
instructed to complete the electronic diary to document heartburn episodes and study drug administration. Rescue antacid use should be reported during 
all periods.  
(l)  Subjects are to start dose administration from Day 1. 
(m)  Rescue antacid will be dispensed as needed after the Screening Period.  
(n)  Sites will document dispensing rescue antacid. Subjects do not need to return unused rescue antacid. 
(o) Day -1 baseline gastrin levels will not be blinded.  
(p) Run-In failure 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 
follicle-stimulating hormone (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  
• 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, serum human chorionic gonadotropin (hCG) will be 
performed at Screening and regular urine hCG pregnancy tests will be performed only for 
women of childbearing potential. 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: Liver Function Tests 
13.3.1 
Liver Function Test Monitoring 
Liver function will be carefully monitored throughout the study. Additional monitoring may be 
necessary and is recommended for subjects with abnormal LFTs. 
If subjects with normal baseline ALT or AST levels experience ALT or AST >3 × ULN and a 2-
fold increase above baseline, follow-up laboratory tests (at a minimum, serum alkaline 
phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase (GGT), and international 
normalized ratio [INR]) should be repeated within a maximum of 7 days and preferably within 
48 to 72 hours after the abnormality was found. 
If subjects with elevated baseline ALT or AST levels experience ALT or AST >5 × ULN, follow-
up laboratory tests (at a minimum, serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, 
and INR) should be repeated within a maximum of 7 days and preferably within 48 to 72 hours 
after the abnormality was found. 
If subjects with either a normal or elevated baseline ALT or AST levels experience ALT or AST 
>8 × ULN, follow-up laboratory tests (at a minimum, serum alkaline phosphatase, ALT, AST, 
total bilirubin, GGT, and INR) should be repeated within a maximum of 48 hours after the 
abnormality was found. 
13.3.2 
Considerations for Temporary Discontinuation of Study Drug 
If the ALT or AST levels remain elevated >3 × ULN in subjects with normal baseline ALT or 
AST levels and a 2-fold increase above baseline OR if the ALT or AST levels remain elevated >5 
× ULN in subjects with elevated baseline ALT or AST levels on 2 consecutive occasions, the 
investigator must contact the medical monitor to discuss additional testing, recommended 
monitoring, possible temporary discontinuation of study drug, and possible alternative etiologies. 


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13.3.3 
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:  
13.3.4 
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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13.4 Appendix 4: Rome IV Criteria for Functional Heartburn and Functional 
Dyspepsia 
Rome IV criteria (2016) available at https://theromefoundation.org/rome-iv/rome-iv-criteria/. 
13.4.1 
Functional Heartburn 
Functional Heartburn Diagnostic Criteria (Note: criteria fulfilled for the last 3 months with 
symptom onset at least 6 months prior to diagnosis with a frequency of at least twice a week) 
• Burning retrosternal discomfort or pain 
• No symptom relief despite optimal antisecretory therapy 
• Absence of evidence that gastroesophageal reflux (elevated acid exposure time and/or 
symptom reflux association) or EE is the cause of the symptom 
• Absence of major esophageal motor disorders (Achalasia/esophogastric junction 
outflow obstruction, diffuse esophageal spasm, jackhammer esophagus, absent 
peristalsis) 
13.4.2 
Functional Dyspepsia  
Functional dyspepsia must fulfill criteria for postprandial distress syndrome (PDS; 
Section 13.4.2.1) and/or epigastric pain syndrome (EPS; Section 13.4.2.2) 
 
Diagnostic criteria for Functional Dyspepsia (Note: criteria fulfilled for the last 3 months with 
symptom onset at least 6 months prior to diagnosis) 
 
1. One or more of the following:  
• Bothersome postprandial fullness 
• Bothersome early satiation 
• Bothersome epigastric pain 
• Bothersome epigastric burning 
AND 
2. No evidence of structural disease (including at upper endoscopy) that is likely to explain the 
symptoms 
 


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13.4.2.1 Postprandial Distress Syndrome 
Diagnostic criteria for PDS (Note: criteria fulfilled for the last 3 months with symptom onset at 
least 6 months prior to diagnosis) must include one or both of the following at least 3 days a 
week: 
1. Bothersome postprandial fullness (ie, severe enough to impact on usual activities) 
2. Bothersome early satiation (ie, severe enough to prevent finishing a regular size 
meal) 
No evidence of organic, systemic, or metabolic disease that is likely to explain the 
symptoms on routine investigations (including at upper endoscopy) 
Supportive criteria 
• Postprandial epigastric pain or burning, epigastric bloating, excessive belching, and 
nausea can also be present 
• Vomiting warrants consideration of another disorder 
• Heartburn is not a dyspeptic symptom but may often co-exist 
• Symptoms that are relieved by evacuation of feces or gas should generally not be 
considered as part of dyspepsia 
• Other individual digestive symptoms or groups of symptoms (eg, from GERD and 
IBS) may co-exist with PDS 
13.4.2.2 Epigastric Pain Syndrome 
Diagnostic criteria for EPS (Note: Criteria fulfilled for the last 3 months with symptom onset at 
least 6 months prior to diagnosis ) must include one or both of the following symptoms at least 
1 day a week: 
 
• Bothersome epigastric pain (ie, severe enough to have an impact on usual activities) 
• Bothersome epigastric burning (ie, severe enough to have an impact on usual 
activities) 
No evidence of organic, systemic, or metabolic disease that is likely to explain the 
symptoms on routine investigations (including at upper endoscopy). 
 
Supportive criteria 
• Pain may be induced by ingestion of a meal, relieved by ingestion of a meal, or may 
occur while fasting 
• Postprandial epigastric bloating, belching, and nausea can also be present 
• Persistent vomiting likely suggests another disorder 
• Heartburn is not a dyspeptic symptom but may often co-exist 


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• The pain does not fulfill biliary pain criteria 
• Symptoms that are relieved by evacuation of feces or gas generally should not be 
considered as part of dyspepsia 
• Other digestive symptoms (such as from GERD and IBS) may co-exist with EPS 


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13.5 Appendix 5: 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. 
13.5.1 Protocol Amendment 1 
Protocol Synopsis 
Study Population: 
Main Exclusion Criteria: 
• The subject has active irritable bowel syndrome or had a flare of IBS requiring 
therapy within the prior 6 months. 
On-Demand Treatment Period (Main Inclusion Criteria): 
• The subject has stable disease, ie, no heartburn in the last 7 days of the Run-In Period. 
• The subject completes the Run-In Period and continues to meetfulfill all of the inclusion 
and exclusioneligibility criteria for the Run-In Period (except heartburn inclusion 
criteria). 
Study Design: 
On-Demand Treatment Period: 
Subjects who have stable disease (ie, no heartburn on the last 7 days of the Run-In Period) and 
are compliant with the diary and study medication will be randomized to receive either 
vonoprazan 10 mg, 20 mg, or 40 mg or placebo On-Demand (but no more than 1 dose within 24 
hours) for 6 weeks to treat episodic heartburn. Study-supplied rescue antacid will be allowed 3 
hours after taking study medication if needed. Subjects will complete an electronic diary to 
assess presence and severity of heartburn symptoms and use of rescue antacid. In addition, a 
more detailed diary will also document time of study drug administration and when heartburn 
relief occurs. Subjects will be contacted by phone weekly during the first 3 weeks to assess 
their understanding of diary instructions and On-Demand dosing and to emphasize the 
importance of completing the diary assessments. 
Sample Size: 
Based on these assumptions, a sample size of 200 heartburn episodes per treatment group (or 50 
subjects with at least 4 heartburn episodes per treatment group) provides at least 80% statistical 


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power at the 0.05 significance level. During the study if less than 200 subjects are projected 
to enroll into the On-Demand Treatment Period, additional subjects may be enrolled into 
the Run-In Period to ensure that a sufficient number of subjects enroll into the On-
Demand Treatment Period. 
Assuming 4060% of subjects at the end of the Run-In Period do not meet the eligibility criteria 
for the On-Demand Treatment Period, a total of 334approximately 500 subjects will be enrolled 
into the Run-In Period to achieve 200 subjects for the On-Demand Treatment Period.  
Study Design (Section 3.1) 
Figure 3-1 was updated to reflect the subject number changes and the addition of new telephone 
contacts. 
On-Demand Treatment Period: 
Subjects who have stable disease (ie, no heartburn on the last 7 days of the Run-In Period) and 
are compliant with the Diary and study medication will be randomized to receive either 
vonoprazan 10 mg, 20 mg, or 40 mg or placebo On-Demand for 6 weeks to treat episodic 
heartburn. Study drug should only be taken once in a 24-hour period. Study-supplied rescue 
antacid will be allowed 3 hours after taking study medication if needed. Subjects will complete 
an electronic diary to assess presence and severity of heartburn symptoms and use of rescue 
antacid. In addition, a more detailed diary will also document time of study drug administration 
and when heartburn relief occurs. Subjects will be contacted by phone weekly during the first 
3 weeks to assess their understanding of diary instructions and On-Demand dosing and to 
emphasize the importance of completing the diary assessments. 
Selection of Study Population (Section 4.1) 
This study will be conducted at approximately 65 sites in the United States and will enroll 
approximately 334500 subjects in the Run-In Period to allow randomization of approximately 
200 subjects (approximately 50 subjects per arm) in the On-Demand Treatment Period. 
Exclusion Criteria for Run-In Period (Section 4.1.1.2) 
2. The subject has active irritable bowel syndrome (IBS.) or had a flare of IBS requiring 
therapy within the prior 6 months. 
6. The subject has any other clinically significant 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 


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sclerotherapy or esophageal variceal band ligation). However, subjects diagnosed with Schatzki’s 
ring (mucosal tissue ring around lower esophageal sphincter) or hiatal hernia are eligible to 
participate. 
11. The subject has received anyvonoprazan in a clinical trial at any time or any other 
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. 
14. The subject has had clinically significant upper or lower gastrointestinal bleeding within 
4 weeks prior to randomizationScreening. 
17. The subject has a history of alcohol abuse, illegal drug use, drug addiction, 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 within the 12 months prior to screening. Subjects 
must have a negative urine drug screen for cannabinoids/tetrahydrocannabinol and non-
prescribed medications at screening. Subjects taking prescription drugs (except prescription 
cannabinoids/tetrahydrocannabinol) will be allowed. 
Inclusion Criteria for On-Demand Treatment Period (Section 4.1.2.1) 
2. The subject has stable disease, ie, no heartburn the last 7 days of the Run-In Period. 
3. The subject continues to meet the inclusion and exclusionfulfill all eligibility criteria for the 
Run-In Period (except Inclusion Criteria 4). 
Run-In Failures (Section 4.1.2.2) 
Run-In failures refer to instances when subjects consent to participate in the clinical study, are 
subsequently entered in the Run-In Period of the study, and do not meet the eligibility criteria for 
the On-Demand Treatment Period. Run-In failures may also include those subjects who 
withdraw from the study drug or the study (Section 4.2) during the Run-In Period. Run-In 
failures who do not meet On-Demand entrance eligibility criteria are to undergo all 
applicable Week 4 Run-In Period assessments (Table 13-1-Schedule of Events). 
Handling of Withdrawals (Section 4.2.2) 
Subjects who discontinue study drug or active participation in the study will no longer receive 
study drug. When a subject withdraws from the study drug or active participation in the study, 
the reason(s) for withdrawal shall be recorded by the investigator on the relevant page of the 
eCRF. Whenever possible, all subjects who discontinue study drug or withdraw from the study 
prematurely will undergo all end-of-study assessments. (subjects who discontinue from the 
Run-In Period will undergo all Week 4 Run-In Period assessments). Subjects who fail to 


