Conditions: Non-Erosive Gastro-Esophageal Reflux Disease Heartburn
Keywords: NERD Vonoprazan
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 776
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to assess the efficacy of vonoprazan (10 mg and 20 mg once daily \[QD\]) compared to placebo (QD) in relief of heartburn over 4 weeks in participants with NERD.

Detailed description:

Arms:
arm 1: Participants will be administered vonoprazan at a dose of 10 mg QD in the 4 week Placebo-controlled Treatment Period. Participants randomized to vonoprazan 10 mg in the Placebo-controlled Treatment Period will continue to take the same dose in the 20 week Extension Period. arm 2: Participants will be administered vonoprazan at a dose of 20 mg QD in the 4 week Placebo-controlled Treatment Period. Participants randomized to vonoprazan 20 mg in the Placebo-controlled Treatment Period will continue to take the same dose in the 20 week Extension Period. arm 3: Participants will be administered the placebo QD in the 4 week Placebo-controlled Treatment Period. Participants randomized to placebo in the Placebo-controlled Treatment Period will be re-randomized to receive either vonoprazan 10 mg QD or vonoprazan 20 mg QD in the 20 week Extension Period.

Interventions: intervention 1: Vonoprazan intervention 2: Placebo
Intervention descriptions: intervention 1: Orally via capsule intervention 2: Orally via capsule

Protocol document:
Prot_000.pdf: 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 2 
Protocol Approval – Sponsor Signatory 
Study Title 
A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the 
Efficacy and Safety of Vonoprazan 10 and 20 mg Compared to Placebo for 
Relief of Heartburn in Subjects with Symptomatic Non-Erosive 
Gastroesophageal Reflux Disease (NERD) After 4 Weeks and to Evaluate 
the Efficacy and Safety of Vonoprazan 10 and 20 mg for Relief of Heartburn 
in Subjects with NERD After 6 Months 
Protocol Number 
NERD-301 
Protocol Version 
and Date 
Version 3.0 
25 April 2022 
 
DocuSign Envelope ID: B8E47B40-99DA-4FEC-B249-6F470FE40F3B


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 3 
 
Protocol Approval – Principal/Coordinating Investigator 
Study Title 
A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate 
the Efficacy and Safety of Vonoprazan 10 and 20 mg Compared to 
Placebo for Relief of Heartburn in Subjects with Symptomatic 
Non-Erosive Gastroesophageal Reflux Disease (NERD) After 
4 Weeks and to Evaluate the Efficacy and Safety of Vonoprazan 
10 and 20 mg for Relief of Heartburn in Subjects with NERD After 
6 Months 
Protocol Number NERD-301 
Protocol Version 
and Date 
Version 3.0 
25 April 2022 
 
Protocol accepted and approved by: 
Principal/Coordinating Investigator 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: 8BCFED87-EE87-4CF5-A1B9-1F7B0FA277A6


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 4 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 3, Randomized, 
Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Vonoprazan 10 and 
20 mg Compared to Placebo for Relief of Heartburn in Subjects with Symptomatic 
Non-Erosive Gastroesophageal Reflux Disease (NERD) After 4 Weeks and to Evaluate the 
Efficacy and Safety of Vonoprazan 10 and 20 mg for Relief of Heartburn in Subjects with 
NERD After 6 Months” and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 3.0, dated 25 April 2022, 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-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 5 
Summary of Changes 
Protocol Amendment History and Reasons for Amendment 
Version 
Date 
Reasons for Amendment 
Version 1.0 
28 September 2021 
Original Protocol 
Version 2.0 
(Protocol 
Amendment 1) 
09 February 2022 
• To clarify the definition of symptomatic 
gastroesophageal reflux disease in inclusion 
criterion #4 
• To add an exclusion criterion for active 
Helicobacter pylori infection during the 
Screening Period 
• To add collection of coronavirus-19 vaccination 
history 
• To clarify that an external biostatistician, not 
involved in study conduct, will generate the 
randomization schedule 
• To update the definition of the intent-to-treat 
analysis set 
Version 3.0 
(Protocol 
Amendment 2) 
25 April 2022 
• To move the endpoints of the percentage of 
days without nighttime heartburn and the 
percentage of days without daytime heartburn 
over the Placebo-controlled Treatment Period 
from secondary to exploratory endpoints 
• To delete the secondary endpoint of the 
percentage of subjects with onset of sustained 
resolution of heartburn by Day 3 
• To modify the planned analysis of the primary 
and secondary endpoints to use a general linear 
model instead of a Wilcoxon rank-sum test 
• To modify the overall planned significance 
level for the study from 0.01 to the standard 
0.05  
• To clarify that the intent-to-treat and safety 
analysis sets for the Follow-up Period will be 
defined the same as these sets for the Extension 
Period 
• To correct the description of the calculation of 
the total N-GSSIQ score 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 6 
Version 
Date 
Reasons for Amendment 
Version 3.0 
(Protocol 
Amendment 2;  
continued) 
25 April 2022 
• To clarify test methods for Helicobacter pylori 
infection  
• To add completion of the Study Subject 
Informational Questionnaire prior to 
randomization 
• To clarify in the Schedule of Events when the 
first dose of study drug in the Extension Period 
should be administered 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 7 
Table of Contents 
Summary of Changes .................................................................................................................5 
Table of Contents .......................................................................................................................7 
List of Tables ............................................................................................................................ 11 
Protocol Synopsis.....................................................................................................................12 
List of Abbreviations................................................................................................................17 
1 
Introduction ......................................................................................................................19 
1.1 
Study Rationale .......................................................................................................19 
1.2 
Background .............................................................................................................19 
1.2.1 
Epidemiology, Symptoms, and Current Treatments for NERD ...............19 
1.2.2 
Vonoprazan ..............................................................................................20 
1.3 
Justification for Dose ..............................................................................................23 
2 
Study Objectives and Endpoints.......................................................................................24 
2.1 
Primary Efficacy Objective and Endpoint ..............................................................24 
2.2 
Safety Objectives and Endpoints ............................................................................24 
2.3 
Secondary Efficacy Objective and Endpoint ..........................................................24 
2.4 
Exploratory Endpoints ............................................................................................25 
3 
Investigational Plan ..........................................................................................................28 
3.1 
Study Design ...........................................................................................................28 
3.1.1 
Rationale of Study Design .......................................................................31 
3.1.1.1 
Rationale for the Placebo-controlled Treatment Period ...........................31 
3.1.1.2 
Rationale for the Extension Period and Follow-up Period ......................31 
4 
Subject Selection and Withdrawal Criteria ......................................................................32 
4.1 
Selection of Study Population .................................................................................32 
4.1.1 
Inclusion Criteria .....................................................................................32 
4.1.2 
Exclusion Criteria ....................................................................................33 
4.1.3 
Screen Failures .........................................................................................36 
4.1.4 
Lifestyle Considerations ..........................................................................36 
4.2 
Withdrawal of Subjects From Study Drug and/or the Study ..................................37 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................37 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 8 
4.2.2 
Handling of Withdrawals .........................................................................38 
4.2.3 
Lost to Follow-up ....................................................................................39 
4.2.4 
Replacements ...........................................................................................40 
5 
Study Drugs ......................................................................................................................41 
5.1 
Method of Assigning Subjects to Treatment Groups ..............................................41 
5.2 
Treatments Administered ........................................................................................41 
5.3 
Rescue Antacid........................................................................................................42 
5.4 
Identity of Investigational Product and Rescue Antacid .........................................42 
5.4.1 
Vonoprazan and Placebo ..........................................................................42 
5.4.2 
Rescue Antacid ........................................................................................42 
5.5 
Management of Clinical Supplies ...........................................................................42 
5.5.1 
Study Drug Packaging and Storage .........................................................42 
5.5.2 
Study Drug and Rescue Antacid Accountability .....................................43 
5.6 
Overdose Management ...........................................................................................43 
5.6.1 
Treatment of Overdose ............................................................................44 
5.7 
Blinding ..................................................................................................................44 
5.7.1 
Breaking the Blind ...................................................................................44 
5.8 
Study Compliance ...................................................................................................45 
5.8.1 
Treatment Compliance .............................................................................45 
5.8.2 
Diary Compliance ....................................................................................45 
5.9 
Prior and Concomitant Therapy ..............................................................................45 
5.9.1 
Excluded Medications .............................................................................46 
6 
Study Assessments and Procedures ..................................................................................48 
6.1 
Endoscopy and H pylori Testing During the Screening Period ..............................48 
6.2 
Efficacy Assessments ..............................................................................................49 
6.2.1 
Electronic Symptom Diary ......................................................................49 
6.2.1.1 
Morning and Evening Diary ....................................................................49 
6.2.1.2 
Severity Definitions .................................................................................49 
6.2.2 
PAGI-SYM Questionnaire .......................................................................50 
6.2.3 
PAGI-QoL Questionnaire ........................................................................50 
6.2.4 
EQ-5D-5L Questionnaire .........................................................................51 
6.2.5 
PSQI Questionnaire .................................................................................51 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 9 
6.2.6 
N-GSSIQ ..................................................................................................52 
6.3 
Safety Assessments .................................................................................................52 
6.3.1 
Pretreatment Events and Adverse Events ................................................52 
6.3.1.1 
Definitions ...............................................................................................52 
6.3.1.2 
Documenting Adverse Events ..................................................................58 
6.3.1.3 
Time Period and Frequency for Collecting AE and SAE Information ....61 
6.3.1.4 
Regulatory Reporting Requirements for SAEs ........................................64 
6.3.2 
Pregnancy ................................................................................................65 
6.3.3 
Laboratory Analyses ................................................................................65 
6.3.4 
Physical Examinations .............................................................................68 
6.3.5 
Vital Signs ................................................................................................68 
6.3.6 
Electrocardiograms ..................................................................................69 
6.4 
Safety Monitoring Committee ................................................................................69 
7 
Statistical and Analytical Plan ..........................................................................................70 
7.1 
Sample Size Calculations ........................................................................................70 
7.2 
Analysis Sets ...........................................................................................................70 
7.2.1 
Intent-to-treat Set .....................................................................................70 
7.2.2 
Safety Set .................................................................................................70 
7.3 
Statistical Analysis Methodology ...........................................................................71 
7.3.1 
Efficacy Analyses ....................................................................................72 
7.3.1.1 
Placebo-controlled Treatment Period.......................................................72 
7.3.1.2 
Extension Period ......................................................................................72 
7.3.1.3 
Follow-up Period .....................................................................................73 
7.3.2 
Safety Analyses ........................................................................................73 
7.3.3 
Other Analyses .........................................................................................74 
7.3.4 
Interim Analyses ......................................................................................74 
8 
Data Quality Assurance ....................................................................................................75 
8.1 
Data Management ...................................................................................................75 
9 
Ethics ................................................................................................................................76 
9.1 
Independent Ethics Committee or Institutional Review Board ..............................76 
9.2 
Ethical Conduct of the Study ..................................................................................76 
9.3 
Subject Information and Consent ...........................................................................76 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 10 
10 Investigator’s Obligations ................................................................................................78 
10.1 Confidentiality ........................................................................................................78 
10.2 Financial Disclosure and Obligations .....................................................................78 
10.3 Investigator Documentation ....................................................................................79 
10.4 Study Conduct .........................................................................................................79 
10.5 Adherence to Protocol ............................................................................................80 
10.6 Adverse Events and Study Report Requirements ...................................................80 
10.7 Investigator’s Final Report .....................................................................................80 
10.8 Records Retention ...................................................................................................80 
10.9 Publications .............................................................................................................80 
11 Study Management ...........................................................................................................82 
11.1 Monitoring ..............................................................................................................82 
11.1.1 
External Data Monitoring Committee .....................................................82 
11.1.2 
Monitoring of the Study ...........................................................................82 
11.1.3 
Inspection of Records ..............................................................................82 
11.2 Management of Protocol Amendments and Deviations..........................................82 
11.2.1 
Modification of the Protocol ....................................................................82 
11.2.2 
Protocol Deviations .................................................................................83 
11.3 Study Termination ...................................................................................................83 
11.4 Final Report ............................................................................................................84 
12 Reference List...................................................................................................................85 
13 Appendices .......................................................................................................................88 
13.1 Appendix 1: Schedule of Events .............................................................................88 
13.2 Appendix 2: Contraceptive Guidance .....................................................................92 
13.3 Appendix 3: Liver Function Tests ...........................................................................94 
13.3.1 
Liver Function Test Monitoring ...............................................................94 
13.3.2 
Considerations for Temporary Discontinuation of Study Drug ...............94 
13.3.3 
Permanent Discontinuation of Study Drug ..............................................95 
13.3.4 
Re-initiation of Study Drug .....................................................................96 
13.4 Appendix 4: Rome IV Criteria ................................................................................97 
13.4.1 
Functional Heartburn ...............................................................................97 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 11 
13.4.2 
Functional Dyspepsia ...............................................................................97 
13.4.2.1 Postprandial Distress Syndrome ..............................................................98 
13.4.2.2 Epigastric Pain Syndrome ........................................................................99 
13.5 Appendix 5: Protocol Amendments ......................................................................100 
13.5.1 
Protocol Amendment 1 ..........................................................................100 
13.5.2 
Protocol Amendment 2 ..........................................................................106 
 
List of Tables 
Table 2-1 
Primary Efficacy Objective and Endpoint ...................................................... 24 
Table 2-2 
Safety Objectives and Endpoints .................................................................... 24 
Table 2-3 
Secondary Efficacy Objective and Endpoint for the Placebo-controlled 
Treatment Period ............................................................................................. 25 
Table 5-1 
Excluded Medications and Treatments ........................................................... 47 
Table 6-1 
Definitions of Heartburn Severity (Daytime/Nighttime) for the Screening, 
Placebo-controlled Treatment, Extension, and Follow-up Periods ................. 50 
Table 6-2 
Medically Significant Adverse Event List ...................................................... 54 
Table 6-3 
Adverse Events of Special Interest List .......................................................... 55 
Table 6-4 
Protocol-Required Safety Laboratory Assessments ........................................ 67 
Table 13-1 
Schedule of Events .......................................................................................... 89 
Table 13-2 
Abnormal Liver Function Criteria For Permanent Discontinuation of Study 
Drug ................................................................................................................ 95 
 
List of Figures 
Figure 3-1 
Study Scheme.................................................................................................. 29 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 12 
Protocol Synopsis 
 
Protocol 
Number: 
NERD-301 
Title: 
A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the 
Efficacy and Safety of Vonoprazan 10 and 20 mg Compared to Placebo 
for Relief of Heartburn in Subjects with Symptomatic Non-Erosive 
Gastroesophageal Reflux Disease (NERD) After 4 Weeks and to Evaluate 
the Efficacy and Safety of Vonoprazan 10 and 20 mg for Relief of 
Heartburn in Subjects with NERD After 6 Months 
Sponsor:  
Phathom Pharmaceuticals, Inc. 
2150 East Lake Cook Road, Suite 800 
Buffalo Grove, IL 60089 USA 
Study Phase: 
3 
Study Sites: 
Approximately 100 sites in the United States 
Indication: 
Relief of heartburn associated with NERD 
Rationale: 
Gastroesophageal reflux disease (GERD) is prevalent globally and 
represents one of the most common gastrointestinal diseases. Per the 
Montreal definition, 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 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 for healing 
of all grades of EE and relief of heartburn, maintenance of healing of all 
grades of EE and relief of heartburn, treatment of heartburn in NERD, 
and treatment of Helicobacter pylori infection.  
Vonoprazan at doses ≥10 mg has been shown in both single and multiple 
repeat-dosing studies to have a rapid onset of action and near maximal 
effect on pH holding time within 24 hours of dosing, which is maintained 
with chronic dosing. It is believed that this pharmacologic profile may 
make it an optimum agent for the treatment of NERD. This study will 
evaluate the safety and effectiveness of vonoprazan 10 mg and 20 mg to 
treat heartburn in patients with NERD. 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 13 
Objectives: 
Primary Efficacy: 
• To assess the efficacy of vonoprazan (10 mg and 20 mg once daily 
[QD]) compared to placebo (QD) in relief of heartburn over 4 weeks 
in subjects with NERD. 
Safety: 
• To assess the safety of vonoprazan (10 mg and 20 mg QD) compared 
to placebo (QD) in subjects with NERD over 4 weeks. 
• To assess the long-term safety of vonoprazan (10 mg and 20 mg QD) 
over 6 months. 
Secondary: 
• To assess the use of rescue antacid with vonoprazan (10 mg and 
20 mg QD) compared to placebo (QD) over 4 weeks in subjects with 
NERD. 
Study 
Population: 
Subjects ≥18 years of age with NERD confirmed by endoscopy during the 
Screening Period. Heartburn must be reported on 4 or more days during 
any consecutive 7-day period of the Screening Period as recorded in the 
electronic diary. 
Study Design:  
This is a Phase 3, multicenter, double-blind study of vonoprazan versus 
placebo assessing the relief of heartburn. Subjects with NERD (as 
confirmed by endoscopy) and heartburn symptoms will be randomized to 
receive vonoprazan 10 mg, vonoprazan 20 mg, or placebo QD for 
4 weeks. Subjects will complete an electronic diary twice daily to record 
the presence and maximum severity of daytime and nighttime heartburn 
symptoms and use of rescue antacid throughout the study. Study-supplied 
rescue antacid will be allowed. After the Placebo-controlled Treatment 
Period, all subjects will receive blinded vonoprazan (10 mg or 20 mg QD) 
in the Extension Period. 
 
 
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 14 
 
Study Design  
(continued): 
The study will include 4 periods: 
Screening Period (Day -35 to Day -2): Subjects will provide informed 
consent and undergo screening assessments to determine study eligibility, 
and baseline assessment will be performed. Subjects will complete the 
electronic diary twice daily during the Screening Period. If all eligibility 
criteria are met, the subject will enter the study. 
Placebo-controlled Treatment Period (Day -1 to Day 28): Subjects 
with NERD whose eligibility is confirmed will be randomized to receive 
vonoprazan 10 mg or 20 mg or placebo QD for 4 weeks. The date of the 
first dosing is defined as Day 1. An electronic diary will continue to be 
completed twice daily during the Placebo-controlled Treatment Period. 
Extension Period (Day 29 to Day 169): Subjects randomized to 
vonoprazan 10 mg or 20 mg in the Placebo-controlled Treatment Period 
will continue to take the same dose in a blinded manner for an additional 
20 weeks. Subjects randomized to placebo in the Placebo-controlled 
Treatment Period will be re-randomized to receive either vonoprazan 
10 mg QD or vonoprazan 20 mg QD for 20 weeks. An electronic diary 
will continue to be completed twice daily during the Extension Period. 
The first dose of study drug for the Extension Period will be taken the day 
after the Week 4 visit. 
Follow-up Period: A safety follow-up visit will occur 4 weeks after the 
last dose of study drug. An electronic diary will continue to be completed 
twice daily during the Follow-up Period. 
A subject will be considered to have completed the study if the subject 
completes the safety follow-up visit. 
Estimated Study 
Duration: 
The total duration of the study is up to 33 weeks. The Screening Period is 
up to 5 weeks, Placebo-controlled Treatment Period is 4 weeks, Extension 
Period is 20 weeks, and safety follow-up is 4 weeks after last study drug 
administration. 
 
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 15 
 
Efficacy 
Assessments: 
Primary: 
• The percentage of days without daytime or nighttime heartburn over 
the Placebo-controlled Treatment Period as assessed by the daily 
diary. 
Secondary: 
• The percentage of days without rescue antacid use over the 
Placebo-controlled Treatment Period as assessed by the daily diary. 
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 
• Vital signs 
Study Drug, 
Dosage, and 
Route of 
Administration: 
Placebo-controlled Treatment Period: 
Blinded study drug (vonoprazan 10 mg, vonoprazan 20 mg, or placebo) to 
be taken orally QD for 4 weeks. 
Extension Period: 
Blinded study drug (vonoprazan 10 mg or vonoprazan 20 mg) to be taken 
orally QD for 20 weeks. 
Sample Size: 
A sample size of 250 subjects per treatment group provides greater than 
90% power at the 0.05 2-sided level of significance using a two-sample 
t-test to detect a difference of 20% between a vonoprazan dose (50%) and 
placebo (30%) in the percentage of days without daytime or nighttime 
heartburn over the 4-week Placebo-controlled Treatment Period, 
assuming a common standard deviation of 35%. 
 
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 16 
 
Statistical 
Methods: 
Primary Efficacy Endpoint: 
For the primary endpoint of the percentage of days without daytime or 
nighttime heartburn over the Placebo-controlled Treatment Period as 
assessed by the daily diary, each of the vonoprazan treatment groups will 
be compared to the placebo treatment group using a general linear model 
with treatment group as factor and severity and frequency of heartburn at 
baseline as covariates. 
Secondary Efficacy Endpoints: 
For the percentage of days without rescue antacid use over the Placebo-
controlled Treatment Period as assessed by the daily diary, each of the 
vonoprazan treatment groups will be compared to the placebo treatment 
group using a general linear model with treatment group as factor and 
severity and frequency of heartburn at baseline as covariates. 
Safety: 
Safety data will be summarized separately for the Placebo-controlled 
Treatment Period and the Extension Period. 
Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of subjects 
experiencing treatment-emergent AEs will be summarized by MedDRA 
system organ class and preferred term overall, by severity, and by 
relationship to study drug for each treatment group. Separate summaries 
will also be generated for treatment-related AEs overall and by severity. 
Clinical laboratory tests, gastrin and pepsinogen I/II levels, 
electrocardiograms, and vital signs will be summarized with descriptive 
statistics at each visit by treatment group. 
Version and 
Date of Protocol: 
Version 3.0  
25 April 2022 
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 17 
List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
COVID-19 
coronavirus-19 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EE 
erosive esophagitis 
EPS 
epigastric pain syndrome 
EQ-5D-5L 
EuroQol 5-dimension 5-level questionnaire 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
GGT 
gamma-glutamyl transferase 
H+, K+-ATPase 
hydrogen, potassium–adenosine triphosphatase 
H2RA 
histamine-2 receptor antagonist 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
H pylori 
Helicobacter pylori 
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 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 18 
Abbreviation 
Definition 
NERD 
symptomatic non-erosive gastroesophageal reflux disease 
N-GSSIQ 
Nocturnal Gastroesophageal Reflux Disease Symptom Severity and 
Impact Questionnaire 
PAGI-QoL 
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life 
PAGI-SYM 
Patient Assessment of Upper Gastrointestinal Disorders-Symptom 
Severity Index  
PCAB 
potassium-competitive acid blocker 
PDS 
postprandial distress syndrome 
PPI 
proton pump inhibitor 
PSQI 
Pittsburgh Sleep Quality Index 
PT 
preferred term 
PTE 
pretreatment event 
QD 
once daily 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SOC 
system organ class 
SoE 
schedule of events 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
Note: Abbreviations used only in tables and figures are defined with the relevant tables and figures. 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: NERD-301 Version 3.0 (Amendment 2) 
25 April 2022 
Page 19 
1 
Introduction 
Vonoprazan belongs to a new class of acid-inhibitory agents called potassium-competitive 
acid blockers (PCABs). In addition to the treatment of heartburn in patients with 
symptomatic non-erosive gastroesophageal reflux disease (NERD), vonoprazan 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, and treatment of 
Helicobacter pylori (H pylori) infection. 
In other countries, vonoprazan has been studied in additional acid-related diseases including 
gastric ulcer/duodenal ulcer healing, and for the prevention of recurrence of gastric or 
duodenal ulcer during nonsteroidal anti-inflammatory drug or aspirin administration. 
Vonoprazan has received regulatory approval in Japan, Russia, and other countries in Asia 
and Latin America for a variety of indications. 
Phathom Pharmaceuticals, Inc. licensed the exclusive rights from Takeda Pharmaceutical 
Company Limited to develop, manufacture, and commercialize vonoprazan in the United 
States, Europe, and Canada. 
1.1 
Study Rationale 
Vonoprazan at doses ≥10 mg has been shown in both single and multiple repeat-dosing 
studies to have a rapid onset of action and near maximal effect on pH holding time within 
24 hours of dosing, which is maintained with chronic dosing. It is believed that this 
pharmacologic profile may make it an optimum agent for the treatment of NERD. This study 
will evaluate the safety and effectiveness of vonoprazan 10 mg and 20 mg to treat heartburn 
in patients with NERD. 
1.2 
Background 
1.2.1 
Epidemiology, Symptoms, and Current Treatments for NERD 
Gastroesophageal reflux disease (GERD) is prevalent globally and represents one of the most 
common gastrointestinal diseases. Per the Montreal definition, GERD is a condition that 
develops when the reflux of stomach contents causes troublesome symptoms and/or 
complications [Vakil 2006]. The term GERD covers a spectrum of conditions, including 
NERD, EE, and Barrett’s esophagus. The Genval workshop suggested that the definition of 


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NERD should be reserved for individuals who satisfy the definition of GERD but who do not 
have either Barrett's esophagus or definite endoscopic esophageal mucosal breaks (erosion or 
ulceration) [Dent 1999]. 
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 2014]. 
Clinical studies have demonstrated that heartburn severity and intensity are similar in patients 
with EE and those with NERD [Smout 1997]. The impact of heartburn severity on patients’ 
quality of life was also similar in both EE and NERD [Carlsson 1998, Venables 1997], and 
sleep dysfunction was also similar [Yi 2007]. In contrast to EE, NERD is mostly viewed as a 
non-progressive disease and the treatment approach is symptom-driven [Savarino 2017].  
To date, proton pump inhibitors (PPIs) have been shown to be the most effective available 
antisecretory agents for relieving GERD symptoms, healing the injured mucosa, and 
maintaining a healed mucosa [Freston 2004]. A meta-analysis demonstrated that the relative 
risk for heartburn remission in placebo-controlled trials of patients with NERD was 
0.68 (95% confidence interval [CI]: 0.59-0.78) for PPIs versus placebo [Savarino 2017]. 
Proton pump inhibitors are recommended for treatment of NERD for 4 to 8 weeks. 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 [Katz 2013]. A study of 
pantoprazole and esomeprazole has shown that in NERD patients the median time to onset of 
symptom relief is 2 days and median time to sustained symptom relief is 10 to 13 days 
[Monnikes 2005]. This finding is consistent with the known mechanism of action of PPIs, in 
which there is a build-up effect on acid suppression after repeated daily dosing.  
1.2.2 
Vonoprazan 
The gastric hydrogen, potassium–adenosine triphosphatase (H+, K+-ATPase), also known as 
the proton pump, is responsible for acid secretion from parietal cells in the stomach. It is 
inactive in the cytosol but relocates from the cytosol to the secretory membrane of the 
parietal cells when food is present in the stomach, thereby becoming active and pumping 
H+ ions out of the cells and into the canaliculi in exchange for K+ ions. It represents an 
attractive pharmacological target since it is the final step of the acid secretion process.  


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Two classes of pharmaceuticals, with distinct mechanisms of action for inhibiting the gastric 
proton pump, have been developed for clinical application: PPIs and PCABs. As a PCAB, 
vonoprazan has a unique mechanism of action and pharmacokinetics relative to PPIs: 
• Acid activation and stability: Conventional PPIs are prodrugs, which are activated by 
acid and covalently bind the H+, K+-ATPase; however, activated PPIs are not stable 
in acidic conditions. In contrast, vonoprazan does not require acid activation, is stable 
in acidic conditions, and has a more durable effect. Further, vonoprazan is rapidly 
protonated in the parietal cell canaliculi, which concentrates the drug proximal to the 
H+, K+-ATPase [Scarpignato 2019]. 
• Activity against active and inactive proton pumps: Vonoprazan inhibits acid secretion 
by competitively inhibiting the binding of potassium ions to the H+, K+-ATPase. 
Vonoprazan selectively concentrates in the parietal cells in both the resting and 
stimulated states, binds to the active pumps, and remains associated with the active 
and inactive pumps. In contrast, PPIs covalently bind H+, K+-ATPase only when the 
pump is active, as an acidic environment is required for the activation and 
accumulation of PPIs in the parietal cell [Scott 2015].  
• Vonoprazan maintains acid control over 24 hours with once daily (QD) dosing 
[Engevik 2020]. Vonoprazan can also be dosed in the presence or absence of food, 
while most PPIs require dosing before a meal to optimize their acid-suppressant effect 
because activated pumps are at their highest level post-prandially due to activation of 
pumps by the meal [Shin 2013]. 
• Extended half-life: The mean plasma half-life is typically 7 to 8 hours after single and 
multiple QD administration of vonoprazan 20 mg. This is significantly longer than 
the half-life of conventional PPIs (<2 hours) [Shin 2013]. 
• Metabolism: Vonoprazan is predominantly metabolized by cytochrome P450 
(CYP)3A4/5, which lacks a high degree of genetic polymorphism as compared with 
CYP2C19, which is the primary enzyme responsible for the metabolism of PPIs 
[Shin 2013]. 


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These unique aspects of the vonoprazan mechanism of action and pharmacokinetics relative 
to PPIs translate into greater magnitude and duration of gastric acid suppression, which are 
reflected in the pharmacodynamic profile [Jenkins 2015, Sakurai 2015]. 
The pharmacokinetic and pharmacodynamic 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 [Jenkins 2015].  
Takeda conducted 2 studies in Japan to evaluate the treatment of heartburn in subjects with 
NERD (TAK-438/CCT-201 [Kinoshita 2016] and Vonoprazan-3001 [Kinoshita 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.  
Phathom is currently conducting a Phase 2, dose-ranging study in subjects with NERD 
(NERD-201) to evaluate the potential for vonoprazan as an on-demand therapeutic option for 
treating heartburn episodes. Subjects receive open-label vonoprazan 20 mg QD during a 
4-week Run-In Period. Subjects with stable disease (ie, no heartburn on the last 7 days of the 
Run-In Period) are randomized to receive either vonoprazan 10 mg, 20 mg, 40 mg, or 
placebo taken as needed during a 6-week On-Demand Treatment Period. 
The safety profile of vonoprazan in Phase 3 studies across indications showed there was no 
evidence of a dose-related increase in adverse effects with vonoprazan, and the safety profile 
of vonoprazan was similar to that of lansoprazole. As of 16 June 2021, the global cumulative 
post-marketing patient exposure to vonoprazan is estimated to be over 68 million patients.  
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 the 
treatment of heartburn in patients with NERD. 


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1.3 
Justification for Dose 
Selection of the vonoprazan 10 mg and 20 mg doses for the Placebo-controlled Treatment 
Period and Extension Period is based on a 7-day multiple repeat-dose study conducted by 
Takeda in healthy subjects administered 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, for 
24 hours after the Day 4 dose and for 48 hours after receiving the Day 7 dose of vonoprazan. 
Following a single 20-mg dose of vonoprazan, the onset of the antisecretory effect as 
measured by intragastric pH is rapid and occurs within 2 to 3 hours. The elevated intragastric 
pH compared to placebo is maintained for over 24 hours.  The inhibitory effect of 
vonoprazan on acid secretion increases somewhat with repeated daily dosing and steady state 
is achieved by Day 4.  The pharmacodynamic effect is dose dependent, with the percentage 
of time pH>4 at steady state averaging 60% following a 10-mg dose and 85% following a 
20-mg dose for 7 days. 
In Japan, vonoprazan 20 mg QD is the approved daily dose in the healing of EE and has also 
been shown to relieve heartburn in these patients [Ashida 2018]. Both vonoprazan 20 mg QD 
and 10 mg QD are approved for the maintenance of healing of EE and demonstrated 
sustained relief of heartburn. These doses are also being evaluated in the United States and 
Europe for the healing of EE (20 mg) and maintenance of healed EE (10 mg and 20 mg). 
Based on the pharmacodynamic profile, vonoprazan 20 mg QD has the potential to be more 
effective than vonoprazan 10 mg QD in NERD patients and therefore both 10 mg and 20 mg 
doses will be evaluated in this Phase 3 study. 


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2 
Study Objectives and Endpoints 
The purpose of this study is to demonstrate the efficacy and safety of vonoprazan relative to 
placebo in the Placebo-controlled Treatment Period and to describe the long-term efficacy 
and safety of vonoprazan in the Extension Period. 
2.1 
Primary Efficacy Objective and Endpoint 
The primary efficacy objective and corresponding endpoint are presented in Table 2-1. 
Table 2-1 
Primary Efficacy Objective and Endpoint 
Objective 
Endpoint 
Primary Efficacy: Placebo-controlled Treatment Period 
• To assess the efficacy of vonoprazan (10 mg 
and 20 mg QD) compared to placebo (QD) in 
relief of heartburn over 4 weeks in subjects with 
NERD.  
• 
The percentage of days without daytime or 
nighttime heartburn over the Placebo-
controlled Treatment Period as assessed by 
the daily diary. 
NERD: symptomatic non-erosive gastroesophageal reflux disease; QD: once daily 
 
2.2 
Safety Objectives and Endpoints 
Safety objectives with corresponding endpoints are presented in Table 2-2. 
Table 2-2 
Safety Objectives and Endpoints 
Objectives 
Endpoints 
Safety: Placebo-controlled Treatment Period and Extension Period 
• To assess the safety of vonoprazan (10 mg and 
20 mg QD) compared to placebo (QD) in 
subjects with NERD over 4 weeks. 
• To assess the long-term safety of vonoprazan 
(10 mg and 20 mg QD) over 6 months. 
• 
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 
AE: adverse event; ECG: electrocardiogram; NERD: symptomatic non-erosive gastroesophageal reflux disease; 
QD: once daily 
 
2.3 
Secondary Efficacy Objective and Endpoint 
The secondary efficacy objective and corresponding endpoint are presented in Table 2-3. 