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return for final assessments will be contacted by the site to make every attempt to comply with 
the protocol.  
Method of Assigning Subjects to Treatment Groups (Section 5.1) 
Subjects with stable disease (as defined by those who have no heartburn on the last 7 consecutive 
days of the Run-In Period) and are compliant with the diary and study medication will be 
randomized using a 1:1:1:1 allocation ratio to receive either vonoprazan 10 mg, 20 mg, or 40 mg 
or placebo during the 6-week On-Demand Treatment Period. Subjects will be provided study 
medication on Day -1 of the On-Demand Treatment Period and instructed to take their first dose 
of study medication after experiencing the first heartburn episode. 
Treatment Compliance (Section 5.8.1) 
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, willalso be recorded in the eCRF. 
Table 5-1 Excluded Medications and Treatments 
Excluded Medications and Treatments 
Beginning of Exclusion 
End of Exclusion 
Other investigational drugs or drugs administered 
due to participation in another clinical trial 
30 days prior to start 
of Screening Period 
Follow-up Visit 
Antacids (except study-supplied Gelusil) 
Screening Period 
Follow-up Visit 
H2RAs 
Screening Period 
Follow-up Visit 
PPIs 
Screening Period 
Follow-up Visit 
Strong inhibitors or inducers of CYP3A4 (eg, 
itraconazole, ketoconazole, indinavir, nelfinavir, 
ritonavir, saquinavir, telithromycin) 
14 days prior to Run-
In Period Day 1 
End of On-
Demand 
treatment 
CYP3A4 substrates with a narrow therapeutic 
index 
14 days prior to Run-
In Period Day 1 
End of On-
Demand 
treatment 
Surgical procedures that could affect gastric acid 
secretion (eg, any form of partial gastrectomy, 
vagotomy) 
30 days prior to Run-
In Period Day 1 
Follow-up Visit 
Other agents affecting digestive organs, including 
muscarinic antagonists (eg, hyoscyamine), 
prokinetics, oral anticholinergic agents, 
prostaglandins, bismuth, sucralfate 
30 days prior to Run-
In Period Day 1 
Follow-up Visit 
Atazanavir sulfates; rilpivirine hydrochloride 
(contraindicated with vonoprazan) 
5 days prior to Run-
In Period Day 1 
Follow-up Visit 


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Excluded Medications and Treatments 
Beginning of Exclusion 
End of Exclusion 
Abbreviations: CYP, cytochrome P450 isoenzyme; H2RA, histamine-2 receptor antagonist; PPI, proton pump 
inhibitor. 
 
Electronic Diary (Section 6.2.1) 
Subjects will be given an electronic diary on the first day of the Screening Period. During the 
Screening, Run-In, and Safety Follow-up Periods subjects will complete the morning and 
evening Heartburn Diary and Rescue Antacid Diary. During the On-Demand Treatment Period, 
subjects will complete the heartburn episode diary, including the Timed Heartburn Assessments 
and Rescue Antacid Diary. Subjects must bring the electronic diary device to each site visit 
for the investigator to verify Run-In and On-Demand diary eligibility criteria and to move 
the subject to the appropriate period within the electronic diary device, as noted in the 
eDiary Vendor User Manual. Subjects must return the devices that have been assigned to 
them upon completion/termination from the study. 
On-Demand Heartburn Episode Diary (Section 6.2.1.3 
During the On-Demand Treatment Period, subjects will document episodes of heartburn 
experienced and the use of on demand On-Demand study medication as they occur. On days 
that a subject has not reported an episode of heartburn, sSubjects will also be expected to 
complete the diary in thereminded every morning and every evening to documentrecord any 
unrecorded heartburn episodes (no longer than the prior day) OR to document that they if 
they have or have not had any heartburn episodes. 
On-Demand Heartburn Timed Assessments (Section 6.2.1.4) 
Once heartburn is reported and the subject is eligible to take study medication (ie, 24 hours since 
the last administration), the diary will be programmed to collect the heartburn episode 
assessments for 3 hours in order to assess when heartburn relief occurs. The diary will prompt 
responses 30 minutes after study drug administration is reported and then 1, 1.5, 2, and 3 hours 
after study drug treatment. Subjects will be allowed toOn rare occasions, when required, 
subjects may opt out of the timed assessments. 


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Table 6-4 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)(e) 
• 
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 
• 
Serum hCG pregnancy test(c) at Screening Visit 1 
• 
Urine hCG pregnancy test(c) at Run-In Period Visit 2, randomization Visit 3, and final 
visit for On-Demand Treatment Period Visit 57 
• 
Serology (HIV antibody, HBsAg, and HCV antibody; hepatitis C, viral load RNA(d) 
[qualitative]) 
• 
Serum gastrin (fasting 12 hours) and serum pepsinogen I and II levels will also be 
evaluated as safety/PD biomarkers at Day -1 of Run-In Period; Week 4 of Run-In 
Period; Week 6 of On-Demand Treatment Period; and safety follow-up visit. Day -1 
baseline gastrin levels will not be blinded. Gastrin at the Week 4 Run-In, Week 6 
On-Demand treatment, and Safety Follow-up visits and all pepsinogen I and II 
results will be blinded and will not be reported to investigative sites or other blinded 
personnel until after the study blind is broken. 


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Laboratory 
Assessments 
Parameters 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; FSH, follicle-stimulating 
hormone; GGT, gamma-glutamyl transferase; HBsAg, hepatitis B surface antigen; hCG, human 
chorionic gonadotropin; HCV, hepatitis C virus; HIV, human immunodeficiency virus; MCH, mean 
corpuscular hemoglobin; MCV, mean corpuscular volume; PD, pharmacodynamics; RBC, red blood cell; 
SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase; WBC, 
white blood cell. 
(a)  See Section 13.3 for the appropriate guidance on reporting of abnormal liver function tests. For liver 
function test monitoring, see Section 13.3.1. For temporary and permanent discontinuation of study 
drugs due to abnormal liver function tests, see Section 13.3.2 and Section 13.3.3, respectively. 
(b)  Follicle stimulating hormone will be conducted at the investigator’s discretion to determine the 
postmenopausal status of womenRequired only for confirmation of postmenopausal females as 
defined in Section 13.2 (Appendix 2). Women whose duration of (consecutive) amenorrhea is 
borderline or open to doubt and where the investigator believes the subject to be menopausal by history 
should have confirmatory FSH drawn. 
(c)  As needed for women of childbearing potential. During the Run-In Period and On-Demand Treatment 
Period, serum pregnancy test will be performed if the urine pregnancy test is positive. 
(d)  Reflex - if hepatitis C positive. 
(e) 8 hours fasting at Screening Visit 1. 
 
Vital Signs (Section 6.3.5) 
Vital signs will include body temperature (oral, temporal, or tympanic measurement), sitting 
blood pressure (resting more than 5 minutes), and heart rate (beats per minute). When vital signs 
are scheduled at the same time as blood collections, the blood collections will take priority.  
Electrocardiograms (Section 6.3.6) 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using one of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The 
following parameters will be recorded on the eCRF from the subject’s ECG trace: heart rate, PR 
interval, RR interval, QT interval, QTcF (derived) 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. 
Sample Size Calculations (Section 7.1) 
Based on these assumptions, a sample size of 200 heartburn episodes per treatment group (or 50 
subjects with at least 4 heartburn episodes per treatment group) provides at least 80% statistical 
power at the significance level of 0.05. During the study if less than 200 subjects are 
projected to enroll into the On-Demand Treatment Period, additional subjects may be 


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enrolled into the Run-In Period to ensure that a sufficient number of subjects enroll into 
the On-Demand Treatment Period. 
Assuming 4060% of subjects at the end of the Run-In Period do not meet the eligibility criteria 
for the On-Demand Treatment Period, a total of 334 approximately 500 subjects will be 
enrolled into the Run-In Period to achieve 200 subjects for the On-Demand Treatment Period.  
Intent-to-Treat Set (Section 7.2.3) 
The ITT On-Demand set includes all subjects in the Safety On DemandRun-In set who were 
randomized and completed at least one heartburn episode diary during the On-Demand 
Treatment Period. 
Description of Subgroups (Section 7.3) 
• mean heartburn severity during the Run InScreening Period (mild, moderate, severe, 
very severe) 






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(a)  Visit window is Day -36 to Day -2 for assessment of clinical laboratory assessments, ECG, and endoscopy in the Screening Period. Any endoscopic confirmation 
performed in a routine clinical setting within 7 days before signing the informed consent is acceptable to use for the purpose of fulfilling the screening requirement. 
(b)  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, AE assessment, and clinical laboratory tests. If the visit results in premature termination, then all 
procedures outlined for the Final final visit should be performed. 
(c)  The date of first dosing day is defined as Day 1 in both Run-In Period and On-Demand Treatment Period. The date of randomization is defined as Day -1 of On-
Demand Treatment Period. 
(d)  Subjects should continue to meet inclusion criteria (Section 4.1.1.1) and exclusion criteria (Section 4.1.1.2), except Inclusion CriteriaCriterion 4. 
(e) Full physical examination is performed at ScreeningPeriod; a brief physical examination is performed at all other visits. 
(f) Required only for confirmation of postmenopausal females as described in Section 13.2 (Appendix 2). Women whose duration of (consecutive) amenorrhea is 
borderline or open to doubt and where the investigator believes the subject to be menopausal by history should have confirmatory FSH drawn. 
(g)  See Section 6.3.3 and Table 6-4 for all required laboratory assessments.  
(h)  Gastrin Week 4 Run-In, Week 6 On-Demand treatment and Safety follow-up visits and pepsinogen I and II results will be blinded and will not be reported to 
investigative sites or other blinded personnel until the study blind is broken. 
(i)  Only female subjects with childbearing potential. Serum hCG at screening and urine hCG at all subsequent visits.  
(j)  The screening endoscopy can be performed any time during that period; however, it should be performed after the subject has fulfilled all other admission criteria. 
Any endoscopic confirmation performed in a routine clinical setting within 7 days before signing the informed consent is acceptable to use for the purpose of 
fulfilling the screening requirement. 
(k)  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 Screening, Run-In and Follow-up Period. During the On-Demand Treatment Period, subjects will be instructed to complete the 
electronic diary to document heartburn episodes and study drug administration. Rescue antacid use should be reported during all periods.  
(l)  Subjects are to start dose administration from Day 1. 
(m)  Rescue antacid will be dispensed as needed after the Screening Period.  
(n)  Sites will document dispensing rescue antacid. Subjects do not need to return unused rescue antacid. 
(o) Day -1 baseline gastrin levels will not be blinded.  
(p) Run-In failure procedures.  
 
 

SAP_001.pdf: 
Protocol Number: NERD-201 
Official Title: A Phase 2, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and 
Safety of Vonoprazan 10 mg, 20 mg, and 40 mg Compared to Placebo for Relief of Episodic 
Heartburn in Subjects with Symptomatic Non-Erosive Gastroesophageal Reflux Disease  
Document Date: 25 January 2022 
NCT Number: NCT04799158 
 




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Signature Page 
 
Study Title 
Phase 2, Randomized, Double-Blind, Multicenter Study to 
Evaluate the Efficacy and Safety of Vonoprazan 10 mg, 20 mg, 
and 40 mg Compared to Placebo for Relief of Episodic 
Heartburn in Subjects with Symptomatic Non-Erosive 
Gastroesophageal Reflux Disease 
 
 
 
 
Protocol Number:  NERD-201 
 
Approved by: 
 
 
Senior Director, Biostats & Programming 
 
 
 
 
 
 
 
DocuSign Envelope ID: E1AB519E-ED82-47AE-8829-E51F6884B80A


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TABLE OF CONTENTS 
DOCUMENT HISTORY – CHANGES COMPARED TO FINAL VERSION 1.0 .......................6 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1.0 
INTRODUCTION ...............................................................................................................8 
2.0 
OBJECTIVES ......................................................................................................................8 
3.0 
INVESTIGATIONAL PLAN ..............................................................................................8 
3.1 
Overall Study Design and Plan ......................................................................................8 
3.2 
Study Endpoints .............................................................................................................9 
3.3 
Treatments....................................................................................................................12 
3.3.1 Run-In Period .........................................................................................................12 
3.3.2 On-Demand Treatment Period ...............................................................................12 
3.3.3 Rescue Antacid ......................................................................................................12 
3.4 
Dose Adjustment/Modifications ..................................................................................13 
4.0 
GENERAL STATISTICAL CONSIDERATIONS ...........................................................13 
4.1 
Sample Size ..................................................................................................................13 
4.2 
Randomization and Blinding .......................................................................................14 
4.3 
Study Day.....................................................................................................................14 
4.3.1 Run-In Period .........................................................................................................14 
4.3.2 On-Demand Treatment Period ...............................................................................15 
4.3.3 Follow-Up Period...................................................................................................15 
4.4 
Analysis Sets ................................................................................................................15 
4.4.1 Screened Set ...........................................................................................................15 
4.4.2 All Subjects Set ......................................................................................................16 
4.4.3 Randomized Set .....................................................................................................16 
4.4.4 Safety Sets ..............................................................................................................16 
4.4.5 Intent-to-Treat (ITT) On-Demand Set ...................................................................16 
4.5 
Visit Windows .............................................................................................................16 
5.0 
SUBJECT DISPOSITION .................................................................................................16 
5.1 
Disposition ...................................................................................................................16 
5.1.1 Screened and Screen Failure Subjects ...................................................................16 
5.1.2 Run-In Period All Subjects ....................................................................................17 
5.1.3 Randomized Subjects .............................................................................................17 
5.2 
Protocol Deviations ......................................................................................................18 
6.0 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................18 
6.1 
Demographics and Baseline Characteristics ................................................................18 
6.2 
Medical History ...........................................................................................................19 
6.2.1 General Medical History ........................................................................................19 
7.0 
TREATMENTS AND MEDICATIONS ...........................................................................20 


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7.1 
Prior and Concomitant Medications ............................................................................20 
7.2 
Study Treatments .........................................................................................................21 
7.2.1 Extent of Exposure .................................................................................................21 
7.2.2 Treatment Compliance of the Run-In Period .........................................................22 
8.0 
EFFICACY ANALYSIS ...................................................................................................23 
8.1 
Primary Efficacy Endpoint ..........................................................................................23 
8.1.1 Primary Analysis ....................................................................................................23 
8.1.2 Supplementary Analyses ........................................................................................23 
8.1.3 Sensitivity Analyses ...............................................................................................24 
8.1.4 Subgroup Analysis .................................................................................................24 
8.2 
Secondary Efficacy Endpoint ......................................................................................24 
8.2.1 Sensitivity Analyses ...............................................................................................25 
8.3 
Exploratory Endpoints .................................................................................................25 
8.3.1 On-Demand Treatment Period ...............................................................................25 
8.3.2 Run-In Period .........................................................................................................28 
8.3.3 Follow-Up Period...................................................................................................29 
9.0 
SAFETY ANALYSIS ........................................................................................................29 
9.1 
Adverse Events ............................................................................................................29 
9.1.1 Adverse Events of Special Interest (AESI) ............................................................32 
9.2 
Clinical Laboratory Evaluations ..................................................................................34 
9.3 
Vital Sign .....................................................................................................................35 
9.4 
Physical Examination...................................................................................................36 
9.5 
Electrocardiogram ........................................................................................................36 
10.0 
INTERIM ANALYSIS/OTHER ANALYSES ..................................................................36 
10.1 
Interim Analysis ...........................................................................................................36 
10.2 
Coronavirus Pandemic .................................................................................................37 
11.0 
APPENDICES ...................................................................................................................37 
11.1 
Schedule of Events .......................................................................................................38 
11.2 
Imputation Rules for Missing Date Imputation ...........................................................41 
11.2.1 Rules for Concomitant Medication Start Date Imputation ....................................41 
11.2.2 Rules for Concomitant Medication End Date Imputation .....................................42 
11.2.3 Rules for Prior Medication Start Date Imputation .................................................43 
11.2.4 Rules for AE Start Date Imputation .......................................................................43 
11.3 
Electronic Diary ...........................................................................................................43 
11.3.1 Screening, Run-In and Follow-up Period ..............................................................43 
11.3.2 Rescue Antacid Diary ............................................................................................45 
11.3.3 On-Demand Treatment Period ...............................................................................45 
11.4 
PAGI-QOL and PAGI-SYM Scoring .......................................................................48 


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11.4.1 PAGI-QOL .............................................................................................................48 
11.4.2 PAGI-SYM ............................................................................................................49 
 
LIST OF IN-TEXT TABLES 
Table 1 Adverse Events Special Interest – Search Criteria ...........................................................33 
Table 2 Schedule of Events............................................................................................................38 
Table 3 Definitions of Heartburn Severity (Daytime/Nighttime) for the Screening, Run-In, 
and Follow-Up Periods ..........................................................................................44 
Table 4 Definitions of Heartburn Severity for the On-Demand Treatment Period .......................46 
 
LIST OF IN-TEXT FIGURES 
 
Figure 1 Study Scheme ....................................................................................................................9 
Figure 2 Prior and Concomitant Medications ................................................................................21 
  
 
 


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DOCUMENT HISTORY – CHANGES COMPARED TO FINAL VERSION 1.0 
Version 
Date 
Changes 
Final version 1.0 
16-Aug-2021 
Final version 
 
Final version 2.0 
 
25-Jan-2022 
 
1. A supplementary analysis of the primary endpoint was added 
in Section 8.1.2 to account for multiple heartburn episodes 
within a subject. 
2. An additional sensitivity analysis of the primary endpoint 
was added to Section 8.1.3 to consider heartburn episodes 
with any use of rescue antacid as not completely relieved. 
3. Sensitivity analyses were added for secondary endpoints in 
Section 8.2.1 for the percentage of evaluable heartburn 
episodes for each subject that are relieved, among subjects 
who experienced 4 or more episodes of heartburn and for the 
percentage of 24-hour heartburn free days for which no 
rescue medication was taken. 
4. A subset of the exploratory endpoints during the On-Demand 
Treatment Period will also be summarized among subjects 
who experienced 4 or more episodes of heartburn. 
5. An additional exploratory endpoint was added for the Run-In 
Period, the percentage of subjects that are heartburn free over 
the last 7 days of the Run-In Period. 
6. In Section 4.3.1, clarity added for definition of Run-In 
treatment end date. 
7. In Section 4.3.2, the definition of Day 1 and last day of the 
On-Demand Treatment Period was clarified. 
8. In Section 4.3.3, definitions for the start and end of the 
Follow-Up Period were added. 
9. Added Section 4.5 to clarify that data summarized by visit 
will be based on the visit as collected on the eCRF. 
10. Changed the analysis set for summaries of medical history 
and concomitant medications from the Safety On-Demand 
set to the Randomized set. 
11. In Section 11.3.3.3, clarified the data handling for diary 
entries indicating absence of heartburn during the On-
Demand Treatment Period.  
12. Throughout the document, additional edits were made for 
clarity and formatting with no change to content. 
 
 


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LIST OF ABBREVIATIONS  
AE 
adverse event 
AESI 
Adverse Events of Special Interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CTMS 
Clinical Trial Management System 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EE 
erosive esophagitis 
H2RA 
Histamine-2 receptor antagonist 
GEE 
Generalized Estimating Equations 
GERD 
Gastroesophageal reflux disease 
ICF 
informed consent form 
ITT 
intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NERD 
non-erosive gastroesophageal reflux disease 
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 
PT 
preferred term 
QD 
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
Standard Deviation 
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, maintenance of healing of all grades of EE and relief of heartburn, treatment of 
Helicobacter pylori infection, and treatment of heartburn in subjects with symptomatic non-
erosive gastroesophageal reflux disease (NERD). 
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. 
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 Version 2.0, dated 16Jul2021. 
2.0 
OBJECTIVES  
The primary objectives of this study are as follows: 
• To assess the efficacy of vonoprazan (10 mg, 20 mg, and 40 mg On-Demand) compared 
to placebo (On-Demand) in relief of episodic heartburn over 6 weeks in subjects with 
symptomatic NERD. 
• To assess the safety of vonoprazan (10 mg, 20 mg, and 40 mg On-Demand) compared to 
placebo (On-Demand) in subjects with symptomatic NERD. 
 