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Table 2-3 
Secondary Efficacy Objective and Endpoint for the Placebo-controlled 
Treatment Period 
Objectives 
Endpoint 
• To assess the use of rescue antacid with 
vonoprazan (10 mg and 20 mg QD) compared 
to placebo (QD) over 4 weeks in subjects with 
NERD. 
• 
The percentage of days without rescue antacid 
use over the Placebo-controlled Treatment 
Period as assessed by the daily diary. 
NERD: symptomatic non-erosive gastroesophageal reflux disease; QD: once daily 
 
2.4 
Exploratory Endpoints 
Exploratory endpoints for the Placebo-controlled Treatment Period include: 
• The percentage of days without daytime heartburn over the Placebo-controlled 
Treatment Period as assessed by the daily diary 
• The percentage of days without nighttime heartburn over the Placebo-controlled 
Treatment Period as assessed by the daily diary 
• The percentage of days without daytime or nighttime heartburn over the last 7 days 
of the Placebo-controlled Treatment Period as assessed by the daily diary 
• The mean severity of daytime and nighttime heartburn over the Placebo-controlled 
Treatment Period as assessed by the daily diary 
• The mean severity of daytime heartburn over the Placebo-controlled Treatment 
Period as assessed by the daily diary 
• The mean severity of nighttime heartburn over the Placebo-controlled Treatment 
Period as assessed by the daily diary 
• The time to sustained resolution of heartburn during the Placebo-controlled 
Treatment Period (sustained resolution is defined as at least 7 consecutive days with 
no daytime or nighttime heartburn as assessed by the daily diary) 


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• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the Patient Assessment of Upper Gastrointestinal 
Disorders-Symptom Severity Index (PAGI-SYM) questionnaire 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the Patient Assessment of Upper Gastrointestinal 
Disorders-Quality of Life (PAGI-QoL) questionnaire 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
the EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the Nocturnal Gastroesophageal Reflux Disease 
Symptom Severity and Impact Questionnaire (N-GSSIQ) 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the Pittsburgh Sleep Quality Index (PSQI) 
questionnaire 
Exploratory endpoints for the Extension Period include: 
• The percentage of days without daytime or nighttime heartburn over the Extension 
Period as assessed by the daily diary 
• The percentage of days without nighttime heartburn over the Extension Period as 
assessed by the daily diary 
• The percentage of days without daytime heartburn over the Extension Period as 
assessed by the daily diary 
• The percentage of days without daytime or nighttime heartburn from Week 4 to 
Week 8 in subjects re-randomized at Week 4 from placebo to either vonoprazan 
10 mg or 20 mg 
• The mean severity of daytime and nighttime heartburn over the Extension Period as 
assessed by the daily diary 


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• The mean severity of daytime heartburn over the Extension Period as assessed by the 
daily diary 
• The mean severity of nighttime heartburn over the Extension Period as assessed by 
the daily diary 
• The percentage of days without rescue antacid use over the Extension Period as 
assessed by the daily diary 
• The change from baseline to Week 12 and Week 24 of the Extension Period for each 
subscale and the total score of the PAGI-SYM questionnaire 
• The change from baseline to Week 12 and Week 24 of the Extension Period for each 
subscale and the total score of the PAGI-QoL questionnaire 
• The change from baseline to Week 12 and Week 24 of the Extension Period for the 
EQ-5D-5L 
• The change from baseline to Week 12 and Week 24 of the Extension Period for each 
subscale and the total score of the N-GSSIQ 
• The change from baseline to Week 12 and Week 24 of the Extension Period for each 
subscale and the total score of the PSQI 
Exploratory endpoints for the Follow-up Period include: 
• The percentage of days without daytime or nighttime heartburn during the Follow-up 
Period as assessed by the daily diary 
• The percentage of days without rescue antacid use over the Follow-up Period as 
assessed by the daily diary 
 


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3 
Investigational Plan 
3.1 
Study Design 
This is a Phase 3, multicenter, double-blind study of vonoprazan versus placebo assessing the 
relief of heartburn. Subjects with NERD (as confirmed by endoscopy) and heartburn 
symptoms will be randomized to receive vonoprazan 10 mg, vonoprazan 20 mg, or placebo 
QD for 4 weeks. Subjects will complete an electronic diary twice daily to record the presence 
and maximum severity of daytime and nighttime heartburn symptoms and use of rescue 
antacid throughout the study. Study-supplied rescue antacid will be allowed. After the 
Placebo-controlled Treatment Period, all subjects will receive blinded vonoprazan (10 mg or 
20 mg QD) in the Extension Period.  
A schematic diagram of the overall study design is presented in Figure 3-1. 
 




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The study will include 4 periods (see the schedule of events [SoE] in Section 13.1 for 
details): 
Screening Period (Day -35 to Day -2): Subjects will provide informed consent and 
undergo screening assessments to determine study eligibility, and baseline assessment 
will be performed. Subjects will complete the electronic diary twice daily during the 
Screening Period. If all eligibility criteria are met, the subject will enter the study. 
Placebo-controlled Treatment Period (Day -1 to Day 28): Subjects with NERD 
whose eligibility is confirmed will be randomized to receive vonoprazan 10 mg or 
20 mg or placebo QD for 4 weeks. The date of the first dosing is defined as Day 1. An 
electronic diary will continue to be completed twice daily during the 
Placebo-controlled Treatment Period. 
Extension Period (Day 29 to Day 169): Subjects randomized to vonoprazan 10 mg 
or 20 mg in the Placebo-controlled Treatment Period will continue to take the same 
dose in a blinded manner for an additional 20 weeks. Subjects randomized to placebo 
in the Placebo-controlled Treatment Period will be re-randomized to receive either 
vonoprazan 10 mg QD or vonoprazan 20 mg QD for 20 weeks. An electronic diary 
will continue to be completed twice daily during the Extension Period. The first dose 
of study drug for the Extension Period will be taken the day after the Week 4 visit. 
Follow-up Period: A safety follow-up visit will occur 4 weeks after the last dose of 
study drug. An electronic diary will continue to be completed twice daily during the 
Follow-up Period. 
A subject will be considered to have completed the study if the subject completes the safety 
follow-up visit. 


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3.1.1 
Rationale of Study Design 
3.1.1.1 Rationale for the Placebo-controlled Treatment Period 
The Placebo-controlled Treatment Period is designed to demonstrate the superiority of 
vonoprazan 10 mg and 20 mg QD to placebo in relief of heartburn over 4 weeks in subjects 
with NERD. Double-blind, parallel-group, placebo-controlled designs are considered optimal 
for providing unbiased estimates of efficacy. Four weeks of treatment is consistent with the 
duration of studies to evaluate efficacy for the treatment of heartburn and is also an 
acceptable duration to allow a placebo-controlled arm. 
3.1.1.2 Rationale for the Extension Period and Follow-up Period 
An Extension Period is included to assess the long-term safety and efficacy of vonoprazan 
(10 mg and 20 mg QD) in relief of heartburn in subjects with NERD. The 6-month duration 
was deemed sufficient to evaluate long-term safety in the NERD population and will also 
allow the evaluation of the persistence of vonoprazan efficacy. It is not considered ethical to 
expose subjects to 24 weeks of placebo. Therefore, subjects who receive placebo in the 
Placebo-controlled Treatment Period will be re-randomized to receive either vonoprazan 
10 mg QD or vonoprazan 20 mg QD in the Extension Period. 
A safety follow-up visit is planned at 4 weeks after the last dose of study drug. Subjects who 
discontinue the study will also have a safety follow-up visit. 


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4 
Subject Selection and Withdrawal Criteria 
4.1 
Selection of Study Population 
This study will be conducted at approximately 100 sites in the United States and will 
randomize approximately 750 subjects (250 subjects per treatment group) in the 
Placebo-controlled Treatment Period. 
A Study Subject Informational Questionnaire should be completed for each randomized 
subject (prior to randomization) as a tool to assess eligibility for the study. The completed 
questionnaire should be filed with the subject’s study records at the site.  
4.1.1 
Inclusion Criteria 
Subjects are eligible for enrollment in the study if they meet all of the following inclusion 
criteria: 
1. The subject is ≥18 years of age at the time of informed consent signing. 
2. In the opinion of the investigator or subinvestigators, the subject is capable of 
understanding and complying with protocol requirements, including compliance with 
the electronic diary. 
3. The subject signs and dates a written informed consent form (ICF) and any required 
privacy authorization prior to the initiation of any study procedures. The subject is 
informed of the full nature and purpose of the study, including possible risks and side 
effects. The subject has the ability to cooperate with the investigator. Ample time and 
opportunity should be given to read and understand verbal and/or written instructions. 
4. The subject has a diagnosis of symptomatic GERD with heartburn as the subject’s 
predominant symptom prior to the Screening Period, as documented in the subject’s 
medical record. 
5. History of onset of heartburn at least 6 months prior to the Screening Period. 
6. Heartburn reported on 4 or more days during any consecutive 7-day period of 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 
non-sterilized 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 Section 13.2. 
4.1.2 
Exclusion Criteria 
Subjects are not eligible for study participation if they meet any of the following exclusion 
criteria: 
1. The subject has endoscopically confirmed EE during the Screening Period. 
Endoscopy conducted during the Screening Period should be performed after subjects 
meet Inclusion Criterion 6 (ie, heartburn reported on 4 or more days during any 
consecutive 7-day period of the Screening Period as recorded in the electronic diary).  
2. The subject has active irritable bowel syndrome (IBS) or has 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 upper gastrointestinal 
disorders, such as: 
a. Functional heartburn, as described in the Rome IV Criteria (Section 13.4.1) 
b. Functional dyspepsia as described in the Rome IV Criteria (Section 13.4.2) 
4. The subject has endoscopic Barrett’s esophagus (>1 cm of columnar-lined esophagus) 
and/or definite dysplastic changes in the esophagus. 
5. 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. 
6. The subject has scleroderma (systemic sclerosis) or systemic lupus erythematosus. 


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7. The subject has a history of surgery or endoscopic treatment affecting 
gastroesophageal reflux, including fundoplication and dilation for esophageal 
stricture (except dilation for a Schatzki’s ring) or a history of gastric or duodenal 
surgery (except endoscopic removal of benign polyps). 
8. The subject has an active gastric or duodenal ulcer within 4 weeks before the first 
dose of study drug. 
9. The subject requires or is expected to require use of prescription or non-prescription 
PPIs or H2RAs throughout the study. 
10. The subject has received any investigational compound (including those in 
post-marketing studies) within 30 days prior to the start of the Screening Period or 
vonoprazan in a clinical trial at any time (including participation in 
Study NERD-201). 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. 
11. 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. 
12. The subject has had clinically significant upper or lower gastrointestinal bleeding 
within 4 weeks prior to the Screening Period. 
13. The subject has Zollinger-Ellison syndrome or other gastric acid hypersecretory 
conditions. 
14. 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, and titanium oxide, or red or yellow ferric oxide). Skin testing may 
be performed according to local standard practice to confirm hypersensitivity. 
15. The subject has a history of alcohol abuse, illegal drug use, or drug addiction within 
the 12 months prior to screening, or regularly consumes >21 units of alcohol 
(1 unit = 12 oz/300 mL beer, 1.5 oz/25 mL hard liquor/spirits, or 5 oz/100 mL wine) 


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per week based on self-report. Subjects must have a negative urine drug screen for 
cannabinoids/tetrahydrocannabinol (including prescription cannabinoids) and 
non-prescribed medications during the Screening Period. 
16. The subject is taking any excluded medications or treatments listed in the protocol, 
including prescription cannabinoids/tetrahydrocannabinol (Section 5.9.1). 
17. 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. 
18. 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. 
19. The subject requires hospitalization or has surgery scheduled during the course of the 
study (from Visit 1 to end of Follow-up Period at Visit 10) or has undergone major 
surgical procedures within 30 days prior to the Screening Period. 
20. The subject has a history of malignancy (including mucosa-associated lymphoid 
tissue lymphoma) or has been treated for malignancy within 5 years prior to the start 
of the Screening Period (Visit 1). (The subject may be included in the study if he/she 
has cured cutaneous basal cell carcinoma or cervical carcinoma in situ). 
21. The subject has acquired immunodeficiency syndrome or human immunodeficiency 
virus infection, or tests positive for the hepatitis B surface antigen, hepatitis C virus 
(HCV) antibody, or HCV-ribonucleic acid (RNA). However, subjects who test 
positive for HCV antibody but negative for HCV-RNA are permitted to participate. 
22. 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). 


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b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the 
upper limit of normal (ULN) or total bilirubin >2 × ULN (except for subjects 
with a diagnosis of Gilbert’s syndrome). 
23. The subject tests positive for active H pylori infection during the Screening Period, 
after ≥4 weeks free from antibiotics and bismuth and ≥2 weeks free from PPIs and 
histamine-2 receptor antagonists (H2RAs). 
4.1.3 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently entered in the Placebo-controlled Treatment 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 publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, pretreatment event (PTE), adverse events (AEs), and 
any serious adverse events (SAEs). 
Screen failures are expected to promptly return the electronic diary to the investigational site. 
Subjects may be allowed to be rescreened only upon discussion with and approval by the 
medical monitor.  
4.1.4 
Lifestyle Considerations 
Subjects should be instructed as follows: 
1. 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. 
2. Not to donate blood during the study, and to report on any such donation 
immediately. 


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4.2 
Withdrawal of Subjects From Study Drug and/or the Study 
The duration of the study is defined for each subject as the date signed written informed 
consent is provided through the last follow-up visit performed 4 weeks after completing the 
last dose of study drug in the Extension Period. 
4.2.1 
Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time (eg, Placebo-controlled Treatment Period, 
Extension 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 of the study drug or withdrawal of the subject from 
the study should be recorded in the electronic case report form (eCRF). For screen failure 
subjects, refer to Section 4.1.3.  
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 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 


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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. 
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 (as described for the 


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Early Termination Visit). Subjects who fail to return for final assessments will be contacted 
by the site to make every attempt to comply with the protocol. 
Subjects who discontinue study drug or active participation in the study (including screen 
failures) are expected to promptly return the electronic diary to the investigational site. 
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 follow-up procedures to 
assess safety. 
See the SoE in Section 13.1 for data to be collected at the time of discontinuation of study 
drug and follow-up and for any further evaluations that need to be completed. 
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 4.2.1. 
4.2.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she signs the ICF, repeatedly fails to 
return for scheduled visits during the Placebo-controlled Treatment Period or Extension 
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: 
1. 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. 
2. 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. 


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3. 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 
An interactive response technology (IRT) system will be used to administer the 
randomization schedule. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized in a 1:1:1 ratio by the IRT system to 1 of the following 3 groups during the 
Placebo-controlled Treatment Period: 
• Vonoprazan 10 mg QD for 4 weeks  
• Vonoprazan 20 mg QD for 4 weeks  
• Placebo QD for 4 weeks  
Following completion of the Placebo-controlled Treatment Period at Week 4, all subjects will 
be assigned study drug for the Extension Period by the IRT system. Subjects randomized to 
placebo during the Placebo-controlled Treatment Period will be re-randomized to receive 
vonoprazan 10 mg or vonoprazan 20 mg QD for the 20-week Extension Period. Subjects 
randomized to 1 of the 2 vonoprazan treatment groups during the Placebo-controlled 
Treatment Period will continue to receive the same vonoprazan dose during the Extension 
Period. 
An external biostatistician 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. The external biostatistician will not 
be involved in study conduct or have access to efficacy and/or safety data while the study is 
ongoing. 
5.2 
Treatments Administered 
Blinded study drug will be dispensed during both the Placebo-controlled Treatment Period 
and Extension Period. Subjects will be instructed to take the assigned study drug orally with 
approximately 240 mL (8 oz) water at about the same time each day. 


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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, Placebo-controlled Treatment, Extension, and Follow-up 
Periods. Use of Gelusil should be documented in the electronic diary. 
5.4 
Identity of Investigational Product and Rescue Antacid 
5.4.1 
Vonoprazan and Placebo 
Vonoprazan study medication will be supplied as 10-mg and 20-mg capsules. The tablet drug 
product will be over-encapsulated into Swedish Orange DB-A capsules containing 
microcrystalline cellulose at the contract manufacturing organization,
 
 
 manufactures the vonoprazan drug substance. 
 
 manufactures the vonoprazan tablet drug product. 
The placebo for vonoprazan product will be a Swedish Orange DB-A capsule containing 
microcrystalline cellulose manufactured at the contract manufacturing organization, 
 
 
The over-encapsulated vonoprazan 10-mg and 20-mg dose strengths and placebo will be 
identical in appearance.  
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 Placebo-controlled 
Treatment, Extension, and Follow-up Periods.  
5.5 
Management of Clinical Supplies 
5.5.1 
Study Drug Packaging and Storage 
Over-encapsulated vonoprazan and placebo will be distributed in blister cards 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]; 


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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. 
Sites should refer to the pharmacy manual for reporting temperature excursions. 
5.5.2 
Study Drug and Rescue Antacid Accountability 
The investigator will maintain accurate records of receipt of all study drug, 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 rescue antacid is 
dispensed in the study. Subjects should return all unused rescue antacid. 
Sites should refer to the pharmacy manual and follow the accountability process described 
for this clinical 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 
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. 


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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 during the Placebo-controlled Treatment Period and the Extension 
Period will be maintained using the IRT. 
A double-blind design is employed for the Placebo-controlled Treatment Period so that both 
the investigators and the subjects will be unaware of the treatment assignment. 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 during the Placebo-controlled Treatment Period. 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. 
During the Extension Period, both investigators and subjects will remain blinded to the 
subject's individual treatment assignment through the Extension Period.  
Following the interim analysis (if performed; see Section 7.3.4), Phathom and 
 would be 
unblinded to the treatment assignment of individual subjects during the Placebo-controlled 
Treatment Period. 
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 (vonoprazan or placebo) at home, compliance 
with study drug is to be assessed as specified in SoE (Section 13.1). Compliance will be 
assessed by direct questioning and counting returned capsules at scheduled 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 also be recorded in the eCRF. 
Noncompliance is defined as taking less than 80% or more than 120% of study drug during 
any evaluation period (visit to visit). Subjects exhibiting poor compliance as assessed by 
capsule counts should be counseled on the importance of good compliance to the study 
dosing regimen. 
5.8.2 
Diary Compliance 
Diary noncompliance within the Placebo-controlled Treatment Period and the Extension 
Period is defined as completing less than 80% of study diary entries in the respective study 
period. 
Subjects exhibiting poor compliance as assessed by diary entries must be contacted as soon 
as it is discovered, and retrained by site staff. 
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 screening (or has 
received within 30 days before the time of screening) or receives during the study must be 
recorded along with the following: 
• Reason for use 
• Dates of administration, including start and end dates 


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• Dosage information, including dose and frequency 
Complete coronavirus-19 (COVID-19) vaccination history (including more than 30 days 
prior to the Screening Period) must be recorded. 
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 
Excluded Medications 
A list of excluded medications is provided in Table 5-1. 


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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 a 
Follow-up Visit 
PPIs 
Screening Period a 
Follow-up Visit 
Antibiotics 
Screening Period a 
Screening Period a 
Strong inhibitors or inducers of CYP3A4 
(eg, itraconazole, ketoconazole, indinavir, nelfinavir, 
ritonavir, saquinavir, telithromycin) 
14 days prior to Day 1 
End of Extension 
Period 
CYP3A4 substrates with a narrow therapeutic index 
(eg, cyclosporine and tacrolimus) 
14 days prior to Day 1 
End of Extension 
Period 
Surgical procedures that could affect gastric acid 
secretion (eg, any form of partial gastrectomy, 
vagotomy) 
30 days prior to 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 Day 1 a 
Follow-up Visit 
Atazanavir sulfates; rilpivirine hydrochloride 
(contraindicated with vonoprazan) 
5 days prior to Day 1 
Follow-up Visit 
Prescription cannabinoids/tetrahydrocannabinol 
14 days prior to start of 
Screening Period 
Follow-up Visit 
CYP: cytochrome P450 isoenzyme; H2RA: histamine-2 receptor antagonist; PPI: proton pump inhibitor 
a Subjects should be free of antibiotics and bismuth for ≥4 weeks and free of H2RAs and PPIs for ≥2 weeks 
before the Screening Period test for active Helicobacter pylori infection. 