The secondary objective of this study is as follows: 
• To assess the use of study medication and rescue antacid in subjects treated with 
vonoprazan (10 mg, 20 mg, and 40 mg On-Demand) compared to placebo (On-Demand) 
over the On-Demand Treatment Period. 
3.0 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 2, multicenter, double-blind study of vonoprazan versus placebo assessing the 
relief of episodic heartburn. Subjects with symptomatic NERD (as confirmed by endoscopy) and 
heartburn symptoms (as documented in the electronic diary) will receive open-label vonoprazan 
20 mg QD for 4 weeks. Subjects with stable disease (ie, no heartburn on the last 7 days of the 
Run-In Period) who are compliant with the diary and study medication and meet all other 
eligibility criteria will be randomized to receive either vonoprazan 10 mg, 20 mg, 40 mg or 


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placebo On-Demand for 6 weeks to treat episodic heartburn. Subjects will complete an electronic 
diary to assess presence and severity of heartburn symptoms and use of rescue antacid (if 
needed) in all periods. During the On-Demand Treatment Period, a more detailed diary will also 
document time of study drug administration and when heartburn relief occurs. 
A schematic diagram of the overall study design is presented in Figure 1. 
Figure 1 Study Scheme 
 
 
3.2 
Study Endpoints 
The primary efficacy endpoint is as follows: 
• The percentage of evaluable(a) heartburn episodes completely relieved within 3 hours and 
with no further heartburn reported for 24 hours after taking study drug(b). 
(a) An evaluable heartburn episode is an episode for which study drug was taken and for which 
the subject completed at least one entry in the heartburn episode diary. 
(b) For a heartburn episode to be considered completely relieved, a subject must not have taken 
rescue antacid within 3 hours of taking study drug. 
 
The secondary efficacy endpoints are as follows: 


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• The percentage of evaluable heartburn episodes completely relieved within 3 hours after 
taking study drug. 
• The percentage of subjects with complete relief of heartburn within 3 hours after the first 
episode and with no further heartburn reported for 24 hours after taking study drug. 
• The percentage of evaluable heartburn episodes for each subject that are completely 
relieved within 3 hours and with no further heartburn reported for 24 hours after taking 
study drug. 
• The percentage of days study drug was taken over the On-Demand Treatment Period. 
• The mean number of tablets of rescue antacid taken per day over the On-Demand 
Treatment Period. 
• The percentage of 24-hour heartburn-free days over the On-Demand Treatment Period. 
 
The exploratory efficacy endpoints of the On-Demand Treatment Period are as follows: 
• The percentage of evaluable heartburn episodes completely relieved within 30 minutes or 
1, 1.5, or 2 hours and with no further heartburn reported for 24 hours after taking study 
drug. 
• The percentage of evaluable heartburn episodes that are completely relieved within 30 
minutes or 1, 1.5, or 2 hours after taking study drug. 
• The percentage of evaluable heartburn episodes that improved at 30 minutes or 1, 1.5, 2, 
or 3 hours after taking study drug. 
• The percentage of episodes for which subjects continue to be heartburn-free after 24 or 
48 hours of taking study drug. 
• The percentage of subjects with at least 50%, at least 75%, and 100% of their evaluable 
heartburn episodes completely relieved within 3 hours with no further heartburn reported 
for 24 hours after taking study drug. 
• The percentage of subjects with at least 50%, at least 75%, and 100% of their evaluable 
heartburn episodes completely relieved within 3 hours after taking study drug. 
• The percentage of subjects with complete relief of the first episode of heartburn within 3 
hours after taking study drug. 
• The mean number of days between heartburn episodes. 


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• The percentage of days without daytime heartburn over the On-Demand Treatment 
Period. 
• The percentage of days without nighttime heartburn over the On-Demand Treatment 
Period. 
• The mean severity of daytime and nighttime heartburn over the On-Demand Treatment 
Period. 
• The mean severity of nighttime heartburn over the On-Demand Treatment Period. 
• The mean severity of daytime heartburn over the On-Demand Treatment Period.  
• The percentage of days without rescue antacid use over the On-Demand Treatment 
Period.  
• The change from baseline to the end of the On-Demand Treatment Period for each 
subscale and the total score of the PAGI SYM questionnaire. 
• The change from baseline to the end of the On-Demand Treatment Period for each 
subscale and the total score of the PAGI QoL questionnaire. 
• The patient global impression of change in GERD symptoms at the end of the On-
Demand Treatment Period. 
• The patient global impression of severity in GERD symptoms over the last 7 days of the 
On-Demand Treatment Period 
• The percentage of subjects with each dosing preference. 
The exploratory efficacy endpoints of the Run-In Period are as follows: 
• The percentage of 24-hour heartburn-free days over the Run-In Period. 
• The percentage of subjects that are heartburn free over the last 7 days of the Run-In 
Period. 
• The percentage of days without daytime heartburn over the Run-In Period. 
• The percentage of days without nighttime heartburn over the Run-In Period. 


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• The mean severity of daytime and nighttime heartburn over the Run-In Period. 
• The mean severity of nighttime heartburn over the Run-In Period. 
• The mean severity of daytime heartburn over the Run-In Period. 
• The percentage of days without rescue antacid use over the Run-In Period. 
• The change from baseline to the end of the Run-In Period for each subscale and the total 
score of the PAGI-SYM questionnaire. 
• The change from baseline to the end of the Run-In Period for each subscale and the total 
score of the PAGI-QoL questionnaire. 
• The patient global impression of change in GERD symptoms at the end of the Run-In 
Period. 
• The patient global impression of severity in GERD symptoms over the last 7 days of the 
Run-In Period. 
3.3 
Treatments 
3.3.1 
Run-In Period 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria and have 
symptomatic NERD during the screening period will be dosed during an open-label Run-In 
Period with vonoprazan 20 mg QD for 4 weeks. 
3.3.2 
On-Demand Treatment Period 
Subjects with stable disease (as defined by those who have no heartburn on the last 7 consecutive 
days of the Run-In Period) and are compliant with the diary and study medication will be 
randomized using a 1:1:1:1 allocation ratio to receive either vonoprazan 10 mg, 20 mg, or 40 mg 
or placebo during the 6-week On-Demand Treatment Period. Subjects will be provided study 
drug on Day -1 (i.e. the day of randomization) of the On-Demand Treatment Period and 
instructed to take their first dose of study drug after experiencing the first heartburn episode. 
3.3.3 
Rescue Antacid 
Subjects may use up to 12 tablets per day (not more than 4 tablets at one time) of study provided 
rescue antacid (Gelusil®) during the Screening Period, Run-In Period, On-Demand Treatment 
Period, and Safety Follow-up Period. During the On-Demand Treatment Period, rescue antacid 
should not be taken until 3 hours after study drug administration. 


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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 observed 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.  
For the Run-In Period, all analyses will be conducted on the Safety Run-In set. See Section 4.4 
for the Safety Run-In set definition. 
For the On-Demand Treatment Period, efficacy analyses will be conducted on the Intent-to-Treat 
On-Demand set using the planned randomized treatment. Safety analyses will be conducted on 
the Safety On-Demand set using the actual treatment. If a subject receives more than one type of 
randomized study drug during this period, the planned randomized treatment will be assigned as 
the actual treatment received for this subject in the safety summary tables for this period. If a 
subject receives only one type of randomized study drug during this period, but this randomized 
study drug type is inconsistent with the planned randomized treatment, the actual treatment 
received will be assigned as the actual treatment for this subject in the safety summary tables for 
this period. See Section 4.4 for the ITT On-Demand set and Safety On-Demand set definitions. 
All the 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. 
4.1 
Sample Size 
The sample size for the On-Demand Treatment Period is calculated based on the following 
assumptions: 
• Subjects will be randomized to receive either vonoprazan 10 mg, 20 mg, or 40 mg or 
placebo with a randomization ratio of 1:1:1:1. 
• Each subject experiences at least 4 evaluable heartburn episodes. 


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• Comparison between each dose of vonoprazan to placebo will be performed using the 
Fisher’s Exact test. 
• A clinically relevant difference of 15% between each dose of vonoprazan and placebo in 
the proportion of evaluable heartburn episodes completely relieved within 3 hours and 
with no further heartburn reported for 24 hours after taking study drug. 
Based on these assumptions, a sample size of 200 heartburn episodes per treatment group (or 50 
subjects with at least 4 heartburn episodes per treatment group) provides at least 80% statistical 
power at the significance level of 0.05. During the study if less than 200 subjects are projected to 
enroll into the On-Demand treatment period, additional subjects may be enrolled into the Run-In 
period to ensure that a sufficient number of subjects enroll into the On-Demand treatment period. 
Assuming 60% of subjects at the end of the Run-In Period do not meet the eligibility criteria for 
the On-Demand Treatment Period, approximately 500 subjects will be enrolled into the Run-In 
Period to achieve 200 subjects for the On-Demand Treatment Period. 
The hypothesis testing is as follows: 
       Null Hypothesis                             H0: Pvono = Pplacebo 
      Alternative Hypothesis                   Ha: Pvono ≠ Pplacebo 
where P is the proportion of heartburn episodes. 
4.2 
Randomization and Blinding 
Subjects who meet the eligibility criteria for the On-Demand Treatment Period will be 
randomized using a 1:1:1:1 allocation ratio to receive either vonoprazan 10 mg, 20 mg, or 40 mg 
or placebo during the 6-week On-Demand Treatment Period.  
4.3 
Study Day 
4.3.1 
Run-In Period 
The date of the first dosing day of the Run-In Period is defined as Day 1. 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. 


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If the Run-In Treatment Period end date is missing, then the first date of the Run-In Treatment 
Period + 27 days will be used. 
4.3.2 
On-Demand Treatment Period 
Since subjects will take study drug on-demand during the On-Demand Treatment Period, the first 
dosing day may differ for each subject. Study day during the On-Demand Treatment Period will 
be defined relative to the date of randomization.  
The date of possible first dosing of the On-Demand Treatment Period is defined as Day 1. It is 
calculated as: 
• date of possible first dosing = date of randomization +1, or date of the actual first dose of 
study drug, whichever is earlier. 
When study day is used for display or in comparisons the following algorithm will be used: 
• study day = date of possible first dosing - Day 1 +1,  
if date of assessment ≥ Day 1. 
• study day = date of possible first dosing - Day 1, 
if date of assessment < Day 1. 
Similarly, the last dosing day during the On-Demand Treatment Period will likely differ for each 
subject. The end of the On-Demand Treatment Period will be defined as the date of the possible 
last dose, i.e. the last visit date, the date of the last record in Timed Assessment Diary, or actual 
last dose of study drug, whichever is later. 
4.3.3 
Follow-Up Period 
The start date of the Follow-Up Period will be defined as the last date of the On-Demand 
Treatment Period +1.  
The end date of the Follow-Up Period will be the last visit date or the date of the last evening, 
morning, or rescue antacid diary entry, whichever is later. 
4.4 
Analysis Sets 
4.4.1 
Screened Set 
All subjects who signed the informed consent form (ICF) before entering the Run-In Period. 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently entered into the Run-In Period of the study. 


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4.4.2 
All Subjects Set 
All subjects who enrolled into the Run-In Period. Run-In failures refer to instances when 
subjects consent to participate in the clinical study, are subsequently entered in the Run-In Period 
of the study, and do not meet the eligibility criteria for the On-Demand Treatment Period. Run-In 
failures may also include those subjects who withdraw from the study drug or the study during 
the Run-In Period.  
4.4.3 
Randomized Set 
All subjects randomly assigned to receive study drug regardless of whether or not they received a 
dose of study drug during the On-Demand Treatment Period.  
4.4.4 
Safety Sets 
4.4.4.1 
Safety Run-In Set 
The Safety Run-In set includes subjects in the All Subjects set who received at least one dose of 
study drug (vonoprazan 20 mg) during the Run-In Period. 
4.4.4.2 
Safety On-Demand Set 
The Safety On-Demand set includes all subjects in the Safety Run-In set who were randomized 
and treated at least one heartburn episode with randomized treatment during the On-Demand 
Treatment Period. All analyses using the Safety On-Demand set will group subjects according to 
the treatment actually received. 
4.4.5 
Intent-to-Treat (ITT) On-Demand Set 
The ITT On-Demand Set includes all subjects in the Safety Run-In set who were randomized and 
completed at least one heartburn episode diary during the On-Demand Treatment Period. 
4.5 
Visit Windows 
All data summarized by visit will be based on the visit name collected on the eCRF page. For 
data from unscheduled visits, these will be listed but not included in any by-visit summaries or 
analyses. 
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.  


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The following will be summarized for the Screened set: 
• The total number of screened subjects. 
• The number of subjects who enrolled into the Run-In Period.  
• The number and percentage of screen failures. 
• The number and percentage of each primary reason for screen failures. 
Percentages will be based on the Screened set.  
Reasons for screen failure will be listed for the Screened set. A list of Inclusion/Exclusion criteria 
will be listed. Subjects who met eligibility criteria for both run-in period and on-demand period 
will be listed, associated exclusion criteria will be displayed as well as inclusion criteria that is 
not met for the Screened set. 
5.1.2 
Run-In Period All Subjects 
The following will be summarized for All Subjects set: 
• The total number of subjects who enrolled into the Run-In Period. 
• The number and percentage of subjects who are in the Safety Run-In set. 
• The number and percentage of Run-In failures. 
• The number and percentage of each primary reason for Run-In failures. 
 
Percentages will be based on the All Subjects set. 
Subject disposition data for the Run-In period will be listed for the All Subjects set.  
5.1.3 
Randomized Subjects 
The following will be summarized for the Randomized set: 
• The total number of randomized subjects. 
• The number and percentage of subjects in the Safety On-Demand set and the ITT On-
Demand set. 
• The number and percentage with each reason for exclusion from the Safety On-Demand 
set and the ITT On-Demand set. 
• The number and percentage of subjects who completed the participation of the entire 
study. 
• The number and percentage of each primary reason for study discontinuation. 
• The number and percentage of subjects who discontinued from the follow-up period. 


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The number of subjects and percentage will be presented by treatment group and overall for all 
randomized subjects. 
Subject disposition data for the On-Demand Treatment Period will be listed for the Randomized 
set. Disposition data for the On-Demand Treatment Period will be listed separately for subjects 
who discontinued from study for the Randomized set.  
5.2 
Protocol Deviations 
Protocol deviations will be recorded within the
 Clinical Trial Management System (CTMS) 
and will undergo a blinded review prior to database lock and unblinding. Significant protocol 
deviations are defined as the subset of deviations which are considered to affect primary efficacy 
and safety assessments, the safety or mental integrity of a subject, or the scientific value of the 
trial.  
The number and percentage of subjects with significant protocol deviations will be summarized 
by CTMS activity subtype, treatment group and overall using the Randomized set.  
Individual subject protocol deviations, both significant and non-significant, will be presented in a 
data listing using the All Subjects set. 
6.0 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
6.1 
Demographics and Baseline Characteristics 
Demographics and other baseline characteristics will be summarized for the Run-In Period and 
for the On-Demand Treatment Period. For the Run-In Period, demographics and other baseline 
characteristics will be summarized using the Safety Run-In set. For the On-Demand Treatment 
Period, demographics and other baseline characteristics will be summarized by treatment group 
and overall using the ITT On-Demand set and Safety On-Demand set. 
Demographic variables collected at Screening, such as age (years), sex, race, ethnicity, height 
(cm), weight (kg), and body mass index (BMI) will be summarized. Continuous variables 
collected at Screening, including age, BMI, weight, height, and mean severity of daytime and 
nighttime heartburn will be summarized using descriptive statistics. The following categorical 
variables will be summarized by reporting the number and percentage of subjects in each 
category for both periods. 
• Age group at Screening (<45, ≥45 - <65, ≥65 - <75, ≥75) 
• Age group 2 at Screening (≥18 - ≤64, ≥65 - ≤84, ≥85) 
• Sex (Male, Female) 


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• BMI category (<25, ≥25 - <30, ≥30) 
• Serum gastrin (<200, ≥200) 
• Pepsinogen I/II level (≤2, >2 - ≤3, >3) 
• 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) 
 
For all three demographic and baseline characteristic summaries, the following variables will be 
summarized based on symptoms reported during the Screening Period in the Morning Diary and 
Evening Diary from the last 7 days prior to Day -1 (i.e. Day -8 to Day -2) of the Run-In Period.  
• Mean severity of: 
o Daytime/Nighttime Heartburn (mild, moderate, severe and very severe) 
o Heartburn during the day (mild, moderate, severe and very severe) 
o Heartburn at night (mild, moderate, severe and very severe) 
• 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) 
• Number of days with use of rescue antacid ((≥0 - ≤3, >3 - ≤5, >5 - ≤7) 
• Mean number of rescue antacid tablets taken per day 
 
Refer to Section 11.3 for diary data handling. Demographic and baseline characteristics data will 
be listed using the All Subjects set. 
6.2 
Medical History 
6.2.1 
General Medical History 
Medical history will be coded using Version 23.0 of the Medical Dictionary for Regulatory 
Activities (MedDRA). The number and percentage of subjects with medical history coded to 
each MedDRA system organ class (SOC) and preferred term (PT) will be summarized. For the 
Run-In Period, medical history will be summarized by treatment group and overall using the 
Safety Run-In set. For the On-Demand Treatment Period, medical history will be summarized by 
treatment group and overall using the Randomized  set. 
Each subject’s medical history will be listed using the All Subjects set. 


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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 the Run-In Period, prior medications are those with the start and stop dates prior to the first 
dose of the Run-In Period study drug. Concomitant medications are those with start dates prior to 
the first dose of the Run-In Period and continuing after the first dose of the Run-In Period or with 
start dates between the first dose of the Run-In Period and Day 1 of the On-Demand Treatment 
Period (see Section 4.3.2 for the definition of Day 1 of the On-Demand Treatment Period).  
For the On-Demand Treatment Period, concomitant medications are those with start dates prior 
to Day 1 of the On-Demand Treatment Period and continuing after Day 1 of the On-Demand 
Treatment Period or with start dates on or after Day 1 of the On-Demand Treatment Period. 
The number and percentage of subjects with prior use of histamine-2 receptor antagonists 
(H2RAs) or proton pump inhibitors (PPIs) will be summarized by treatment and overall, using 
the ITT On-Demand Set. The number and percentage of subjects who had relieved symptoms per 
H2RA or PPI will also be summarized. A supportive listing will be provided. 
See Figure 2 for details on the categorization of prior and concomitant medications. 


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Figure 2 Prior and Concomitant Medications 
 
Prior and concomitant medications will be summarized and listed for both periods. For the Run-
In Period, prior and concomitant medications will be summarized separately using the Safety 
Run-In set. For the On-Demand Treatment Period, concomitant medications will be summarized 
and listed by treatment group using the Randomized  Set. 
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 11.2.  
7.2 
Study Treatments 
7.2.1 
Extent of Exposure 
Treatment exposure for the Run-In Period will be summarized using the Safety Run-In set. 
Treatment exposure for the On-Demand Treatment Period will be summarized by treatment 
using the Safety On-Demand set. 
7.2.1.1 
Run-In Period 
Appropriate statistical summaries will be applied to present the following statistics for the Run-
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• Duration of dosing (days): date of last dose of the Run-In period – date of first dose of the 
Run-In period + 1 
7.2.1.2 
On-Demand Treatment Period 
Appropriate statistical summaries will be applied to present the following statistics for the On-
Demand Treatment Period: 
• Duration of dosing (days): number of days on which subjects have recorded taking on-
demand study drug in the on-demand heartburn episode diary 
• Cumulative duration of dosing (days): total days of dosing since first dose of the On-
Demand treatment period 
• Duration of participation (days): date of Week 6/End Of Study visit – date of possible 
first dose + 1 
• Total dose (mg): total number of capsules taken × dose level 
 
Duration of dosing and duration of participation will be categorized and summarized as follows: 
≥1 to ≤7 days, >7 to ≤14 days, >14 to ≤21 days, >21 to ≤28 days, >28 to ≤35 days, >35 to ≤42 
days and >42 days. 
Treatment exposure will be listed for the On-Demand Treatment Period using the Safety On-
Demand Set. Drug accountability will be listed for the Run-In Period and On-Demand Treatment 
Period using the Safety Run-In Set and Safety On-Demand Set, respectively.  
7.2.2 
Treatment Compliance of the Run-In Period 
Treatment compliance will be calculated only for the Run-In Period using the Safety Run-In set 
as: 
Compliance (%) = (total actual capsules taken / total expected capsules) × 100, where 
total expected capsules = (date of last dose of this period – date of first dose of this 
period + 1) and  
Total actual capsules taken = total number of capsules dispensed for this period – total 
number of capsules returned for this period  
 
If a kit is not returned, the compliance of the lost kit will be imputed as 100%. 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%. 
Summary statistics for treatment compliance percentages and compliance categories (<80, ≥80 - 
≤100, >100 - ≤120, >120) will be summarized. Individual drug accountability for the Run-In 
Period will be listed using the Safety Run-In set. 