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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. 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 and H pylori Testing During the Screening Period 
During the Screening Period (Day -35 to Day -2), an endoscopy will be performed on all 
subjects to confirm the absence of EE. The screening endoscopy should be performed after 
the subject meets Inclusion Criterion 6 (heartburn reported on 4 or more days during any 
consecutive 7-day period of the Screening Period as recorded in the electronic diary) and will 
be assessed by the investigator.  
During the Screening Period (Day -35 to Day -2), subjects will be tested for active H pylori 
infection (ie, serology testing is not acceptable) after being free from antibiotics and bismuth 
for ≥4 weeks and free from PPIs and H2RAs for ≥2 weeks. The test will be performed locally, 
using a FDA approved testing method. Approved testing methods include, but are not limited 
to, rapid urease, stool antigen tests, and urea breath tests. Any other type of test should be 
discussed with the 
 Medical Monitor and Sponsor for approval. 
 


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6.2 
Efficacy Assessments  
6.2.1 
Electronic Symptom Diary 
Subjects will be given an electronic diary on the first day of the Screening Period. During the 
Screening, Placebo-controlled Treatment, Extension, and Follow-up Periods, subjects will 
complete the diary in the morning and evening.  
Subjects should bring the electronic diary device to each site visit. Subjects, including screen 
failures, must return the devices that have been assigned to them upon 
completion/termination from the study. 
6.2.1.1 Morning and Evening Diary 
During the Screening, Placebo-controlled Treatment, Extension, and Follow-up Periods, 
subjects will document the presence and maximum severity of daytime and nighttime 
heartburn symptoms and use of rescue antacid twice daily in their diary. If the subject 
experiences no heartburn on any given day, they should still complete the diary to provide 
this information. The electronic diary should be completed every morning upon waking (to 
record the previous evening's maximum heartburn severity rating) and every evening before 
bedtime (to record that day's maximum heartburn severity rating). The last entry that the 
subject will make to their electronic diary should be on the morning of the Safety Follow-up 
Visit, prior to their site visit. 
6.2.1.2 Severity Definitions 
The severity of heartburn will be graded by the subject according to the definitions outlined 
in Table 6-1. 


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Table 6-1 
Definitions of Heartburn Severity (Daytime/Nighttime) for the 
Screening, Placebo-controlled Treatment, Extension, and 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 
 
6.2.2 
PAGI-SYM Questionnaire 
Each subject will self-administer a paper version of the PAGI-SYM at the times specified in 
Table 13-1. 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.  
The PAGI-SYM questionnaire will include questions that ask about the severity of symptoms 
the subject may have related to his/her gastrointestinal problem. The questionnaire will 
consist 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 will be grouped into 6 subscales and a total 
score. Higher scores indicate worse symptoms. 
6.2.3 
PAGI-QoL Questionnaire 
Each subject will self-administer a paper version of the PAGI-QoL at the times specified in 
Table 13-1. 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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The PAGI-QoL questionnaire will include questions that ask about how some of the 
gastrointestinal problems the subject may have experienced may have affected his/her quality 
of life. The questionnaire will consist 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 will be 
grouped into 5 subscales and a total score. Higher scores indicate worse quality of life. 
6.2.4 
EQ-5D-5L Questionnaire 
Each subject will self-administer a paper version of the EQ-5D-5L at the times specified in 
Table 13-1. 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.  
The EQ-5D-5L is a standardized instrument developed by the EuroQol Group as a measure 
of health-related quality of life. The EQ-5D-5L consists of a descriptive system and a visual 
analogue scale. The descriptive system comprises 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. The visual analogue scale records the 
subject’s self-rated health on a vertical scale. 
The EQ-5D-5L will be converted into a single index value. The EQ-5D-5L index score will 
be on a scale from 0 (worst imaginable health state) to 1 (best imaginable health state). 
6.2.5 
PSQI Questionnaire 
Each subject will self-administer a paper version of the PSQI at the times specified in 
Table 13-1. 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.  
The PSQI is a self-reported questionnaire which assesses sleep quality and disturbances over 
a 1-month recall period. The PSQI has 19 self-rated items organized into 7 subscales, each of 
which has a range of 0 to 3 points. The subscale measures consist of subjective sleep quality, 
sleep latency (ie, how long it takes to fall asleep), sleep duration, habitual sleep efficiency 
(ie, the percentage of time in bed that one is asleep), sleep disturbances, use of sleeping 
medication, and daytime dysfunction. The 7 subscale scores are then added to produce a 
global score. Overall scores range from 0 to 21 with a lower score indicating better sleep 
quality. 


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6.2.6 
N-GSSIQ 
Each subject will self-administer a paper version of the N-GSSIQ at the times specified in 
Table 13-1. 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.  
The N-GSSIQ is a validated instrument to assess the severity and impact of nocturnal GERD 
symptoms over the past 2 weeks. The questionnaire is comprised of 20 items covering 
3 subscales: Nocturnal GERD Symptom Severity (13 items; score range of 0 to 65), Morning 
Impact of Nocturnal GERD (2 items; score range of 0 to 10), and Concern about Nocturnal 
GERD (5 items; score range of 0 to 20). The subscale scores are calculated as the sum of the 
corresponding items for the subscale. The total N-GSSIQ score is calculated as the mean of 
the subscale scores for Nocturnal GERD Symptom Severity and Morning Impact of 
Nocturnal GERD only. Higher scores represent greater severity of symptoms, greater 
symptom impact, and greater concern. 
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 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 can be any unfavorable and unintended sign (eg, an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, without any judgment 
about causality or relationship to the drug. 


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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 a CONGENITAL ANOMALY/BIRTH DEFECT.  
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:  
• May require intervention to prevent items 1 through 5 above 
• May 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 


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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 
must also be performed. In addition, if the LFT increases are SAEs, a Liver Function Test 
Increase Form must be completed and transmitted (see Section 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, 


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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, including hypersensitivity 
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.  
• Is caused by a study procedure (eg, a bruise after blood collection); these events should 
be recorded as a PTE/AE. 


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Diagnoses versus signs and symptoms: 
• Each event is required to be recorded to represent a single diagnosis or disorder using 
standard medical terminology rather than 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 (eg, 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. 
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…”). 


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• 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. 
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 


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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. 
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. 
 


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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. 
 
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. 


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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. 
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 


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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 cerebrovascular 
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 
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. 


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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: 
• Event term 
• Start and stop date 
• Severity 
• Investigator’s opinion of the causal relationship between the event and administration 
of study drug(s) (related or not related) (not completed for PTEs) 
• Investigator’s opinion of the causal relationship to study procedure(s), including the 
details of the suspected procedure 
• Action concerning study drug (not applicable for PTEs) 
• Outcome of event 
• 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 
• Investigator’s name 


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• 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 PPD Pharmacovigilance. 
 
 
 
 
 
 
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. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 


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6.3.1.3.4 Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities 
The sponsor designee 
 will be delegated the responsibility for reporting all suspected 
unexpected serious adverse reactions (SUSARs) and any other applicable SAEs to regulatory 
authorities, including the European Medicines Agency, investigators, and the 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 product. 
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. 
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 


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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. 
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. 


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• 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 
• 
Percent 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) b 
• 
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) 
Serum gastrin and 
serum pepsinogen I and 
II levels 
• 
Measured at Visits 2, 4, 6, 9, and 10 after fasting for 12 hours. Gastrin 
results from Visit 2 will not be blinded and will be reported to 
investigative sites. Gastrin at Visits 4, 6, 9, 10 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. 
Other tests 
• 
FSH if menopause is suspected c 
• 
Urine drug screen including amphetamines (including 
methamphetamine), barbiturates, benzodiazepines, cannabinoids, 
cocaine, opiates, methadone, and phencyclidine 
• 
Serum hCG pregnancy test d at Visit 1 
• 
Urine hCG pregnancy test d at Visits 2, 4, 6, 9, and 10 
• 
Serology (HIV antibody, HBsAg, and HCV antibody; hepatitis C, viral 
load RNA e [qualitative])  


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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; RBC: red blood cell; RNA: ribonucleic acid; 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 
Glucose will be obtained after an 8-hour fast at Visit 1 and at any unscheduled visit. 
c 
Required only for confirmation of postmenopausal females as defined in Section 13.2. 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. 
d 
As needed for women of childbearing potential. During the Treatment, Extension, and Follow-up 
Periods, serum pregnancy test will be performed if the urine pregnancy test is positive. 
e 
Reflex - if hepatitis C positive. 
 
Investigators must document their review of each laboratory safety report. 
6.3.4 
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 skin, 
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, 
cardiovascular, respiratory, and gastrointestinal systems. 
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 and QRS interval. The QT interval adjusted for 
heart rate will be derived in the electronic database from the RR and QT intervals, using the 
Fridericia method. 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 
A Safety Monitoring Committee is not planned for this study. 


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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 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 statistical analysis plan will be finalized before database lock. 
7.1 
Sample Size Calculations 
A sample size of 250 subjects per treatment group provides greater than 90% power at the 
0.05 2-sided level of significance using a two-sample t-test to detect a difference of 20% 
between a vonoprazan dose (50%) and placebo (30%) in the percentage of days without 
daytime or nighttime heartburn over the 4-week Placebo-controlled Treatment Period, 
assuming a common standard deviation of 35%. 
7.2 
Analysis Sets 
Two analysis sets will be used in the statistical analysis: intent-to-treat (ITT) set and safety 
set as defined in the 2 following sections. 
7.2.1 
Intent-to-treat Set 
For the Placebo-controlled Treatment Period, the ITT set will be defined as all subjects 
randomized into the Placebo-controlled Treatment Period who receive at least 1 dose of study 
drug during the Placebo-controlled Treatment Period. 
For the Extension and Follow-up Periods, the ITT set will be defined as all subjects 
randomized into the Extension Period who receive at least 1 dose of study drug during the 
Extension Period. 
The efficacy analyses will be conducted on the ITT set using the planned treatment. 
7.2.2 
Safety Set 
For the Placebo-controlled Treatment Period, the safety set will be defined as all subjects 
randomized into the Placebo-controlled Treatment Period who receive at least 1 dose of study 
drug during the Placebo-controlled Treatment Period. 


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For the Extension and Follow-up Periods, the safety set will be defined as all subjects 
randomized into the Extension Period who receive at least 1 dose of study drug during the 
Extension Period. 
Safety analyses will be conducted on the safety set using the actual treatment the subjects 
received. 
7.3 
Statistical Analysis Methodology 
Summaries for data collected during the Placebo-controlled Treatment Period will be 
summarized by double-blind treatment group: vonoprazan 10 mg QD, vonoprazan 20 mg 
QD, or placebo QD. 
Unless otherwise specified, summaries for data collected during the Extension and Follow-up 
Periods will be summarized for the following groups: 
• Vonoprazan 10 mg QD during the Placebo-controlled Treatment and Extension 
Periods  
• Vonoprazan 20 mg QD during the Placebo-controlled Treatment and Extension 
Periods  
• Placebo QD during the Placebo-controlled Treatment Period and Vonoprazan 10 mg 
QD during the Extension Period  
• Placebo QD during the Placebo-controlled Treatment Period and Vonoprazan 20 mg 
QD during the Extension Period  
Unless otherwise specified, baseline will be the last assessment prior to the first dose of study 
drug in the Placebo-controlled Treatment Period. 
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 will be performed using SAS software 
Version 9.4 or later. 


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7.3.1 
Efficacy Analyses 
7.3.1.1 Placebo-controlled Treatment Period 
For the Placebo-controlled Treatment Period, each treatment comparison of vonoprazan 
10 mg and of vonoprazan 20 mg to placebo will be tested at the 0.05 significance level. 
Methodology for control of type I error for the comparisons of each dose group of 
vonoprazan to placebo for the primary and secondary efficacy endpoints will be addressed in 
the statistical analysis plan. 
7.3.1.1.1 Primary Efficacy Endpoint for Placebo-controlled Treatment 
Period 
For the primary endpoint of the percentage of days without daytime or nighttime heartburn 
over the Placebo-controlled Treatment Period as assessed by the daily diary, each of the 
vonoprazan treatment groups will be compared to the placebo treatment group using a 
general linear model with treatment group as factor and severity and frequency of heartburn 
at baseline as covariates. 
7.3.1.1.2 Secondary Efficacy Endpoints for Placebo-controlled Treatment 
Period 
For the percentage of days without rescue antacid use over the Placebo-controlled Treatment 
Period as assessed by the daily diary, each of the vonoprazan treatment groups will be 
compared to the placebo treatment group using a general linear model with treatment group 
as factor and severity and frequency of heartburn at baseline as covariates. 
7.3.1.1.3 Exploratory Efficacy Endpoints for Placebo-controlled 
Treatment Period 
Details for the analysis of the exploratory endpoints for the Placebo-controlled Treatment 
Period will be provided in the statistical analysis plan. 
7.3.1.2 Extension Period 
The percentage of days without daytime or nighttime heartburn, the percentage of days 
without nighttime heartburn, the percentage of days without daytime heartburn, and the 


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percentage of days without rescue antacid use over the Extension Period as assessed by the 
daily diary will be summarized. 
Details for the analysis of the exploratory endpoints in the Extension Period will be provided 
in the statistical analysis plan. 
7.3.1.3 Follow-up Period 
The percentage of days without daytime or nighttime heartburn and the percentage of days 
without rescue antacid use over the Follow-up Period will be summarized. 
7.3.2 
Safety Analyses 
Safety data will be summarized separately for the Placebo-controlled Treatment Period and 
the Extension Period.  
Safety will be assessed by summarizing the incidence of AEs and changes in clinical 
laboratory tests, gastrin and pepsinogen I and II levels, ECGs and vital signs. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of subjects experiencing TEAEs will be 
summarized by MedDRA system organ class (SOC) and preferred term (PT) overall, by 
severity, and by relationship to study drug for each treatment group. Separate summaries will 
also be generated for treatment-related AEs overall and by severity. For tabulations of TEAE 
frequency, if a subject has more than 1 episode of the same event, the subject will be counted 
only once for that event. If a subject has more than 1 TEAE that is coded to the same PT, the 
subject will be counted only once for that PT. If a subject has more than 1 TEAE within a 
SOC, the subject will be counted only once for that SOC. In the tabulation of TEAE 
frequency by intensity, a subject will be counted only once using the highest severity for each 
PT and SOC. 
Clinical laboratory tests, gastrin and pepsinogen I and II levels, ECGs, 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. 


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7.3.3 
Other Analyses 
For the Placebo-controlled Treatment and Extension Periods, demographics and other 
baseline characteristics will be summarized overall and by treatment group. Summary 
statistics (number of observations, mean, median, standard deviation, and range) will be 
generated for continuous variables (eg, age and weight). The number and percentage of 
subjects will be presented for categorical variables (eg, sex and race). 
7.3.4 
Interim Analyses 
An analysis of the Placebo-controlled Treatment Period data may be performed after all 
subjects have completed the Placebo-controlled Treatment Period. The data for the 
Placebo-controlled Treatment Period would be locked and the blind broken to perform this 
analysis. This analysis would be conducted after all randomized subjects have completed the 
Placebo-controlled Treatment Period and no changes to the conduct of the Extension Period 
would be made based on the results from the Placebo-controlled Treatment Period. 
Following the interim analysis, Phathom and 
 would be unblinded to the treatment 
assignment of individual subjects during the Placebo-controlled Treatment Period to perform 
this analysis. The treatment assignment would remain blinded to the investigative site. 


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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 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, correcting 
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. 
After the final database lock, each study site will receive a file containing all of their 
site-specific eCRF data as entered into Medidata Rave for the study, including full 
discrepancy and audit history. Additionally, a file 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 file 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 United States 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(R2) 8.2 
and Title 21 of the CFR by providing the following essential documents, including but not 
limited to the following: 
1. IRB/IEC approval 
2. Original investigator-signed investigator agreement page of the protocol 
3. Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 for United States sites and equivalent form for non-United States sites 
4. Curriculum vitae for the investigator and each subinvestigator listed on Form 
FDA 1572 or equivalent form for non-United States sites 
5. 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. 
6. 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 
7. 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(R2). 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. 


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10.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
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. 


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


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designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB/IEC for approval before subjects can be enrolled into an amended protocol. 
11.2.2 Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review, 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 may lead to the subject being withdrawn from 
the study (Section 4.2). 
Protocol deviations will be documented by investigative site staff, the clinical monitor and/or 
the contract research organization throughout the course of the study. Principal investigators 
will be notified in writing by the monitor of any deviations discovered during a monitoring 
visit. The IRB/IEC should be notified of all protocol deviations they consider reportable 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. 
The study results will be posted on publicly available clinical trial registers. The investigator 
is encouraged to share the summary results with the study subjects, as appropriate.  


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12 Reference List 
Ashida K, Iwakiri K, Hiramatsu N, et al. Maintenance for healed erosive esophagitis: 
Phase III comparison of vonoprazan with lansoprazole. World J Gastroenterol 
2018;24(14):1550-61. 
Carlsson R, Dent J, Watts R, et al. Gastro-oesophageal reflux disease in primary care: an 
international study of different treatment strategies with omeprazole. International GORD 
Study Group. Eur J Gastroenterol Hepatol 1998;10(2):119-24. 
Dent J, Brun J, Fendrick A, et al. An evidence-based appraisal of reflux disease 
management-the Genval Workshop Report. Gut 1999;44(suppl 2):S1-16. 
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. 
Engevik AC, Kaji I, Goldenring JR. The physiology of the gastric parietal cell. Physiol 
Rev 2020;100(2):573-602. 
Freston JW. Therapeutic choices in reflux disease: defining the criteria for selecting a proton 
pump inhibitor. Am J Med 2004;117(suppl 5A):S14-22. 
Jenkins H, Sakurai Y, Nishimura A, et al. Randomised clinical trial: safety, tolerability, 
pharmacokinetics and pharmacodynamics of repeated doses of TAK-438 (vonoprazan), a 
novel potassium-competitive acid blocker, in healthy male subjects. Aliment Pharmacol Ther 
2015;41(7):636-48. 
Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of 
gastroesophageal reflux disease. Am J Gastroenterol 2013;108(3):308-28. 


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Kinoshita Y, Sakurai Y, Shiino M, 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, 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.  
Monnikes H, Pfaffenberger B, Gatz G, Hein J, Bardhan KD. Novel measurement of rapid 
treatment success with ReQuest: first and sustained symptom relief as outcome parameters in 
patients with endoscopy-negative GERD receiving 20 mg pantoprazole or 20 mg 
esomeprazole. Digestion 2005;71(3):152-8. 
Rome IV Criteria page. Rome Foundation web site. Available at: 
https://theromefoundation.org/rome-iv/rome-iv-criteria/. Accessed January 14, 2021. 
Sakurai Y, Mori Y, Okamoto H, et al. Acid-inhibitory effects of vonoprazan 20 mg compared 
with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects-a randomised 
open-label cross-over study. Aliment Pharmacol Ther 2015;42(6):719-30. 
Savarino E, de Bortoli N, De Cassan C, et al. The natural history of gastro-esophageal reflux 
disease: a comprehensive review. Dis Esophagus 2017;30(2):1-9. 
Scarpignato C, Hunt RH. The potential role of potassium-competitive acid blockers in the 
treatment of gastroesophageal reflux disease. Curr Opin Gastroenterol 2019;35(4):344–55. 
Scott DR, Munson KB, Marcus EA, Lambrecht NW, Sachs G. The binding selectivity of 
vonoprazan (TAK-438) to the gastric H+, K+ -ATPase. Aliment Pharmacol Ther 
2015;42(11-12):1315-26. 
Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. 
J Neurogastroenterol Motil 2013;19(1):25-35. 
Smout AJPM. Endoscopy-negative acid reflux disease. Aliment Pharmacol Ther 
1997(suppl 2);11:81-5. 


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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. 
Venables TL, Newland RD, Patel AC, Hole J, Wilcock C, Turbitt ML. Omeprazole 
10 milligrams once daily; omeprazole 20 mg milligrams once daily, or ranitidine 
150 milligrams twice daily, evaluated as initial therapy for the relief of symptoms of 
gastro-oesophageal reflux disease in general practice. Scand J Gastroenterol 
1997;32(10):965-73. 
Yi CH, Hu CT, Chen CL. Sleep dysfunction in patients with GERD: erosive versus 
nonerosive reflux disease. Am J Med Sci 2007;334(3):168-70. 
 


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13 Appendices 
13.1 Appendix 1: Schedule of Events  
 






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a 
All screening assessments, except endoscopy, can be performed any time during the Screening Period (Day -35 to Day -2). The screening 
endoscopy should be performed after the subject has fulfilled Inclusion Criterion 6 (ie, heartburn reported on 4 or more days during any 
consecutive 7-day period of the Screening Period as recorded in the electronic diary). 
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 
Date of randomization is defined as Day -1. The date of first dosing day is defined as Day 1. 
d 
Full physical examination is performed at baseline (Visit 1); a brief physical examination is performed at all other visits. 
e 
If menopause is suspected and is required only for confirmation of postmenopausal females as defined in Section 13.2. 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. 
f 
Performed after subjects have been free from antibiotics and bismuth for ≥4 weeks and free from proton pump inhibitors and histamine-2 receptor 
antagonists for ≥2 weeks. The test will be performed locally, using an approved testing method as per local standard of care. 
g 
See Section 6.3.3 for all required laboratory assessments. Glucose should be obtained after an 8-hour fast at Visit 1 and at any unscheduled visit. 
h 
Gastrin results at Visit 2 will not be blinded and will be reported to investigative sites. Gastrin at Visits 4, 6, 9, 10 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. 
i 
Only female subjects with childbearing potential.  
j 
Subjects should be instructed to complete the electronic diary every morning upon waking (for nighttime symptoms) and every evening before 
bedtime (for daytime symptoms) on each day of the study during all periods. Subjects (including screen failures) are expected to promptly return 
the electronic diary to the investigational site upon completion/termination from the study. 
k 
The Screening endoscopy can be performed any time during the Screening Period (Day -35 to Day -2); however, it should be performed after the 
subject has fulfilled Inclusion Criterion 6 (ie, heartburn reported on 4 or more days during any consecutive 7-day period of the Screening Period 
as recorded in the electronic diary). 
l 
Following completion of the Placebo-controlled Treatment Period at Week 4, all subjects will be assigned study drug for the Extension Period by 
the interactive response technology system. Subjects randomized to placebo during the Placebo-controlled Treatment Period will be 
re-randomized to receive vonoprazan 10 mg or vonoprazan 20 mg once daily for the 20-week Extension Period. Subjects randomized to 1 of the 
2 vonoprazan treatment groups during the Placebo-controlled Treatment Period will continue to receive the same vonoprazan dose during the 
Extension Period. The first dose of study drug for the Extension Period will be taken the day after the Week 4 visit. 
 
 
 


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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 non-sterilized male partner** must use adequate contraception. In addition, they must 
be advised not to donate ova during this period. 
*Females NOT of childbearing potential are defined as those who have been 
surgically sterilized (hysterectomy, bilateral oophorectomy, or tubal ligation) or who 
are postmenopausal (eg, defined as at least 1 year since last regular menses with a 
follicle-stimulating hormone >40 IU/L or at least 5 years since last regular menses, 
confirmed before any study 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 


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• Hormone shot/injection 
• Combined pill 
• 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 at baseline 
(all subjects) 
• 
ALT or AST >8 × ULN  
• 
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%) 
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:  
Pharmacovigilance 
PPD, Inc. 
3900 Paramount Parkway 
Morrisville, NC 27560 
24-Hour Safety Contact Information 
SAE Hotline: +1-888-483-7729 
SAE Fax: +1-888-529-3580 or +1-919-654-3836 
 
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 
Rome IV Criteria (2016) is 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) 
o Burning retrosternal discomfort or pain 
o No symptom relief despite optimal antisecretory therapy 
o Absence of evidence that gastroesophageal reflux (elevated acid exposure time 
and/or symptom reflux association) or EE is the cause of the symptom 
o Absence of major esophageal motor disorders (achalasia/esophagogastric 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) 
• One or more of the following:  
• Bothersome postprandial fullness 
• Bothersome early satiation 
• Bothersome epigastric pain 
• Bothersome epigastric burning 


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AND 
• No evidence of structural disease (including at upper endoscopy) that is likely to 
explain the symptoms 
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 
1. Postprandial epigastric pain or burning, epigastric bloating, excessive belching, and 
nausea can also be present 
2. Vomiting warrants consideration of another disorder 
3. Heartburn is not a dyspeptic symptom but may often co-exist 
4. Symptoms that are relieved by evacuation of feces or gas should generally not be 
considered as part of dyspepsia 
5. Other individual digestive symptoms or groups of symptoms (eg, from GERD and 
IBS) may co-exist with PDS 


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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 
• 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 
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 red and 
deletions are shown in strike-through text. Corrections of obvious typing errors or omissions 
are not highlighted. 
13.5.1 Protocol Amendment 1 
Inclusion Criteria (Section 4.1.1.) 
4. The subject identified their main symptom as heartburn, a burning sensation in the 
retrosternal area (behind the breastbone) has a diagnosis of symptomatic GERD with 
heartburn as the subject’s predominant symptom prior to the Screening Period, as 
documented in the subject’s medical record 
5. History of episodes onset of heartburn for at least 6 months or longer prior to the 
Screening Period. 
Exclusion Criteria (Section 4.1.2.) 
23. The subject tests positive for active H pylori infection during the Screening Period, 
after ≥4 weeks free from antibiotics and bismuth and ≥2 weeks free from PPIs and 
histamine-2 receptor antagonists (H2RAs). 
Method of Assigning Subjects to Treatment Groups (Section 5.1) 
Biostatistics An external biostatistician 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. The external biostatistician 
will not be involved in study conduct or have access to efficacy and/or safety data while the 
study is ongoing. 
Prior and Concomitant Therapy (Section 5.9) 
Complete coronavirus-19 (COVID-19) vaccination history (including more than 30 days 
prior to the Screening Period) must be recorded. 


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Excluded Medications (Section 5.9.1) 
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 a 
Follow-up Visit 
PPIs 
Screening Period a 
Follow-up Visit 
Antibiotics 
Screening Period a 
Screening Period a 
Strong inhibitors or inducers of CYP3A4 
(eg, itraconazole, ketoconazole, indinavir, nelfinavir, 
ritonavir, saquinavir, telithromycin) 
14 days prior to Day 1 
End of Extension 
Period 
CYP3A4 substrates with a narrow therapeutic index 
(eg, cyclosporine and tacrolimus) 
14 days prior to Day 1 
End of Extension 
Period 
Surgical procedures that could affect gastric acid 
secretion (eg, any form of partial gastrectomy, 
vagotomy) 
30 days prior to 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 Day 1 a 
Follow-up Visit 
Atazanavir sulfates; rilpivirine hydrochloride 
(contraindicated with vonoprazan) 
5 days prior to Day 1 
Follow-up Visit 
Prescription cannabinoids/tetrahydrocannabinol 
14 days prior to start of 
Screening Period 
Follow-up Visit 
CYP: cytochrome P450 isoenzyme; H2RA: histamine-2 receptor antagonist; PPI: proton pump inhibitor 
a Subjects should be free of antibiotics and bismuth for ≥4 weeks and free of H2RAs and PPIs for ≥2 weeks 
before the Screening Period test for active Helicobacter pylori infection.. 
 
Endoscopy and H pylori Testing During the Screening Period (Section 6.1) 
During the Screening Period (Day -35 to Day -2), subjects will be tested for active H pylori 
infection (ie, serology testing is not acceptable) after being free from antibiotics and bismuth 
for ≥4 weeks and free from PPIs and H2RAs for ≥2 weeks. The test will be performed 
locally, using an approved testing method as per local standard of care. Approved testing 


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methods include, but are not limited to, biopsy tests (rapid urease or histologic exam), stool 
tests, and urea breath tests. 
Intent-to-treat Set (Section 7.2.1) 
For the Placebo-controlled Treatment Period, the ITT set will be defined as all subjects 
randomized into the Placebo-controlled Treatment Period who receive at least 1 dose of study 
drug and complete at least 1 diary entry during the Placebo-controlled Treatment Period. 
For the Extension Period, the ITT set will be defined as all subjects randomized into the 
Extension Period who receive at least 1 dose of study drug and complete at least 1 diary entry 
during the Extension Period. 
Schedule of Events (Section 13.1, Appendix 1) 






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a 
All screening assessments, except endoscopy, can be performed any time during the Screening Period (Day -35 to Day -2). The screening endoscopy should 
be performed after the subject has fulfilled Inclusion Criterion 6 (ie, heartburn reported on 4 or more days during any consecutive 7-day period of the 
Screening Period as recorded in the electronic diary). 
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 
Date of randomization is defined as Day -1. The date of first dosing day is defined as Day 1. 
d 
Full physical examination is performed at baseline (Visit 1); a brief physical examination is performed at all other visits. 
e 
If menopause is suspected and is required only for confirmation of postmenopausal females as defined in Section 13.2. 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. 
f 
Performed after subjects have been free from antibiotics and bismuth for ≥4 weeks and free from proton pump inhibitors and histamine-2 receptor 
antagonists for ≥2 weeks. The test will be performed locally, using an approved testing method as per local standard of care. 
fg See Section 6.3.3 for all required laboratory assessments. Glucose should be obtained after an 8-hour fast at Visit 1 and at any unscheduled visit. 
gh Gastrin results at Visit 2 will not be blinded and will be reported to investigative sites. Gastrin at Visits 4, 6, 9, 10 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. 
hi Only female subjects with childbearing potential.  
ij 
Subjects should be instructed to complete the electronic diary every morning upon waking (for nighttime symptoms) and every evening before bedtime (for 
daytime symptoms) on each day of the study during all periods. Subjects (including screen failures) are expected to promptly return the electronic diary to 
the investigational site upon completion/termination from the study. 
jk The Screening endoscopy can be performed any time during the Screening Period (Day -35 to Day -2); however, it should be performed after the subject has 
fulfilled Inclusion Criterion 6 (ie, heartburn reported on 4 or more days during any consecutive 7-day period of the Screening Period as recorded in the 
electronic diary). 
kl Following completion of the Placebo-controlled Treatment Period at Week 4, all subjects will be assigned study drug for the Extension Period by the 
interactive response technology system. Subjects randomized to placebo during the Placebo-controlled Treatment Period will be re-randomized to receive 
vonoprazan 10 mg or vonoprazan 20 mg once daily for the 20-week Extension Period. Subjects randomized to 1 of the 2 vonoprazan treatment groups 
during the Placebo-controlled Treatment Period will continue to receive the same vonoprazan dose during the Extension Period. 
 


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13.5.2 Protocol Amendment 2 
Protocol Synopsis 
Objectives: 
Secondary: 
 
• To assess the efficacy of vonoprazan (10 mg and 20 mg QD) 
compared to placebo (QD) in relief of nighttime heartburn over 
4 weeks in subjects with NERD. 
• To assess the efficacy of vonoprazan (10 mg and 20 mg QD) 
compared to placebo (QD) in relief of daytime heartburn over 4 
weeks in subjects with NERD. 
• To assess the use of rescue antacid with vonoprazan (10 mg and 
20 mg QD) compared to placebo (QD) over 4 weeks in subjects 
with NERD. 
• To assess the time to onset of sustained heartburn relief of 
vonoprazan (10 mg and 20 mg QD) compared to placebo (QD) 
over 4 weeks in subjects with NERD. 
 
Efficacy 
Assessments: 
Secondary: 
 
• The percentage of days without nighttime heartburn over the 
Placebo controlled Treatment Period as assessed by the daily 
diary. 
• The percentage of days without daytime heartburn over the 
Placebo controlled Treatment Period as assessed by the daily 
diary. 
• The percentage of days without rescue antacid use over the 
Placebo-controlled Treatment Period as assessed by the daily 
diary. 
• The percentage of subjects with onset of sustained resolution of 
heartburn by Day 3 (sustained resolution is defined as at least 
7 consecutive days with no daytime or nighttime heartburn as 
assessed by the daily diary). 
 
Sample Size: 
A sample size of 250 subjects per treatment group provides greater 
than 90% power at the 0.05 2-sided1 level of significance using a 
two-sample t-test Wilcoxon rank sum test to detect a difference of 
20% difference between a vonoprazan dose (50%) and placebo 
(30%) in the percentage of days without daytime or nighttime 
heartburn over the 4-week Placebo-controlled Treatment Period, 
assuming a common standard deviation of 35%. 


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Protocol Synopsis (continued) 
Statistical 
Methods: 
Primary Efficacy Endpoint: 
For the primary endpoint of the percentage of days without daytime 
or nighttime heartburn over the Placebo-controlled Treatment 
Period as assessed by the daily diary, each of the vonoprazan 
treatment groups will be compared to the placebo treatment group 
using a general linear model with treatment group as factor and 
severity and frequency of heartburn at baseline as covariates. 
Wilcoxon rank sum test. A 2 sided 95% confidence interval 
computed from Welch’s t test will be calculated for the difference 
between each vonoprazan treatment group and the placebo 
treatment group for the primary endpoint (vonoprazan minus 
placebo). 
Secondary Efficacy Endpoints: 
For the percentage of days without nighttime heartburn, the 
percentage of days without daytime heartburn, and the percentage 
of days without rescue antacid use over the Placebo-controlled 
Treatment Period as assessed by the daily diary, each of the 
vonoprazan treatment groups will be compared to the placebo 
treatment group using a general linear model with treatment group 
as factor and severity and frequency of heartburn at baseline as 
covariates. Wilcoxon rank sum test  
The percentage of subjects with onset of sustained resolution of 
heartburn by Day 3 will be compared between each vonoprazan 
treatment group and placebo using Fisher’s exact test. Sustained 
resolution is defined as at least 7 consecutive days with no daytime 
or nighttime heartburn as assessed by the daily diary. 
 