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8.0 
EFFICACY ANALYSIS  
For efficacy analyses, On-Demand Treatment Period is defined as any diary with analysis day on 
or after Day 1 and on or before Week 6/End Of Study visit (see Section 4.3.2 for the definition of 
Day 1 of the On-Demand Treatment Period; see Section 11.3 for the definition of analysis day 
for diary data). Run-In Period is defined as any diary with analysis day on or after the date of 
first dose, and on or before the date of last dose during the Run-In Period.  
For the On-Demand Treatment Period, each treatment comparison of vonoprazan 10 mg, 20 mg, 
and 40 mg to placebo will be tested at the 0.05 significance level using the ITT On-Demand set. 
For the Run-In Period, the exploratory endpoints will be summarized for the Run-In treatment, 
i.e. vonoprazan 20 mg, using the Safety Run-In set. 
No adjustments will be made for multiple comparisons given the exploratory nature of this study. 
8.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percentage of evaluable heartburn episodes completely 
relieved within 3 hours and with no further heartburn reported for 24 hours after taking study 
drug. An evaluable heartburn episode is an episode for which study drug was taken and for 
which the subject completed at least one entry in the heartburn episode diary. For a heartburn 
episode to be considered completely relieved, a subject must not have taken rescue antacid 
within 3 hours of taking study drug. See Section 11.3 for details on diary data handling. 
8.1.1 
Primary Analysis 
The primary endpoint of the percentage of evaluable heartburn episodes completely relieved 
within 3 hours and with no further heartburn reported for 24 hours after taking study drug will be 
compared between each dose of vonoprazan and placebo using Fisher’s Exact test for the ITT 
On-Demand set. The percentage will be based on the total number of evaluable heartburn 
episodes within each treatment group. Difference in percentages, 95% CI and p-value will be 
provided for the comparisons between each dose of vonoprazan and placebo. 
Data collected in the Heartburn Diary and Timed Assessments Diary will be listed using the ITT 
On-Demand set. Data collected in the Rescue Antacid Diary will be listed separately for rescue 
antacid use during the Run-In period and On-Demand Treatment periods, using the Safety Run-
In and Safety On-Demand sets, respectively. 
8.1.2 
Supplementary Analyses 
A supplementary analysis on the primary analysis will be performed to account for the possibly 
multiple evaluable heartburn episodes within a subject. During the On-Demand period, a subject 


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could experience more than one episode followed by intake of the study drug. Therefore, a 
generalized linear model with the Generalized Estimating Equation (GEE) method will be used 
to analyze this correlated binary data. The probability each episode will be completely relieved 
will be modeled using GEE within SAS Proc GENMOD. Treatment will be fit as a categorical 
factor. A compound symmetric (exchangeable) correlation structure within subjects will be 
assumed. The GEE for binary data will be based on a  binomial distribution with the logit link 
function.  
Results will be presented for the odds ratio [back transformed log-odds] for the comparisons 
between each dose of vonoprazan and placebo along with the associated 95% CI and 2-sided p-
value. 
8.1.3 
Sensitivity Analyses 
A sensitivity analysis will be performed by including heartburn episodes with rescue antacid use 
within 3 hours after taking study drug as completely relieved, using the same method as the 
primary analysis. In this analysis, heartburn episodes indicated by the subject in the diary as 
completely relieved within 3 hours after taking study drug will be included, regardless of rescue 
antacid use. 
A sensitivity analysis will also be performed by considering heartburn episodes with any use of 
rescue medication as not completely relieved, using the same method as the primary analysis.  
8.1.4 
Subgroup Analysis 
The primary efficacy endpoint will be analyzed separately for the following subgroups using the 
same method as the primary analysis: 
• Age group at Screening (<45, ≥45 - <65, ≥65 - <75, ≥75) 
• Sex (Male, Female) 
• 
Baseline BMI category (<25, ≥25 - <30, ≥30) 
• Mean heartburn severity during the Screening Period (mild, moderate, severe, very 
severe) 
 
If the number of subjects within a subgroup in a treatment group is not sufficient to run a 
Fisher’s Exact test, subgroups might be combined to perform the test. Alternatively, only 
summary statistics might be reported for such subgroups. 
8.2 
Secondary Efficacy Endpoint 
All secondary endpoints will be analyzed for the ITT On-Demand set and compared for each 
dose of vonoprazan to placebo.  


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The following secondary endpoints will be compared using Fisher’s Exact test using the same 
method as the primary analysis. 
• The percentage of evaluable heartburn episodes completely relieved within 3 hours after 
taking study drug. 
• The percentage of subjects with complete relief of heartburn within 3 hours after the first 
episode and with no further heartburn reported for 24 hours after taking study drug. 
The following secondary endpoints will be compared using a Wilcoxon rank-sum test. 
• The percentage of evaluable heartburn episodes for each subject that are completely 
relieved within 3 hours and with no further heartburn reported for 24 hours after taking 
study drug. 
• The percentage of days study drug was taken over the On-Demand Treatment Period. 
• The mean number of tablets of rescue antacid taken per day over the On-Demand 
Treatment Period. 
• The percentage of 24-hour heartburn-free days over the On-Demand Treatment Period. 
8.2.1 
Sensitivity Analyses 
The following sensitivity analyses will be made for the secondary endpoints using a Wilcoxon 
Rank Sum test: 
• The percentage of evaluable heartburn episodes for each subject (who experienced 4 or 
more episodes) that are completely relieved within 3 hours and with no further evaluable 
heartburn episodes reported for 24 hours after taking study drug.  
• The percentage of 24-hour heartburn-free days with no rescue antacid taken over the On-
Demand Treatment Period 
8.3 
Exploratory Endpoints  
8.3.1 
On-Demand Treatment Period  
The exploratory endpoints will be analyzed for the ITT On-Demand set and compared for each 
dose of vonoprazan to placebo. 
The following exploratory endpoints will be compared using Fisher’s Exact test using the same 
method as the primary analysis. 


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• The percentage of evaluable heartburn episodes completely relieved within 30 minutes or 
1, 1.5, or 2 hours and with no further heartburn reported for 24 hours after taking study 
drug. 
• The percentage of evaluable heartburn episodes that are completely relieved within 30 
minutes or 1, 1.5, or 2 hours after taking study drug.  
• The percentage of evaluable heartburn episodes that improved (including complete relief) 
at 30 minutes or 1, 1.5, 2, or 3 hours after taking study drug. 
• The percentage of episodes for which subjects continue to be heartburn-free after 24 or 
48 hours of taking study drug. 
• The percentage of subjects with at least 50%, at least 75%, and 100% of their evaluable 
heartburn episodes completely relieved within 3 hours with no further heartburn reported 
for 24 hours after taking study drug. 
• The percentage of subjects with at least 50%, at least 75%, and 100% of their evaluable 
heartburn episodes completely relieved within 3 hours after taking study drug. 
• The percentage of subjects with complete relief of the first episode of heartburn within 3 
hours after taking study drug. 
In addition, the following subset of the above exploratory endpoints will be compared using the 
same method as the primary analysis, but only including subjects with 4 or more evaluable 
episodes. 
• The percentage of evaluable heartburn episodes that are completely relieved within 30 
minutes or 1, 1.5, or 2 hours and with no further heartburn reported for 24 hours after 
taking study drug. 
• The percentage of evaluable heartburn episodes that are completely relieved within 30 
minutes or 1, 1.5, or 2 hours after taking study drug. 
• The percentage of evaluable heartburn episodes that improved (including complete relief) 
at 30 minutes or 1, 1.5, 2, or 3 hours after taking study drug. 
• The percentage of subjects with at least 50%, at least 75%, and 100% of their evaluable 
heartburn episodes completely relieved within 3 hours with no further heartburn reported 
for 24 hours after taking study drug. 


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• The percentage of subjects with at least 50%, at least 75%, and 100% of their evaluable 
heartburn episodes completely relieved within 3 hours after taking study drug. 
The following exploratory endpoints will be compared using a Wilcoxon rank-sum test. 
• The mean number of days between heartburn episodes. 
• The percentage of days without daytime heartburn over the On-Demand Treatment 
Period.  
• The percentage of days without nighttime heartburn over the On-Demand Treatment 
Period.  
• The mean severity of daytime and nighttime heartburn over the On-Demand Treatment 
Period.  
• The mean severity of nighttime heartburn over On-Demand Treatment Period.  
• The mean severity of daytime heartburn over the On-Demand Treatment Period.  
• The percentage of days without rescue antacid use over the On-Demand Treatment 
Period.  
• The change from baseline (i.e. last assessment on or before first dose on Run-In period) 
to the end of the Run-In, and to the end of the On-Demand Treatment Period for each 
subscale and the total score of the PAGI-SYM questionnaire. 
• The change from baseline (i.e. last assessment on or before first dose on Run-In period) 
to the end of the Run-In, and to the end of the On-Demand Treatment Period for each 
subscale and the total score of the PAGI-QoL questionnaire. 
The following exploratory endpoints will be summarized using descriptive statistics. 
• The patient global impression of change in GERD symptoms at the end of the 
On-Demand Treatment Period. 
• The patient global impression of severity in GERD symptoms over the last 7 days of the 
On-Demand Treatment Period. 
The following exploratory endpoint will be collected on the Patient Preference Questionnaire 
eCRF and will be summarized using descriptive statistics. 


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• The percentage of subjects with each dosing preference. 
Data collected from each questionnaire will be listed separately using the ITT On-Demand set. 
8.3.2 
Run-In Period 
The following exploratory endpoints will be summarized using descriptive statistics based on the 
Safety Run-In set. 
• The percentage of 24-hour heartburn-free days over the Run-In Period.  
• The percentage of subjects that are heartburn free over the last 7 days of the Run-In 
Period. 
• The percentage of days without daytime heartburn over the Run-In Period.  
• The percentage of days without nighttime heartburn over the Run-In Period.  
• The mean severity of daytime and nighttime heartburn over the Run-In Period.  
• The mean severity of nighttime heartburn over the Run-In Period.  
• The mean severity of daytime heartburn over the Run-In Period.  
• The percentage of days without rescue antacid use over the Run-In Period.  
• The mean number of tablets of rescue antacid taken per day over the Run-In Period. 
• The change from baseline to the end of the Run-In Period for each subscale and the total 
score of the PAGI-SYM questionnaire. 
• The change from baseline to the end of the Run-In Period for each subscale and the total 
score of the PAGI-QoL questionnaire. 
• The patient global impression of change in GERD symptoms at the end of the Run-In 
Period.  
• The patient global impression of severity in GERD symptoms over the last 7 days of the 
Run-In Period. 
Data collected in the Morning Diary and Evening Diary will be listed using the Safety Run-In 
set. 