 
 


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Secondary Efficacy Objectives and Endpoints (Section 2.3) 
The sSecondary efficacy objectives with and corresponding endpoints are presented in 
Table 2-3. 
Table 2-3 
Secondary Efficacy Objectives and Endpoints for the Placebo-controlled 
 
 
Treatment Period 
Objectives 
Endpoints 
• To assess the efficacy of vonoprazan (10 mg 
and 20 mg QD) compared to placebo (QD) in 
relief of nighttime heartburn over 4 weeks in 
subjects with NERD. 
• 
The percentage of days without nighttime 
heartburn over the Placebo controlled Treatment 
Period as assessed by the daily diary. 
• To assess the efficacy of vonoprazan (10 mg 
and 20 mg QD) compared to placebo (QD) in 
relief of daytime heartburn over 4 weeks in 
subjects with NERD. 
• 
The percentage of days without daytime 
heartburn over the Placebo controlled Treatment 
Period as assessed by the daily diary. 
• To assess the use of rescue antacid with 
vonoprazan (10 mg and 20 mg QD) compared 
to placebo (QD) over 4 weeks in subjects with 
NERD. 
• 
The percentage of days without rescue antacid 
use over the Placebo-controlled Treatment 
Period as assessed by the daily diary. 
• To assess the time to onset of sustained 
heartburn relief of vonoprazan (10 mg and 
20 mg QD) compared to placebo (QD) over 
4 weeks in subjects with NERD. 
• 
The percentage of subjects with onset of 
sustained resolution of heartburn by Day 3 
(sustained resolution is defined as at least 
7 consecutive days with no daytime or nighttime 
heartburn as assessed by the daily diary). 
NERD: symptomatic non-erosive gastroesophageal reflux disease; QD: once daily 
 
Exploratory Endpoints (Section 2.4) 
Exploratory endpoints for the Placebo-controlled Treatment Period include: 
• The percentage of days without daytime heartburn over the Placebo-controlled 
Treatment Period as assessed by the daily diary 
• The percentage of days without nighttime heartburn over the Placebo-controlled 
Treatment Period as assessed by the daily diary 


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Selection of Study Population (Section 4.1) 
This study will be conducted at approximately 100 sites in the United States and will 
randomize approximately 750 subjects (250 subjects per treatment group) in the 
Placebo-controlled Treatment Period. 
A Study Subject Informational Questionnaire should be completed for each randomized 
subject (prior to randomization) as a tool to assess eligibility for the study. The completed 
questionnaire should be filed with the subject’s study records at the site.  
Endoscopy and H pylori Testing During the Screening Period (Section 6.1) 
During the Screening Period (Day -35 to Day -2), subjects will be tested for active H pylori 
infection (ie, serology testing is not acceptable) after being free from antibiotics and bismuth 
for ≥4 weeks and free from PPIs and H2RAs for ≥2 weeks. The test will be performed locally, 
using an FDA approved testing method as per local standard of care. Approved testing 
methods include, but are not limited to, biopsy tests (rapid urease or histological exam), stool 
antigen tests, and urea breath tests. Any other type of test should be discussed with the PPD 
Medical Monitor and Sponsor for approval. 
N-GSSIQ (Section 6.2.6) 
Each subject will self-administer a paper version of the N-GSSIQ at the times specified in 
Table 13-1. 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.  
The N-GSSIQ is a validated instrument to assess the severity and impact of nocturnal GERD 
symptoms over the past 2 weeks. The questionnaire is comprised of 20 items covering 
3 subscales: Nocturnal GERD Symptom Severity (13 items; score range of 0 to 65), Morning 
Impact of Nocturnal GERD (2 items; score range of 0 to 10), and Concern about Nocturnal 
GERD (5 items; score range of 0 to 20). The total N GSSIQ score is calculated as the sum of 
the scores of all items. The subscale scores are calculated as the sum of the corresponding 
items for the subscale. The total N-GSSIQ score is calculated as the mean of the subscale 
scores for Nocturnal GERD Symptom Severity and Morning Impact of Nocturnal GERD 


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only. with Higher scores representing greater severity of symptoms, greater symptom impact, 
and greater concern. 
Sample Size Calculation (Section 7.1) 
A sample size of 250 subjects per treatment group provides greater than 90% power at the 
0.05 2-sided1 level of significance using a two-sample t-test Wilcoxon rank sum test to 
detect a difference of 20% difference between a vonoprazan dose (50%) and placebo (30%) 
in the percentage of days without daytime or nighttime heartburn over the 4-week 
Placebo-controlled Treatment Period, assuming a common standard deviation of 35%. 
Intent-to-Treat Set (Section 7.2.1) 
For the Placebo-controlled Treatment Period, the ITT set will be defined as all subjects 
randomized into the Placebo-controlled Treatment Period who receive at least 1 dose of study 
drug during the Placebo-controlled Treatment Period. 
For the Extension and Follow-up Periods, the ITT set will be defined as all subjects 
randomized into the Extension Period who receive at least 1 dose of study drug during the 
Extension Period. 
The efficacy analyses will be conducted on the ITT set using the planned treatment. 
Safety Set (Section 7.2.2) 
For the Placebo-controlled Treatment Period, the safety set will be defined as all subjects 
randomized into the Placebo-controlled Treatment Period who receive at least 1 dose of study 
drug during the Placebo-controlled Treatment Period. 
For the Extension and Follow-up Periods, the safety set will be defined as all subjects 
randomized into the Extension Period who receive at least 1 dose of study drug during the 
Extension Period. 
Safety analyses will be conducted on the safety set using the actual treatment the subjects 
received. 
Placebo-controlled Treatment Period (Section 7.3.1.1) 


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For the Placebo-controlled Treatment Period, each treatment comparison of vonoprazan 
10 mg and of vonoprazan 20 mg to placebo will be tested at the 0.051 significance level. 
Methodology for control of type I error for the comparisons of each dose group of 
vonoprazan to placebo for the primary and secondary efficacy endpoints will be addressed in 
the statistical analysis plan. 
Primary Efficacy Endpoint for Placebo-controlled Treatment Period (Section 7.3.1.1.1) 
For the primary endpoint of the percentage of days without daytime or nighttime heartburn 
over the Placebo-controlled Treatment Period as assessed by the daily diary, each of the 
vonoprazan treatment groups will be compared to the placebo treatment group using a 
general linear model with treatment group as factor and severity and frequency of heartburn 
at baseline as covariates. Wilcoxon rank sum test. A 2 sided 95% confidence interval 
computed from Welch’s t test will be calculated for the difference between each vonoprazan 
treatment group and the placebo treatment group for the primary endpoint (vonoprazan minus 
placebo). 
Secondary Efficacy Endpoints for Placebo-controlled Treatment Period (Section 7.3.1.1.2) 
For the percentage of days without nighttime heartburn, the percentage of days without 
daytime heartburn, and the percentage of days without rescue antacid use over the 
Placebo-controlled Treatment Period as assessed by the daily diary, each of the vonoprazan 
treatment groups will be compared to the placebo treatment group using a general linear 
model with treatment group as factor and severity and frequency of heartburn at baseline as 
covariates. Wilcoxon rank sum test.  
The percentage of subjects with onset of sustained resolution of heartburn by Day 3 will be 
compared between each vonoprazan treatment group and placebo using Fisher’s exact test. 
Sustained resolution is defined as at least 7 consecutive days with no daytime or nighttime 
heartburn as assessed by the daily diary.






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a 
All screening assessments, except endoscopy, can be performed any time during the Screening Period (Day -35 to Day -2). The screening endoscopy should 
be performed after the subject has fulfilled Inclusion Criterion 6 (ie, heartburn reported on 4 or more days during any consecutive 7-day period of the 
Screening Period as recorded in the electronic diary). 
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 
Date of randomization is defined as Day -1. The date of first dosing day is defined as Day 1. 
d 
Full physical examination is performed at baseline (Visit 1); a brief physical examination is performed at all other visits. 
e 
If menopause is suspected and is required only for confirmation of postmenopausal females as defined in Section 13.2. 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. 
f 
Performed after subjects have been free from antibiotics and bismuth for ≥4 weeks and free from proton pump inhibitors and histamine-2 receptor 
antagonists for ≥2 weeks. The test will be performed locally, using an approved testing method as per local standard of care. 
g 
See Section 6.3.3 for all required laboratory assessments. Glucose should be obtained after an 8-hour fast at Visit 1 and at any unscheduled visit. 
h 
Gastrin results at Visit 2 will not be blinded and will be reported to investigative sites. Gastrin at Visits 4, 6, 9, 10 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. 
i 
Only female subjects with childbearing potential.  
j 
Subjects should be instructed to complete the electronic diary every morning upon waking (for nighttime symptoms) and every evening before bedtime (for 
daytime symptoms) on each day of the study during all periods. Subjects (including screen failures) are expected to promptly return the electronic diary to 
the investigational site upon completion/termination from the study. 
k 
The Screening endoscopy can be performed any time during the Screening Period (Day -35 to Day -2); however, it should be performed after the subject has 
fulfilled Inclusion Criterion 6 (ie, heartburn reported on 4 or more days during any consecutive 7-day period of the Screening Period as recorded in the 
electronic diary). 
l 
Following completion of the Placebo-controlled Treatment Period at Week 4, all subjects will be assigned study drug for the Extension Period by the 
interactive response technology system. Subjects randomized to placebo during the Placebo-controlled Treatment Period will be re-randomized to receive 
vonoprazan 10 mg or vonoprazan 20 mg once daily for the 20-week Extension Period. Subjects randomized to 1 of the 2 vonoprazan treatment groups 
during the Placebo-controlled Treatment Period will continue to receive the same vonoprazan dose during the Extension Period. The first dose of study drug 
for the Extension Period will be taken the day after the Week 4 visit. 
 
 

SAP_001.pdf: 
 
Confidential 
 
 
 
 
 
 
 
 
 
Phathom Pharmaceuticals, Inc. 
 
NERD-301 
 
A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the 
Efficacy and Safety of Vonoprazan 10 and 20 mg Compared to Placebo for 
Relief of Heartburn in Subjects with Symptomatic Non-Erosive 
Gastroesophageal Reflux Disease (NERD) After 4 Weeks and to Evaluate the 
Efficacy and Safety of Vonoprazan 10 and 20 mg for Relief of Heartburn in 
Subjects with NERD After 6 Months 
 
29-Sep-2022 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Prepared by: 
 
 
 
 
 
 
 
 


Phathom Pharmaceuticals, Inc. 
 
Statistical Analysis Plan, Version 1.0 
NERD-301 
 
Date Issued: 29Sep2022 
 
 
 
 
II
 
Signature Page 
 
Study Title 
A Phase 3, Randomized, Double-Blind, Multicenter Study to 
Evaluate the Efficacy and Safety of Vonoprazan 10 and 20 mg 
Compared to Placebo for Relief of Heartburn in Subjects with 
Symptomatic Non-Erosive Gastroesophageal Reflux Disease 
(NERD) After 4 Weeks and to Evaluate the Efficacy and Safety 
of Vonoprazan 10 and 20 mg for Relief of Heartburn in 
Subjects with NERD After 6 Months 
 
 
 
 
 
Protocol Number:  NERD-301 
 
Approved by: 
 
 
 
 
 
 
 
DocuSign Envelope ID: F0831BF9-79DD-48E1-8C88-1054CF1960E7


Phathom Pharmaceuticals, Inc. 
 
Statistical Analysis Plan, Version 1.0 
NERD-301 
 
Date Issued: 29Sep2022 
 
 
 
 
III 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... VI 
1. 
INTRODUCTION ............................................................................................................ 7 
2. 
OBJECTIVES AND ESTIMANDS ................................................................................. 7 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 8 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 8 
3.2. STUDY ENDPOINTS ............................................................................................................. 9 
3.3. TREATMENTS .................................................................................................................... 11 
3.3.1. 
Placebo-controlled Treatment Period ...................................................................... 11 
3.3.2. 
Extension Period ....................................................................................................... 11 
3.4. DOSE ADJUSTMENT/MODIFICATIONS ............................................................................... 11 
4. 
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 12 
4.1. SAMPLE SIZE .................................................................................................................... 13 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING ........................................................ 13 
4.3. ASSESSMENT WINDOWS ................................................................................................... 14 
4.3.1. 
Study Day .................................................................................................................. 14 
4.3.2. 
Analysis Visit Windows ............................................................................................. 14 
4.4. ANALYSIS SET .................................................................................................................. 16 
4.4.1. 
Screened Set .............................................................................................................. 16 
4.4.2. 
Randomized Set ......................................................................................................... 16 
4.4.3. 
Intent-to-Treat (ITT) Set ........................................................................................... 17 
4.4.4. 
Safety Set ................................................................................................................... 17 
4.5. INTERCURRENT EVENT TYPES .......................................................................................... 17 
4.6. ESTIMAND SPECIFICATIONS .............................................................................................. 17 
5. 
SUBJECT DISPOSITION ............................................................................................. 21 
5.1. DISPOSITION ..................................................................................................................... 21 
5.1.1. 
Screened and Screen Failure Subjects ...................................................................... 21 
5.1.2. 
Placebo-controlled Treatment Period Randomized Subjects ................................... 21 
5.1.3. 
Extension Period Randomized Subjects .................................................................... 21 
5.1.4. 
Placebo-controlled Treatment Period ...................................................................... 22 
5.1.5. 
Extension Period ....................................................................................................... 22 
5.2. PROTOCOL DEVIATIONS ................................................................................................... 23 
6. 
DEMOGRGAPHICS AND BASELINE CHARACTERISTICS ............................... 23 
6.1. DEMOGRAPHICS ................................................................................................................ 23 
6.2. MEDICAL HISTORY ........................................................................................................... 24 
6.2.1. 
General Medical History .......................................................................................... 24 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 24 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 24 
7.2. STUDY TREATMENTS ........................................................................................................ 25 
7.2.1. 
Extent of Exposure .................................................................................................... 25 
7.2.2. 
Treatment Compliance .............................................................................................. 26 


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Statistical Analysis Plan, Version 1.0 
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IV 
7.2.3. 
Diary Compliance ..................................................................................................... 27 
8. 
EFFICACY ANALYSIS................................................................................................. 27 
8.1. PRIMARY EFFICACY ENDPOINT ......................................................................................... 27 
8.1.1. 
Primary Analysis ....................................................................................................... 28 
8.1.2. 
Derivation of the Primary Endpoint ......................................................................... 28 
8.1.3. 
Assumption Testing ................................................................................................... 29 
8.1.4. 
Sensitivity/Supplementary Analyses .......................................................................... 29 
8.1.4.1. 
Non-parametric test ............................................................................................ 29 
8.1.4.2. 
Use of acid reducing medications ...................................................................... 30 
8.1.4.3. 
Imputation for missing diary entries .................................................................. 30 
8.1.5. 
Subgroup Analysis .................................................................................................... 30 
8.1.6. 
Supportive Analyses .................................................................................................. 31 
8.2. SECONDARY EFFICACY ENDPOINT .................................................................................... 31 
8.3. EXPLORATORY ENDPOINTS ............................................................................................... 32 
8.3.1. 
Placebo-controlled Treatment Period ...................................................................... 32 
8.3.2. 
Extension Period ....................................................................................................... 33 
8.3.3. 
Follow-up Period ...................................................................................................... 34 
9. 
SAFETY ANALYSIS ..................................................................................................... 35 
9.1. ADVERSE EVENTS ............................................................................................................. 35 
9.1.1. 
Adverse Events of Special Interest (AESI) ................................................................ 36 
9.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 37 
9.3. VITAL SIGN MEASUREMENTS ........................................................................................... 39 
9.4. PHYSICAL EXAMINATION ................................................................................................. 39 
9.5. ELECTROCARDIOGRAM ..................................................................................................... 39 
10. 
INTERIM ANALYSIS/OTHER ANALYSES ............................................................. 40 
10.1. 
INTERIM ANALYSIS ....................................................................................................... 40 
10.2. 
CORONAVIRUS PANDEMIC ............................................................................................. 40 
11. 
REFERENCES ................................................................................................................ 41 
12. 
APPENDICIES ............................................................................................................... 41 
12.1. 
SCHEDULE OF EVENTS ................................................................................................... 42 
12.2. 
IMPUTATION RULES FOR MISSING DATE INFORMATION ................................................ 46 
12.2.1. Rules for Concomitant Medication Start Date Imputation ....................................... 46 
12.2.2. Rules for Concomitant Medication End Date Imputation ........................................ 46 
12.2.3. Rules for AE Start Date Imputation .......................................................................... 47 
12.3. 
MORNING AND EVENING DIARY.................................................................................... 47 
12.3.1. Diary Data Handling ................................................................................................ 47 
12.3.2. Derivation of Severity of Heartburn Exploratory Endpoints .................................... 48 
12.3.3. Sustained Resolution of Heartburn ........................................................................... 49 
12.4. 
QUESTIONNAIRE SCORING ............................................................................................. 49 
12.4.1. PAGI-SYM Questionnaire ......................................................................................... 49 
12.4.2. PAGI-QoL Questionnaire ......................................................................................... 50 
12.4.3. EQ-5D-5L Questionnaire.......................................................................................... 52 
12.4.4. PSQI Questionnaire .................................................................................................. 52 


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12.4.5. N-GSSIQ Questionnaire............................................................................................ 55 
12.5. 
ESTIMANDS AND SENSITIVITY/SUPPLEMENTARY ANALYSIS ......................................... 56 
 LIST OF IN-TEXT TABLES 
Table 1. Primary Objective, Endpoint, and Estimand .....................................................................7 
Table 2. Secondary Objective, Endpoint, and Estimand .................................................................8 
Table 3. Analysis Visit Windows ..................................................................................................14 
Table 4. Intercurrent Event types ...................................................................................................17 
Table 5. Primary Objective(s) and Estimand(s) with Rationale for Strategies to Address 
Intercurrent Events .........................................................................................................................18 
Table 6. Secondary Objective(s) and Estimand(s) with Rationale for Strategies to Address 
Intercurrent Events .........................................................................................................................20 
Table 7. Adverse Events of Special Interest – Search Criteria ......................................................37 
Table 8. Definitions of Heartburn Severity (Daytime/Nighttime) .................................................48 
Table 9. Summary of Statistical Methods and Sensitivity Analyses .............................................56 


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VI 
List of Abbreviations 
AE 
Adverse event 
AESI 
Adverse event of special interest 
CI 
Confidence interval 
CTMS 
Clinical Trial Management System  
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EE 
Erosive esophagitis 
EQ-5D-5L 
EuroQol 5-dimension 5-level questionnaire 
H2RA 
Histamine-2 receptor antagonist 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NERD 
Symptomatic non-erosive gastroesophageal reflux disease 
N-GSSIQ 
Nocturnal Gastroesophageal Reflux Disease Symptom 
Severity and Impact Questionnaire 
PAGI-SYM 
Patient Assessment of Gastrointestinal Disorders-Symptom 
Severity Index 
PAGI-QoL 
Patient Assessment of Upper Gastrointestinal Disorders-
Quality of Life 
PPI 
Proton pump inhibitor 
PSQI 
Pittsburgh Sleep Quality Index Questionnaire 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
 
 
 
 
 


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1. INTRODUCTION 
Vonoprazan belongs to a new class of acid-inhibitory agents called potassium-competitive 
acid blockers. In addition to the treatment of heartburn in patients with symptomatic non-
erosive gastroesophageal reflux disease (NERD), vonoprazan 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, and treatment of Helicobacter pylori 
infection. 
Study NERD-301 will evaluate the safety and effectiveness of vonoprazan (10 mg and 20 
mg) to treat heartburn in subjects with NERD. 
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 3.0, 
dated 25-April-2022. 
2. OBJECTIVES AND ESTIMANDS 
The primary objective of this study is as follows: 
Table 1. Primary Objective, Endpoint, and Estimand  
Objective  
Endpoint and Estimand with  
Summary Measure and Endpoint 
Primary Efficacy: Placebo-controlled Treatment Period  
• 
To assess the efficacy of vonoprazan 
(10 mg and 20 mg QD) compared to 
placebo (QD) in relief of heartburn over 
4 weeks in subjects with NERD.  
 
• 
Endpoint: The percentage of days without 
daytime or nighttime heartburn over the 
Placebo-controlled Treatment Period as 
assessed by the daily diary. 
• 
Primary Estimand: Difference in the mean 
percentage of days without daytime or 
nighttime heartburn over the 4-week Placebo-
controlled Treatment Period between each 
dose of vonoprazan and placebo (10 mg QD – 
placebo and 20 mg QD – placebo) in subjects 
with NERD, where a heartburn-free day is a 
day for which all entries are heartburn-free 
with no use of rescue antacid, H2RAs, and 
PPIs and assuming the percentage of 
heartburn-free days after treatment 
discontinuation is the percentage of heartburn-
free days during the screening period, 
irrespective of rescue antacid, H2RAs, and 
PPIs used after treatment discontinuation.  
• 
Supportive Estimand: Difference in the mean 
percentage of days without daytime or 
nighttime heartburn over the 4 week Placebo-
controlled Treatment Period as assessed by the 
daily diary between each dose of vonoprazan 
and placebo (10 mg QD – placebo and 20 mg 
QD - placebo) in subjects with NERD whose 


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Date Issued: 29Sep2022 
 
 
 
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response to treatment is of interest only while 
on study drug, i.e., prior to study drug 
discontinuation due to any reason and 
irrespective of excluded/rescue medications 
and treatments. 
 
The safety objectives are as follows: 
• To assess the safety of vonoprazan (10 mg and 20 mg QD) compared to placebo 
(QD) in subjects with NERD over 4 weeks. 
• To assess the long-term safety of vonoprazan (10 mg and 20 mg QD) over 6 
months.  
The secondary objective is as follows: 
Table 2. Secondary Objective, Endpoint, and Estimand 
Objective  
Endpoint and Estimand with  
Summary Measure and Endpoint 
Secondary Efficacy: Placebo-controlled Treatment Period  
• 
To assess the use of rescue antacid with 
vonoprazan (10 mg and 20 mg QD) 
compared to placebo (QD) over 4 
weeks in subjects with NERD.  
 
 
• 
Difference in the percentage of days without 
rescue antacid use over the 4-week Placebo-
controlled Treatment Period as assessed by the 
daily diary between each dose of vonoprazan 
and placebo (10 mg QD – placebo and 20 mg 
QD – placebo) in subjects with NERD whose 
response to treatment is of interest only while 
on study drug, i.e., prior to study drug 
discontinuation due to any reason and 
irrespective of excluded (non-rescue) 
medications and treatments.  
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a Phase 3, multicenter, double-blind study of vonoprazan versus placebo assessing 
the relief of heartburn. Subjects with NERD (as confirmed by endoscopy) and heartburn 
symptoms will be randomized to receive vonoprazan 10 mg, vonoprazan 20 mg, or placebo 
QD for 4 weeks. Subjects will complete an electronic diary twice daily to record the 
presence and maximum severity of daytime and nighttime heartburn symptoms and use of 
rescue antacid throughout the study. Study-supplied rescue antacid will be allowed. After 
the Placebo-controlled Treatment Period, all subjects will receive blinded vonoprazan (10 
mg or 20 mg QD) in the Extension Period. 
The study will include four periods: 
Screening Period (Day -35 to Day -2): Subjects will provide informed consent and 
undergo screening assessments to determine study eligibility, and baseline assessment will 


Phathom Pharmaceuticals, Inc. 
 
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be performed. Subjects will complete the electronic diary twice daily during the Screening 
Period. If all eligibility criteria are met, the subject will enter the study. 
Placebo-controlled Treatment Period (Day -1 to Day 28): Subjects with NERD whose 
eligibility is confirmed will be randomized to receive vonoprazan 10 mg or 20 mg or 
placebo QD for 4 weeks. The date of the first dosing is defined as Day 1. An electronic 
diary will continue to be completed twice daily during the Placebo-controlled Treatment 
Period. 
Extension Period (Day 29 to Day 169): Subjects randomized to vonoprazan 10 mg or 20 
mg in the Placebo-controlled Treatment Period will continue to take the same dose in a 
blinded manner for an additional 20 weeks. Subjects randomized to placebo in the 
Placebo-controlled Treatment Period will be re-randomized to receive either vonoprazan 
10 mg QD or vonoprazan 20 mg QD for 20 weeks. An electronic diary will continue to be 
completed twice daily during the Extension Period. The first dose of study drug for the 
Extension Period will be taken the day after the Week 4 visit. 
Follow-up Period: A safety follow-up visit will occur 4 weeks after the last dose of study 
drug. An electronic diary will continue to be completed twice daily during the Follow-up 
Period. 
A subject will be considered to have completed the study if the subject completes the 
safety follow-up visit. 
3.2. 
Study Endpoints 
The primary efficacy endpoint of this study is as follows: 
• The percentage of days without daytime or nighttime heartburn over the Placebo-
controlled Treatment Period as assessed by the daily diary. 
The secondary endpoint of this study is as follows: 
• The percentage of days without rescue antacid use over the Placebo-controlled 
Treatment Period as assessed by the daily diary. 
The safety endpoints of this study are as follows: 
• Adverse Events (AEs) 
• Laboratory test values (hematology, serum chemistry, urinalysis) 
• Serum gastrin and pepsinogen I/II levels 
• Electrocardiograms (ECGs) 
• Vital signs 
The exploratory endpoints for the Placebo-controlled Treatment Period are as follows: 
• The percentage of days without nighttime heartburn over the Placebo-controlled 
Treatment Period as assessed by the daily diary. 
• The percentage of days without daytime heartburn over the Placebo-controlled 
Treatment Period as assessed by the daily diary. 


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• The percentage of days without daytime or nighttime heartburn over the last 7 days 
of the Placebo-controlled Treatment Period as assessed by the daily diary 
• The mean severity of daytime and nighttime heartburn over the Placebo-controlled 
Treatment Period as assessed by the daily diary 
• The mean severity of daytime heartburn over the Placebo-controlled Treatment 
Period as assessed by the daily diary 
• The mean severity of nighttime heartburn over the Placebo-controlled Treatment 
Period as assessed by the daily diary 
• The time to sustained resolution of heartburn during the Placebo-controlled 
Treatment Period (sustained resolution is defined as at least 7 consecutive days 
with no daytime or nighttime heartburn as assessed by the daily diary) 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the Patient Assessment of Upper 
Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM) questionnaire 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the Patient Assessment of Upper 
Gastrointestinal Disorders-Quality of Life (PAGI-QoL) questionnaire 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
the EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the Nocturnal Gastroesophageal Reflux Disease 
Symptom Severity and Impact Questionnaire (N-GSSIQ) 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the Pittsburgh Sleep Quality Index (PSQI) 
questionnaire  
The exploratory endpoints for the Extension Period are as follows: 
• The percentage of days without daytime or nighttime heartburn over the Extension 
Period as assessed by the daily diary 
• The percentage of days without nighttime heartburn over the Extension Period as 
assessed by the daily diary 
• The percentage of days without daytime heartburn over the Extension Period as 
assessed by the daily diary 
• The percentage of days without daytime or nighttime heartburn from Week 4 to 
Week 8 in subjects re-randomized at Week 4 from placebo to either vonoprazan 10 
mg or 20 mg 
• The mean severity of daytime and nighttime heartburn over the Extension Period as 
assessed by the daily diary 
• The mean severity of daytime heartburn over the Extension Period as assessed by 
the daily diary 
• The mean severity of nighttime heartburn over the Extension Period as assessed by 
the daily diary 


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• The percentage of days without rescue antacid use over the Extension Period as 
assessed by the daily diary 
• The change from baseline to Week 12 and Week 24 of the Extension Period for 
each subscale and the total score of the PAGI-SYM questionnaire 
• The change from baseline to Week 12 and Week 24 of the Extension Period for 
each subscale and the total score of the PAGI-QoL questionnaire 
• The change from baseline to Week 12 and Week 24 of the Extension Period for the 
EQ-5D-5L 
• The change from baseline to Week 12 and Week 24 of the Extension Period for 
each subscale and the total score of the N-GSSIQ 
• The change from baseline to Week 12 and Week 24 of the Extension Period for 
each subscale and the total score of the PSQI  
Exploratory endpoints for the Follow-up Period include: 
• The percentage of days without daytime or nighttime heartburn during the Follow-
up Period as assessed by the daily diary 
• The percentage of days without rescue antacid use over the Follow-up Period as 
assessed by the daily diary 
3.3. 
Treatments   
3.3.1. 
Placebo-controlled Treatment Period 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized in a 1:1:1 ratio by the interactive response technology (IRT) system to 1 of the 
following 3 groups during the Placebo-controlled Treatment Period: 
• Vonoprazan 10 mg QD for 4 weeks 
• Vonoprazan 20 mg QD for 4 weeks 
• Placebo QD for 4 weeks  
3.3.2. 
Extension Period 
Following completion of the Placebo-controlled Treatment Period at Week 4, all subjects 
will be assigned study drug for the Extension Period by the IRT system: 
- 
Subjects randomized to placebo during the Placebo-controlled Treatment Period 
will be re-randomized to receive vonoprazan 10 mg or vonoprazan 20 mg QD for 
the 20-week Extension Period.  
- 
Subjects randomized to 1 of the 2 vonoprazan treatment groups during the Placebo-
controlled Treatment Period will continue to receive the same vonoprazan dose 
during the Extension Period.  
3.4. 
Dose Adjustment/Modifications 
No dose adjustments or modifications are allowed for this study.  


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4. GENERAL STATISTICAL CONSIDERATIONS  
In general, descriptive statistics will be presented by treatment group and by visit, as 
applicable.  
Data collected during the Placebo-controlled Treatment Period will be summarized by the 
following treatment groups:  
• Placebo 
• Vonoprazan 10 mg 
• Vonoprazan 20 mg 
Data collected during the Extension and Follow-up Periods will be summarized by the 
following treatment groups: 
• Placebo – Vonoprazan 10 mg 
• Placebo – Vonoprazan 20 mg 
• Vonoprazan 10 mg – Vonoprazan 10 mg 
• Vonoprazan 20 mg – Vonoprazan 20 mg 
Selected data will be summarized over both treatment periods for patients who received 
vonoprazan throughout the study, that is, only subjects who were randomized to the 
vonoprazan groups during the Placebo-controlled Treatment period will be included in 
these summaries. These summaries will use the following treatment groups: 
• Vonoprazan 10 mg 
• Vonoprazan 20 mg 
For continuous variables, summary statistics for the raw value and change from baseline at 
each time-point will include the number of subjects (n), arithmetic mean, standard 
deviation (SD), median, minimum, and maximum.  
Categorical variables will be summarized using subject counts and percentages. 
Percentages will be calculated using the total subjects per treatment unless otherwise 
specified.  
Change from baseline in absolute terms is defined as the baseline value subtracted from the 
post-baseline value.  
The efficacy analyses will be conducted on the Intent-to-Treat Set using the planned 
treatment. See Section 4.4.3 for the Intent-to-Treat Set definition. 
The safety analyses will be conducted on the Safety Set using the actual treatment the 
subject received. If a subject receives more than one type of study drug during a period, the 
planned treatment will be assigned as the actual treatment for the subject in the safety 
summary tables for this period. Meanwhile, if a subject receives only one type of study 
drug during a period but the study drug type is different than the planned 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 4.4.4 for the Safety Set definition. 


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Statistical tests will be two-sided and will be conducted at the assigned α significance 
level. P-values will be reported to 4 decimal places, with p-values less than 0.0001 
reported as “<0.0001”. 
SAS® Version 9.4 or higher will be used to perform all statistical analyses or procedures. 
4.1. 
Sample Size 
A sample size of 250 subjects per treatment group provides greater than 90% power at the 
0.05 2-sided level of significance using a two-sample t-test to detect a difference of 20% 
between a vonoprazan dose (50%) and placebo (30%) in the percentage of days without 
daytime or nighttime heartburn over the 4-week Placebo-controlled Treatment Period, 
assuming a common standard deviation of 35%. 
4.2. 
Randomization, Stratification, and Blinding 
An IRT system will be used to administer the randomization schedule.  
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized in a 1:1:1 ratio by the IRT system to 1 of the following 3 groups during the 
Placebo-controlled Treatment Period: 
• Vonoprazan 10 mg QD for 4 weeks 
• Vonoprazan 20 mg QD for 4 weeks 
• Placebo QD for 4 weeks  
Following completion of the Placebo-controlled Treatment Period at Week 4, all subjects 
will be assigned study drug for the Extension Period by the IRT system. Subjects 
randomized to placebo during the Placebo-controlled Treatment Period will be re-
randomized to receive vonoprazan 10 mg or vonoprazan 20 mg QD for the 20-week 
Extension Period. Subjects randomized to 1 of the 2 vonoprazan treatment groups during 
the Placebo-controlled Treatment Period will continue to receive the same vonoprazan 
dose during the Extension Period.  
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. The biostatistician generating the schedule will not 
be involved in study conduct or have access to efficacy and/or safety data while the study 
is ongoing. 
The study treatment blind during the Placebo-controlled Treatment Period and the 
Extension Period will be maintained using the IRT. A double-blind design is employed for 
the Placebo-controlled Treatment Period so that both the investigators and the subjects will 
be unaware of the treatment assignment. Moreover, study center staff involved in study 
drug administration and study endpoint assessments, PPD personnel, and the Phathom 
team, including the study statistician, will be blinded to the treatment received during the 
Placebo-controlled Treatment Period.  


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During the Extension Period, both investigators and subjects will remain blinded to the 
subject’s individual treatment assignment through the Extension Period. Following the 
interim analysis (if performed; see Section 10), Phathom and PPD would be unblinded to 
the treatment assignment of individual subjects during the Placebo-controlled Treatment 
Period. 
4.3. 
Assessment Windows 
4.3.1. 
Study Day 
For this study, randomization is to occur on Day -1 while the date of first dose of study 
drug is defined as Day 1 for both the Placebo-controlled Treatment Period and Extension 
Period. There is no Day 0 defined for this study. For analysis purposes, study day is 
calculated as: 
Date of assessment – Day 1 +1, for assessments done after first dose of study drug 
Date of assessment – Day 1, for assessments done before the first dose of study drug 
4.3.2. 
Analysis Visit Windows 
Analysis visit windows will be defined for analysis purposes and for summary tables 
presented by visit. Data (such as AEs and concomitant medications) that are not collected 
by visit and will not be summarized by visit will not use visit windows. Both scheduled 
and unscheduled assessments will be considered as valid assessments for analysis. 
Analysis visit labels will be assigned to each post-baseline record based on the study day 
windows relative to the date of first dose of study drug (Day 1). For the Placebo-controlled 
Treatment Period, if an assessment on Day -1 is missing, the closest visit with non-missing 
assessment on or before the date of first dose of study drug will be used as baseline. For 
the Extension Period, the closest visit in the Placebo-controlled Treatment Period with non-
missing assessment on or before the date of first dose of study treatment during Extension 
Period will be used as baseline. All by-visit summary and analysis will be based on the 
analysis visit windows presented below. 
Table 3. Analysis Visit Windows 
Period 
Nominal Visit 
(recorded on 
eCRF) 
Analysis Visit 
Target Study 
Day of Visit 
Analysis Visit Window 
Placebo-controlled 
Treatment 
Visit 1 
Screening 
Screening 
NA 
Date of informed consent 
to the day prior to first 
dose of study drug 
Placebo-controlled 
Treatment 
Visit 2 Day -1 
Baseline 
-1 
Day prior to first dose of 
study drug 


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Placebo-controlled 
Treatment 
Visit 4 Week 4 
Week 4 
28 
2 to 42 days and prior to 
starting treatment during 
the Extension Period 
Extension 
Visit 6 Week 
12 
Week 12 
85 
57 to 127 days 
Extension 
Visit 9 Week 
24 Final 
Week 24 
169 
128 days or greater and 
within 6 days after the 
last dose of study drug in 
the Extension Period 
Follow-up 
Visit 10 Week 
28 Follow-up 
Week 28 
197 
7 or more days after the 
last dose of study drug in 
the Extension Period 
 
Unscheduled assessments will also be assigned to analysis visits based on the analysis visit 
window defined in Table 3 above. When data is summarized by assigned analysis visit 
based on study day, visits will be referenced in summary tables by analysis visits only. 
Listings will present both nominal visits as recorded on the electronic case report form 
(eCRF) and the analysis visits. After all the records have been assigned to an analysis visit, 
if there are multiple valid records for an assessment within an assigned analysis visit, only 
one of these records will be used for summary statistics and analyses. The record to be 
used is determined based on the following hierarchy (in descending order): 
For safety assessments, including laboratory tests, ECG and vital signs: 
1. the record closest to the target visit day 
2. the record on the latest visit in the analysis visit window 
For data handling purposes, the following visit window definitions will be used for the 
Placebo-controlled Treatment Period, Extension Period, Follow-up Period, and Overall 
study duration summaries: 
• Placebo-controlled Treatment Period: from the date of first dose of study drug to 
the date of last dose of study drug in the Placebo-controlled Treatment Period. If 
the date of first dose of study drug is missing, then it will be imputed as the date of 
randomization + 1. If the date of last dose of study drug is missing, then the earliest 
of the following available dates will be used as the date of the end of the Placebo-
controlled Treatment Period: 
o Date of Week 4 visit 
o Date of treatment discontinuation 
o Date of study discontinuation 


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o Date the patient is expected to run out of study drug based on the kit 
dispensed at randomization  
• Extension Period: from the date of first dose of study drug in the Extension Period 
to the date of last dose of study drug in the Extension Period. If the date of first 
dose of study drug is missing, then it will be imputed as the date of the end of 
Placebo-controlled Treatment Period + 1. If the date of last dose of study drug is 
missing, then the earliest of the following available dates will be used as the date of 
the end of the Extension Period: 
o Date of Week 24 visit 
o Date of treatment discontinuation 
o Date of study discontinuation 
o Date the patient is expected to run out of study drug based on the kit(s) 
dispensed at the latest of Week 4 or Week 12 visit  
• Follow-up Period: from the date of the end of Extension Period + 1 to the date of 
completion/withdrawal/last contact. 
• Overall study duration: from the date of the start of Placebo-controlled Treatment 
Period to the date of completion/withdrawal/last contact. 
4.4. 
Analysis Set 
4.4.1. 
Screened Set 
The screened set will be defined as all subjects who signed the informed consent form 
before entering the Placebo-controlled Treatment Period of the study. Screen failures are 
defined as subjects who were not randomized into the Placebo-controlled Treatment Period 
of the study. 
4.4.2. 
Randomized Set 
For the Placebo-controlled Treatment Period, the randomized set will be defined as all 
subjects randomly assigned to receive study drug regardless of whether they received a 
dose of study drug or not during the Placebo-controlled Treatment Period.   
For the Extension Period, the randomized set will be defined as all subjects randomly 
assigned to receive study drug regardless of whether they received a dose of study drug or 
not during the Extension Period.   