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8.3.3 
Follow-Up Period 
The following exploratory endpoints will be summarized using descriptive statistics based on the 
ITT On-Demand set. 
• The percentage of 24-hour heartburn-free days over the Follow-Up Period.  
• The percentage of days without daytime heartburn over the Follow-Up Period.  
• The percentage of days without nighttime heartburn over the Follow-Up Period.  
• The mean severity of daytime and nighttime heartburn over the Follow-Up Period.  
• The mean severity of nighttime heartburn over the Follow-Up Period.  
• The mean severity of daytime heartburn over the Follow-Up Period.  
• The percentage of days without rescue antacid use over the Follow-Up Period.  
• The mean number of tablets of rescue antacid taken per day over the Follow-Up Period. 
9.0 
SAFETY ANALYSIS 
Safety will be summarized separately for the Run-In Period and the On-Demand Treatment 
Period. Safety data collected during the Follow-Up Period will be summarized with the On-
Demand Treatment Period. For each period, safety will be assessed by summarizing the 
incidence of AEs and changes in clinical laboratory tests, gastrin and pepsinogen I/II levels, 
ECGs and vital signs. The first baseline will be the last assessment on or before the date of first 
dose of study drug in the Run-In Period. For the On-Demand Treatment Period, a second 
baseline will be derived as the last assessment on or before the date of randomization. Changes 
from both baselines will be summarized. 
For the Run-In Period, all safety analyses will be summarized using the Safety Run-In set. For 
the On-Demand Treatment Period, all safety analyses will be conducted for each treatment group 
using the Safety On-Demand set. 
9.1 
Adverse Events 
Adverse events will be coded using Version 23.0 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 or any event at baseline that worsens in either intensity or frequency 
after the first dose of study drug in that period. For Run-In failure subjects, all AEs collected will 
be summarized in the Run-In Period. For subjects who entered the On-Demand Treatment 


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Period, all AEs that start before the date of possible first dose (Day 1 of the On-Demand 
Treatment Period) will be summarized in the Run-In Period. All AEs that start on or after the 
date of possible first dose (Day 1 of the On-Demand Treatment Period) will be counted as a 
TEAE of the On-Demand Treatment Period. Adverse events collected during the Safety Follow-
Up Period will be included with the On-Demand Treatment Period summaries. 
Overall AEs for the Run-In Period and On-Demand Treatment Period will be summarized 
separately, for the following adverse events. 
• Treatment-Emergent Adverse Event 
• Serious Treatment-Emergent Adverse Event 
• Study Drug-Related Treatment-Emergent Adverse Event 
• Study Drug-Related Treatment-Emergent Serious Adverse Event 
• Treatment-Emergent Adverse Event Leading to Treatment Discontinuation 
• Treatment-Emergent Adverse Event Leading to Study Discontinuation 
• Adverse Event Leading to Death 
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 and preferred term 
• by primary system organ class, preferred term and maximum severity 
• by primary system organ class, preferred term and relationship to study drug 
The number and percentage of subjects with TEAEs related to study drug will be summarized in 
the following ways:  


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• by primary system organ class and preferred term 
• by primary system organ class, preferred term and maximum severity 
For the On-Demand Treatment Period, a separate summary will be provided including AEs that 
are Treatment-Emergent with the AE onset day within 3 days of a subject taking any on-demand 
treatment.  
The most common TEAEs (≥10% of subjects in any treatment group) and TEAEs related to 
study drug (≥5% 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 group: 
• Adverse events leading to treatment discontinuation 
• Adverse events leading to study discontinuation 
• Serious Adverse Events (SAEs) 
• Deaths 
• Adverse events of special interest (AESI) 
All adverse events in the On-Demand Treatment Period will be included in a listing using the 
Randomized set. The adverse events that happen on or after On-Demand Treatment Period Day 1 
and before the date of actual first dose will be marked in this listing, but they will not be 
summarized separately. All adverse events in the Run-In Period will be included in a listing using 
the Safety Run-In set. Pre-treatment AEs and Serious AEs will be listed using the Screened set. 
In addition, the following select adverse events will be displayed in separate listings for each 
period: 
• Deaths 
• Serious adverse events 
• Adverse events leading to treatment discontinuation 
• Adverse events leading to study discontinuation 


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• Adverse events of special interest 
9.1.1 
Adverse Events of Special Interest (AESI) 
The number and percentage of subjects with TEAEs and SAEs that are in one of the AESI 
categories presented in Table 1 will be summarized by AESI category, primary system organ 
class and preferred term for the Run-In Period and the On-Demand Treatment Period. The search 
criteria that will be used to identify AESIs are specified in the table.  


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Table 1 Adverse Events 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. 
 
 


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9.2 
Clinical Laboratory Evaluations 
Descriptive statistics for clinical laboratory values (hematology, chemistry and urinalysis 
laboratory tests in US conventional units) and serum gastrin and pepsinogen I/II levels will be 
presented for the Run-In Period and the On-Demand Treatment Period. Laboratory assessments 
collected in the Follow-Up Period will be included in the On-Demand Treatment Period 
summaries. 
Day -1 baseline gastrin levels will not be blinded. Gastrin at the Week 4 Run-In, Week 6 On-
Demand treatment, and Safety Follow-up visits and all pepsinogen I and II results will be blinded 
and will not be reported to investigative sites or other blinded personnel until after the study 
blind is broken. 
Changes from baseline will also be presented for quantitative variables. For categorical variables 
(i.e., normal or abnormal findings, or qualitative clinical laboratory tests), shift tables for the 
change from baseline to the end of each period will be presented. 
Abnormal liver function tests are defined as liver test values that meet at least one of the criteria 
listed below. For each period, 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. 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 


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• AST > 10xULN and ALT > 10xULN 
• AST > 3xULN and ALT > 3xULN and Total Bilirubin > 2xULN 
 
• Alkaline phosphatase > 1.5xULN 
• ALT > 3xULN and Alkaline phosphatase > 1.5xULN 
• AST > 3xULN and Alkaline phosphatase > 1.5xULN 
 
• Alkaline phosphatase > 3xULN 
• ALT > 3xULN and Alkaline phosphatase > 3xULN 
• AST > 3xULN and Alkaline phosphatase > 3xULN 
 
Serum gastrin for all timepoints will be displayed using box plots for the Safety Run-In set and 
the Safety On-Demand set.  
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. 
9.3 
Vital Sign 
Descriptive statistics for vital signs, including body temperature, systolic blood pressure, 
diastolic blood pressure and pulse rate, will be presented for the Run-In Period and the On-
Demand Treatment Period. Changes from baseline will also be presented. Vital signs assessments 
collected in the Follow-Up Period will be included in the On-Demand Treatment Period 
summaries. 
Abnormal vital sign values are defined as vital sign values that meet one of the criteria listed 
below. For each period, 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. 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 


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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, PR interval, RR interval, QRS interval, QT interval, QTc 
Fridericia (QTcF) will be collected on the eCRF, and a listing will be provided. Descriptive 
statistics for these ECG parameters will be presented for the On-Demand Treatment Period using 
the Safety On-Demand set only. For ECG interpretations (within normal limits, abnormal but not 
clinically significant, or abnormal and clinically significant), shift tables for the change from 
baseline to the end of the On-Demand Treatment Period will be presented using the Safety On-
Demand set. 
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 for 
the On-Demand Treatment Period using the Safety On-Demand set. 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 msec 
o QTc interval > 480 msec  
o QTc interval > 500 msec  
• Change from Run-in baseline in QTcF interval: 
o QTc interval increases from baseline >30 msec 
o QTc interval increases from baseline >60 msec 
o QTc interval > 450 msec with increase from baseline >30 msec 
 
10.0 
INTERIM ANALYSIS/OTHER ANALYSES 
10.1 
Interim Analysis 
No interim analysis is planned. 


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10.2 
Coronavirus Pandemic 
In accordance with guidance issued by regulatory agencies, study data collection will document 
visits missed/delayed due to COVID-19 related reasons and assessments completed via 
alternative method due to COVID-19 related reasons. 
The COVID-19 impacts on individual subjects collected on the COVID-19 CRF pages will be 
listed for the All Subjects set. Protocol deviations related to COVID-19 will be marked in the 
protocol deviation listing for the All Subjects 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 
APPENDICES 
 
 






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(b)  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, AE assessment, and clinical laboratory tests. If the visit results in premature termination, then all 
procedures outlined for the final visit should be performed. 
(c)  The date of first dosing day is defined as Day 1 in both Run-In Period and On-Demand Treatment Period. The date of randomization is defined as Day -1 of On-
Demand Treatment Period. 
(d)  Subjects should continue to meet inclusion criteria (Protocol Section 4.1.1.1 ) and exclusion criteria (Protocol Section 4.1.1.2 ), except Inclusion Criteria 4. 
(e)  Full physical examination is performed at Screening; a brief physical examination is performed at all other visits. 
(f) Required only for confirmation of postmenopausal females as described in Protocol Section 13.2 (Appendix). Women whose duration of (consecutive) amenorrhea is 
borderline or open to doubt and where the investigator believes the subject to be menopausal by history should have confirmatory FSH drawn. 
(g)  See Protocol Section 6.3.3 and Table 6-4  for all required laboratory assessments. 
(h)  Gastrin Week 4 Run-In, Week 6 On-Demand treatment and Safety follow-up visits and pepsinogen I and II results will be blinded and will not be reported to 
investigative sites or other blinded personnel until the study blind is broken. 
(i)  Only female subjects with childbearing potential. Serum hCG at screening and urine hCG at all subsequent visits.  
(j)  The screening endoscopy can be performed any time during that period; however, it should be performed after the subject has fulfilled all other admission criteria. 
Any endoscopic confirmation performed in a routine clinical setting within 7 days before signing the informed consent is acceptable to use for the purpose of 
fulfilling the screening requirement. 
(k)  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 Screening, Run-In and Follow-up Period. During the On-Demand Treatment Period, subjects will be instructed to complete the 
electronic diary to document heartburn episodes and study drug administration. Rescue antacid use should be reported during all periods.  
(l)  Subjects are to start dose administration from Day 1. 
(m)  Rescue antacid will be dispensed as needed after the Screening Period.  
(n)  Sites will document dispensing rescue antacid. Subjects do not need to return unused rescue antacid. 
(o) Day -1 baseline gastrin levels will not be blinded. 
(p) Run-In failure procedures.  


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11.2 
Imputation Rules for Missing Date Imputation 
11.2.1 
Rules for Concomitant Medication Start Date Imputation 
The following rules will be applied to impute the missing numerical fields for the Run-In Period 
and the On-Demand Treatment Period. 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.  
For the Run-In Period, the date of first dose of study drug is the actual date that the subject took 
the first dose of Run-In treatment. For the On-Demand Treatment Period, the date of first dose of 
study drug refers to the date of possible first dose, i.e. date of randomization + 1. 
Missing day and month 
• If the year of the incomplete start date is the same as the year of the date of the first dose 
of study drug, then the day and month of the date of the first dose of study drug will be 
assigned to the missing fields. 
• If the year of the incomplete start date is before the year of the date of the first dose of 
study drug, then 31 December will be assigned to the missing fields. 
• If the year of the incomplete start date is after the year of the date of the first dose of 
study drug, then 01 January will be assigned to the missing fields. 
 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
 
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of 
the date of the first dose of study drug, then the day of the date of the first dose of study 
drug will be assigned to the missing day. 
• If either the year is before the year of the date of the first dose of study drug or if both 
years are the same but the month is before the month of the date of the first dose of study 
drug, then the last day of the month will be assigned to the missing day. 
• If either the year is after the year of the date of the first dose of study drug or if both years 
are the same but the month is after the month of the date of the first dose of study drug, 
then the first day of the month will be assigned to the missing day. 
 


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11.2.2 
Rules for Concomitant Medication End Date Imputation 
The following rules will be applied to impute the missing numerical fields for the Run-In Period 
and the On-Demand Treatment Period. For the Run-In Period, if the date of the last dose of study 
drug is missing, then replace it with the last visit date. For the On-Demand Treatment Period, the 
date of the last dose is referring to the date of possible last dose, i.e. the last visit date. If the 
imputed stop date is before the start date (imputed or non-imputed start date), then the imputed 
stop date will be equal to the start date. If the non-imputed stop date is more complete than the 
non-imputed start date (eg. stop date has a missing day and start date has missing month or stop 
date has full date but the start date has missing day or month) then the stop date will be imputed 
(as per rules below) and the start date will be imputed with the end date.  
Missing day and month 
• If the year of the incomplete stop date is the same as the year of the date of the last dose 
of study drug, then the day and month of the date of the last dose of study drug will be 
assigned to the missing fields. 
• If the year of the incomplete stop date is before the year of the date of the last dose of 
study drug, then 31 December will be assigned to the missing fields. 
• If the year of the incomplete stop date is after the year of the date of the last dose of study 
drug, then 01 January will be assigned to the missing fields. 
 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
 
Missing day only 
• If the month and year of the incomplete stop date are the same as the month and year of 
the date of the last dose of study drug, then the day of the date of the last dose of study 
drug will be assigned to the missing day. 
• If either the year is before the year of the date of the last dose of study drug or if both 
years are the same but the month is before the month of the date of the last dose of study 
drug, then the last day of the month will be assigned to the missing day. 
• If either the year is after the year of the last dose of study drug or if both years are the 
same but the month is after the month of the date of the last dose of study drug, then the 
first day of the month will be assigned to the missing day. 


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11.2.3 
Rules for Prior Medication Start Date Imputation 
For prior medications, incomplete (i.e., partially missing) start dates will be imputed and will 
follow the same rules as in Section 11.2.1. 
11.2.4 
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 11.2.1. Incomplete stop dates will not be imputed. 
11.3 
Electronic Diary 
Subjects will be given an electronic diary on the first day of the Screening Period. During the 
Screening, Run-In, and Safety Follow-up Periods subjects will complete the Morning Heartburn 
Diary, Evening Heartburn Diary, and Rescue Antacid Diary. During the On-Demand Treatment 
Period, subjects will complete the heartburn episode diaries, including the Heartburn Diary, 
Timed Assessment Diary, and Rescue Antacid Diary.  
11.3.1 
Screening, Run-In and Follow-up Period 
11.3.1.1 
Data Handling for Morning and Evening Heartburn Diaries 
During the Screening Period, Run-In Period, and Safety Follow-up Period, subjects will 
document the presence and severity of daytime and nighttime heartburn symptoms twice daily in 
their diary.  
For analysis purposes, diary entries will be assigned to an analysis day and time based on the day 
the collection interval started for that entry.  
For the Morning Heartburn Diary and the Evening Heartburn Diary, the form open date will be 
used to determine analysis day. The Day x diary entries will include the evening diary completed 
on Day x (the collection interval started when the subject awoke on Day x) and the morning 
entry completed on Day x+1 (the collection interval started when the subject went to bed on Day 
x).  
Subjects will document the presence (yes/no) and 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 Heartburn Diary for nighttime heartburn and once in the Evening Heartburn 
Diary for daytime heartburn. If the presence of heartburn is answered as “no” in a diary, the 
heartburn severity will be considered as 0 (0=None) in the analysis. 


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See Table 3 for details on definitions of heartburn severity. 
Table 3 Definitions of Heartburn Severity (Daytime/Nighttime) for the Screening, Run-In, 
and Follow-Up Periods 
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 the Run-In Period and the Follow-Up Period, the percentage of days with neither daytime 
nor nighttime heartburn (i.e. 24-hour heartburn free days) will be calculated using all days with 
at least 1 Morning Heartburn Diary or Evening Heartburn Diary entry during an observation 
period. For example, if a subject completed at least 1 diary entry on 22 of 28 days, but missed 
both entries on 6 days, 22 days will be used as the denominator in the efficacy analysis. All 
entries on that day will need to be heartburn-free 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 analysis 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. The mean severity of daytime and 
nighttime heartburn during each period 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 
during the Run-In Period and the Follow-Up Period, the highest recorded heartburn 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. 


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The mean severity of daytime heartburn 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 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. 
11.3.1.2 
Baseline Summary of Subject Diary 
Baseline diary assessments will be summarized using diaries from the last 7 days prior to Day -1, 
i.e, Days -8 to -2, inclusive, of the Screening Period. Only days with at least 1 morning or 
evening diary entry during the specified days will be included in these summaries. 
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). 
11.3.2 
 
Rescue Antacid Diary 
For Rescue Antacid Diary, if the rescue antacid start date is selected as 0 (Yesterday), the 
analysis day will be Day x-1 (the collection interval started when the subject opened the diary on 
Day x). If the rescue antacid start date is selected as 1 (Today), the analysis day will be Day x 
(the collection interval started when the subject opened the diary on Day x). The rescue antacid 
start time will be used as the analysis time.  
During all periods of the study, subjects will record the use of rescue antacid, including the time 
and number of antacid tablets taken. Rescue antacid endpoints will be calculated using all days 
during each period.  
11.3.3 
On-Demand Treatment Period 
During the On-Demand Treatment Period, subjects will document episodes of heartburn 
experienced and the use of on-demand study medication as they occur. Subjects will also receive 
reminders every morning and every evening to record any unrecorded heartburn episodes (no 
longer than the prior day) or to document if they have not had any heartburn episodes. 


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11.3.3.1 
 
Data Handling for On-Demand Heartburn Diary 
 
When subjects experience an episode of Heartburn during the On-Demand Treatment Period, the 
subject will complete the Heartburn Diary and document the severity of heartburn (Mild, 
Moderate, Severe, or Very Severe) of the episode (See Table 4 for details on definitions of 
heartburn severity).  If a subject has not reported an episode on a given day, the subject will be 
prompted to complete the Heartburn Diary each morning and evening during the On-Demand 
Treatment Period. The subject will either confirm that the subject has not experienced heartburn 
or will complete the diary to document episodes of heartburn. 
Table 4 Definitions of Heartburn Severity for the On-Demand Treatment Period 
Mild – Heartburn is present but can be ignored, does not influence daily routine or sleep 
Moderate - Heartburn cannot be ignored and/or occasionally daily routine or sleep 
Severe - Heartburn regularly influences daily routine or sleep 
Very Severe – Heartburn markedly influences daily routine or sleep 
 
 
11.3.3.2 
 
On-Demand Timed Assessments   
Once a heartburn episode is reported and the subject is eligible to take study drug (ie, 24 hours 
since the last administration), the subject will be prompted to complete the Timed Assessments 
Diary. The Timed Assessments Diary will collect heartburn episode assessments for 3 hours to 
assess when heartburn relief occurs. The diary will prompt responses 30 minutes after study drug 
administration is reported and then 1, 1.5, 2, and 3 hours after study drug treatment. The response 
will indicate presence of heartburn (yes/no) and severity (1=Mild, 2=Moderate, 3=Severe, or 
4=Very Severe). If the presence of heartburn is answered as “no” in the diary, the episode of 
heartburn will be considered to have resolved. Subjects will be allowed to opt out of the timed 
assessments.  


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Table 5 Definitions of Heartburn Severity for Time Assessment Diary 
None – No heartburn 
Mild – Heartburn is present but can be ignored, does not influence daily routine or sleep 
Moderate - Heartburn cannot be ignored and/or occasionally daily routine or sleep 
Severe - Heartburn regularly influences daily routine or sleep 
Very Severe – Heartburn markedly influences daily routine or sleep 
 
11.3.3.3 
Data Handling for Evaluable Heartburn for On-Demand Treatment Period 
For analysis purposes, diary entries will be assigned to an analysis day and time based on the day 
the collection interval started for that entry.  
For the Heartburn Diary, if heartburn experience is selected as 0 (I am experiencing heartburn 
right now), the analysis day will be Day x (the collection interval started when the subject 
opened the diary on Day x). If the heartburn experience is selected as 1 (I need to record an 
episode of heartburn that occurred within the past day), the analysis day will be Day x-1 (the 
collection interval started when the subject opened the diary on Day x). The heartburn start time 
and the study drug intake time collected in the Heartburn Diary entries will be used as the 
analysis time.  
To meet the criteria for the primary endpoint of evaluable heartburn episodes with complete 
relief within 3 hours and with no further heartburn reported for 24 hours after study drug is 
taken, the following requirements must be met: 
• A completed entry in the Heartburn Diary indicates presence of heartburn and that study 
drug was taken 
• The last timed assessment for the episode indicates no heartburn within 3 hours of the 
study drug taken time 
• No use of rescue antacid is recorded in the Rescue Antacid Diary, within 3 hours of the 
study drug taken time 
• No heartburn episode is recorded in the Heartburn Diary within 24 hours of the study 
drug taken time 
If a subject does not complete all of the timed assessments for an episode (30 minutes and then 1, 
1.5, 2, and 3 hours after study drug treatment), the episode will be considered completely 


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relieved if the last available assessment indicates that the subject no longer has heartburn and the 
other requirements are met. 
For Heartburn Diary, an episode of heartburn reported with a heartburn start time from 06:00 to 
21:59 will be used for assessing daytime heartburn and with a heartburn start time from 22:00 to 
05:59 will be used for assessing nighttime heartburn. 
For heartburn episodes reported during the On-Demand Treatment Period in the Heartburn Diary, 
the percentage of days with neither daytime nor nighttime heartburn (i.e. 24-hour heartburn free) 
will be calculated using all days during the On-Demand Treatment Period with at least one 
Heartburn Diary entry. In order for a day to be considered heartburn free, no episodes of 
heartburn can be reported for that day and the subject must have completed a Heartburn Diary 
for that day confirming that the subject has not experienced heartburn.  
The percentage of days without daytime heartburn will be calculated using the same method as 
above using diary entries that reflect daytime symptoms only. The percentage of days without 
nighttime heartburn during each period will be calculated using the same method as above using 
diary entries that reflect nighttime symptoms only. For Heartburn diary entries indicating that the 
subject has not experienced heartburn, records reported between 18:00 to 05:59 will be 
considered to reflect daytime symptoms and between 06:00 to 17:59 will be considered to reflect 
nighttime symptoms. 
For heartburn symptoms reported during the On-Demand Treatment Period in the Heartburn 
Diary, the mean severity of daytime and nighttime heartburn for each subject will be calculated 
by taking the mean of the severity of each heartburn episode divided by the total number of 
episodes for that subject during the On-Demand Treatment Period.  
11.4 
PAGI-QOL and PAGI-SYM Scoring 
11.4.1 
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.  
11.4.2 
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).