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4.4.3. 
Intent-to-Treat (ITT) Set 
For the Placebo-controlled Treatment Period, the ITT set will be defined as all subjects 
randomized into the Placebo-controlled Treatment Period who receive at least one dose of 
study drug during the Placebo-controlled Treatment Period. 
For the Extension and Follow-up Periods, the ITT set will be defined as all subjects 
randomized into the Extension Period who receive at least one dose of study drug during 
the Extension Period. 
Analyses will be conducted on the ITT set using the planned treatment.  
4.4.4. 
Safety Set 
For the Placebo-controlled Treatment Period, the safety set will be defined as all subjects 
randomized into the Placebo-controlled Treatment Period who receive at least one dose of 
study drug during the Placebo-controlled Treatment Period. 
For the Extension and Follow-up Periods, the safety set will be defined as all subjects 
randomized into the Extension Period who receive at least one dose of study drug during 
the Extension Period. 
Analyses will be conducted on the safety set using the actual treatment the subject 
received. 
4.5. 
Intercurrent Event Types 
The intercurrent events defined for this study are as follows: 
 
Table 4. Intercurrent Event types 
Label 
Intercurrent Event Type 
IcEv1 (Discontinuation) 
Discontinuation of treatment over the 4-week Placebo-controlled 
Treatment Period due to any reason 
IcEv2 (Excluded 
antisecretory (non-rescue) 
medications) 
Use of PPIs or H2Ras  
IcEv3 (Rescue 
medication) 
Use of rescue medication (sponsor-provided antacid) 
Abbreviation: IcEV=intercurrent event; H2RA: histamine-2 receptor antagonist; PPI: proton pump inhibitor 
 
4.6. 
Estimand Specifications 
The estimand specifications for the primary and secondary efficacy endpoints are as 
follows: 
 
 


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Table 5. Primary Objective(s) and Estimand(s) with Rationale for Strategies to 
Address Intercurrent Events 
Objective 
To assess the efficacy of vonoprazan (10 mg and 20 mg QD) compared to 
placebo (QD) in relief of heartburn over 4 weeks in subjects with NERD 
Estimand Label 
Estimand 1 (Primary) 
Estimand 
Description 
Difference in the mean percentage of days without daytime or nighttime 
heartburn over the 4-week Placebo-controlled Treatment Period between each 
dose of vonoprazan and placebo (10 mg QD – placebo and 20 mg QD – 
placebo) in subjects with NERD, where a heartburn-free day is a day for which 
all entries are heartburn-free with no use of rescue antacid, H2RAs, and PPIs 
and assuming the percentage of heartburn-free days after treatment 
discontinuation is the percentage of heartburn-free days during the screening 
period, irrespective of rescue antacid, H2RAs, and PPIs used after treatment  
discontinuation.  
 
Target Population 
Patients with NERD who would meet all the inclusion/exclusion criteria of the 
study 
Endpoint 
Percentage of days without daytime or nighttime heartburn over the Placebo-
controlled Treatment Period 
Treatment 
Condition(s) 
Experimental: Vonoprazan 10 mg, Vonoprazan 20 mg 
Comparator: Placebo 
Population-Level 
Summary 
Difference in the mean percentage of days without daytime or nighttime 
heartburn over the Placebo-controlled Treatment Period 
Intercurrent Event 
Strategy  
 
IcEv1 
(Discontinuation) 
Composite  
IcEv2 (Excluded 
(non-rescue) 
medications) 
Composite 
IcEv3 (Rescue 
medication) 
Composite 
Rationale for 
Strategies 
 
Composite strategy is utilized as treatment discontinuation may represent an 
unfavorable outcome.  
Composite strategy is utilized as use of rescue medication may indicate the 
subject experienced heartburn even if heartburn was not indicated in the diary.  
Composite strategy is utilized for use of rescue medication and prohibited 
medication (ie, H2RAs, PPIs) as use of other acid-reducing medications may 
confound efficacy results for heartburn. 
 
 


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Table 5. Primary Objective(s) and Estimand(s) with Rationale for Strategies to 
Address Intercurrent Events (continued) 
Estimand Label 
Estimand 2 (Supportive) 
Estimand 
Description 
Difference in the mean percentage of days without daytime or nighttime 
heartburn over the 4-week Placebo-controlled Treatment Period as assessed by 
the daily diary between each dose of vonoprazan and placebo (10 mg QD – 
placebo and 20 mg QD - placebo) in subjects with NERD whose response to 
treatment is of interest only while on study drug, i.e., prior to study drug 
discontinuation due to any reason and irrespective of excluded/rescue 
medications and treatments 
Target Population 
Patients with NERD who would meet all the inclusion/exclusion criteria of the 
study 
Endpoint 
Percentage of days without daytime or nighttime heartburn over the Placebo-
controlled Treatment Period 
Treatment 
Condition(s) 
Experimental: Vonoprazan 10 mg, Vonoprazan 20 mg 
Comparator: Placebo 
Population-Level 
Summary 
Difference in the mean percentage of days without daytime or nighttime 
heartburn over the Placebo-controlled Treatment Period 
Intercurrent Event 
Strategy  
 
IcEv1 
(Discontinuation) 
While on Treatment  
IcEv2 (Excluded 
(non-rescue) 
medications) 
Treatment Policy 
IcEv3 (Rescue 
medication) 
Treatment Policy 
Rationale for 
Strategies 
Treatment Policy strategy is used to understand the treatment effect in the 
Placebo-controlled Treatment Period irrespective of the taken prohibited/rescue 
medications as these reflect what might happen in clinical practice. Every 
attempt is taken to measure the percentage of days without daytime or 
nighttime heartburn over the Placebo-controlled Treatment Period. 
 
While on treatment strategy is used when response to treatment before the 
discontinuation of the study drug is of interest and was selected due to the short 
(<24 hours) half-life of the drug. 
Abbreviation: IcEV = intercurrent event; NERD = Non-Erosive Gastroesophageal Reflux Disease 
Refer to Table 4 for specific intercurrent event definitions.  
 
 
 
 


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Table 6. Secondary Objective(s) and Estimand(s) with Rationale for Strategies to 
Address Intercurrent Events 
Objective 
To assess the use of rescue antacid with vonoprazan (10 mg and 20 mg QD) 
compared to placebo (QD) over 4 weeks in subjects with NERD.  
Estimand Label 
Estimand 3 (Secondary) 
Estimand 
Description 
Difference in the mean percentage of days without rescue antacid use over the 
4-week Placebo-controlled Treatment Period as assessed by the daily diary between 
each dose of vonoprazan and placebo (10 mg QD – placebo and 20 mg QD - 
placebo) in subjects with NERD whose response to treatment is of interest only 
while on study drug, i.e., prior to study drug discontinuation due to any reason and 
irrespective of excluded (non-rescue) medications and treatments. 
Target Population 
Patients with NERD who would meet all the inclusion/exclusion criteria of the study 
Endpoint 
Percentage of days without rescue antacid use over the Placebo-controlled 
Treatment Period 
Treatment 
Condition(s) 
Experimental: Vonoprazan 10 mg, Vonoprazan 20 mg 
Comparator: Placebo 
Population-Level 
Summary 
Difference in the mean percentage of days without recue antacid use over the 
Placebo-controlled Treatment Period 
Intercurrent Event 
Strategy  
 
IcEv1 
(Discontinuation) 
While on Treatment 
IcEv2 (Excluded 
(non-rescue) 
medications) 
Treatment Policy 
IcEv3 (Rescue 
medication) 
Composite 
Rationale for 
Strategies 
Treatment Policy strategy is used to understand the treatment effect in the Placebo-
controlled Treatment Period irrespective of the taken prohibited/rescue medications 
as these reflect what might happen in clinical practice. Every attempt is taken to 
measure the percentage of days without daytime or nighttime heartburn over the 
Placebo-controlled Treatment Period. 
 
While on treatment strategy is used when response to treatment before the 
discontinuation of the study drug is of interest and was selected due to the short (<24 
hours) half-life of the drug. 
 
Composite strategy is implied because the patients’ outcome is incorporated into the 
definition of the endpoint. 
Abbreviation: IcEV = intercurrent event; NERD = Non-Erosive Gastroesophageal Reflux Disease 
Refer to Table 4 for specific intercurrent event definitions.  


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5. SUBJECT DISPOSITION  
5.1. 
Disposition 
5.1.1. 
Screened and Screen Failure Subjects 
The following will be summarized and presented for overall subjects for the Screened Set: 
• total number of screened subjects 
• number and percentage of screen failures 
• number and percentage of screen failures for each primary reason 
Subjects who fail to satisfy all inclusion/exclusion criteria will be listed for the Screened 
Set. 
5.1.2. 
Placebo-controlled Treatment Period Randomized Subjects 
The following will be summarized and presented by treatment group and for overall 
subjects for the Randomized Set: 
• number of randomized subjects 
• number of subjects randomized but not treated 
• number and percentage of subjects who completed the Placebo-controlled 
Treatment Period 
• number and percentage of subjects who discontinued treatment during the Placebo-
controlled Treatment Period 
• number and percentage of subjects for each reason for discontinuing treatment 
during the Placebo-controlled Treatment Period  
• number and percentage of subjects who entered the Extension Period 
• number and percentage of subjects who did not enter the Extension Period 
• number and percentage of subjects for each reason for not entering the Extension 
Period 
Percentages will be based on the number of subjects in the Randomized Set. Subject 
disposition data will be listed for the Randomized Set. Additionally, the reason for 
discontinuation for subjects who discontinued during the Placebo-controlled Treatment 
Period will be listed separately for the Randomized Set. 
5.1.3. 
Extension Period Randomized Subjects 
The following will be summarized and presented by treatment group and for overall 
subjects for the Randomized Set: 
• number of randomized subjects 


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• number of subjects randomized but not treated 
• number and percentage of subjects who completed the Extension Period 
• number and percentage of subjects who discontinued treatment during the 
Extension Period 
• number and percentage of subjects for each reason for discontinuing treatment 
during the Extension Period  
• number and percentage of subjects who completed the study 
• number and percentage of subjects who did not complete the study 
• number and percentage of subjects for each reason for not completing the study 
Percentages will be based on the number of subjects in the Randomized Set. Subject 
disposition data will be listed for the Randomized Set. Additionally, the reason for 
discontinuation for subjects who discontinued during the Extension Period will be listed 
separately for the Randomized Set. 
5.1.4. 
Placebo-controlled Treatment Period  
The following will be summarized for the Placebo-controlled Treatment Period Safety Set:  
• number and percentage of subjects in the Safety Set and ITT Set 
• number and percentage of subjects for each reason for exclusion from the ITT Set 
• number and percentage of subjects who completed the Placebo-controlled 
Treatment Period 
• number and percentage of subjects who discontinued from the Placebo-controlled 
Treatment Period 
• number and percentage of subjects for each reason for discontinuation of study 
drug during the Placebo-controlled Treatment Period 
5.1.5. 
Extension Period 
The following will be summarized for the Extension Period Safety Set:  
• number and percentage of subjects in the Safety Set and ITT Set 
• number and percentage of subjects for each reason for exclusion from the ITT Set 
• number and percentage of subjects who completed the Extension Period 
• number and percentage of subjects who discontinued from the Extension Period 
• number and percentage of subjects for each reason for discontinuation of study 
drug during the Extension Period 


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5.2. 
Protocol Deviations 
Protocol deviations will be recorded within the PPD Clinical Trial Management System 
(CTMS) and will undergo a blinded review prior to database lock and unblinding. 
Significant protocol deviations are defined as the subset of deviations which are considered 
to affect primary efficacy and safety assessments, the safety or mental integrity of a 
subject, or the scientific value of the trial.  
The number and percentage of subjects with subject-specific significant protocol 
deviations will be summarized by CTMS activity subtype, treatment group, and overall for 
the Randomized Set separately for the Placebo-controlled Treatment Period and Extension 
Period.  
Individual subject protocol deviations, both significant and non-significant, will be listed in 
a by-treatment, by-subject data listing separately for the Placebo-controlled Treatment 
Period and Extension Period using the Randomized Set. 
6. DEMOGRGAPHICS AND BASELINE CHARACTERISTICS  
6.1. 
Demographics 
Demographic variables collected at Baseline, such as age (years), sex, race, ethnicity, 
height (cm), weight (kg), and body mass index (BMI) will be summarized using the 
Randomized and ITT Sets.  
Continuous variables, including age, BMI, weight, and height, will be summarized using 
descriptive statistics for each treatment group and overall. Categorical variables will be 
summarized by reporting the number and percentage of subjects in each category for each 
treatment group and overall.  
• Age group 1 at Baseline (<45, ≥45 - <65, ≥65 - <75, ≥75)  
• Age group 2 at Baseline (≥18 - ≤64, ≥65 - ≤84, ≥85)  
• Sex (Female, Male) 
• Fertility Status (Sterile, Post-Menopausal, Potentially Able to Bear Children, N/A) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown, Ethnicity Not 
Reported) 
• Race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander, Other Race, Unknown Race, 
Race Not Reported) 
• Smoking Status (Never smoked, Current smoker, Ex-smoker) 
• Alcohol Use (Drink Everyday, Drink a Couple of Days per Week, Drink a Couple 
of Days per Month, Never Drink) 
• BMI category (<25, ≥25 - <30, ≥30)  
At baseline, the mean severity of heartburn and the number of days with heartburn will be 
summarized based on the daytime and nighttime heartburn symptoms reported in the daily 
diary during the last 7 days prior to Day -1, i.e, Days -8 to -2, inclusive. Only days with at 


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least 1 morning or evening diary entry during the specified days will be included in these 
summaries. In addition, the mean severity of heartburn and number of days with heartburn 
will be summarized using the following categories:   
• Number of days with: 
o Daytime or nighttime heartburn (0, 1-3, 4-5, 6-7) 
o Daytime heartburn (0, 1-3, 4-5, 6-7) 
o Nighttime heartburn (0, 1-3, 4-5, 6-7) 
• Mean severity of  
o Daytime or nighttime heartburn (0, >0 - ≤ 1, > 1 - ≤ 2, > 2 - ≤ 3, >3 – 4) 
o Daytime heartburn (0, >0 - ≤ 1, > 1 - ≤ 2, > 2 - ≤ 3, >3 – 4) 
o Nighttime heartburn (0, >0 - ≤ 1, > 1 - ≤ 2, > 2 - ≤ 3, >3 – 4) 
 
In addition, the percentage of heartburn-free days during the screening period, calculated 
using all available diary data prior to randomization, will also be summarized using the 
same data handling rules as for the percentage of heartburn-free days during the Placebo-
controlled Treatment Period (See Section 8.1.2).  
Demographic and baseline characteristics data will be listed by treatment and subject using 
the Randomized Set. 
6.2. 
Medical History 
6.2.1. 
General Medical History 
Medical history will be coded using Version 23.0 of the Medical Dictionary for Regulatory 
Activities (MedDRA). The number and percentage of subjects with medical history coded 
to each MedDRA SOC and PT will be summarized by treatment group and overall using 
the Safety Set.  
Medical history will be listed by treatment and subject using the Randomized Set. 
7. TREATMENTS AND MEDICATIONS  
7.1. 
Prior and Concomitant Medications 
Any prior and concomitant medication used during the study will be recorded and coded 
using WHODRUG Version B3-March 2019. Summaries of all medications by drug class 
(ATC Level 4 coding) and preferred term will be provided separately for prior medications 
and concomitant medications for each treatment group and overall. Medications with 
missing ATC Level 4 terms will be summarized using the highest-level term that is 
available. All summaries will be performed using the Safety Set. 


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For the Placebo-controlled Treatment Period, prior medications are those with the start and 
stop dates prior to the first dose of study drug in the Placebo-controlled Treatment Period. 
Concomitant medications are those: 
• with start dates prior to the first dose of study drug in the Placebo-controlled 
Treatment Period and continuing after the first dose of study drug in the Placebo-
controlled Treatment Period, or  
• with start dates between the first dose of study drug in the Placebo-controlled 
Treatment Period but on or before the last dose of study drug in the Placebo-
controlled Treatment Period. 
 
Prior and concomitant medications for the Placebo-controlled Treatment Period will be 
summarized separately by treatment group and overall.  
For the Extension Period, concomitant medications are those with: 
• start dates prior to the first dose of study drug in the Extension Period and 
continuing after the first dose of study drug in the Extension Period, or  
• with start dates after the first dose of study drug in the Extension Period but before 
the last dose of study drug in the Extension period 
The concomitant medications for the Extension Period will be summarized by treatment 
group and overall.   
In instances where a medication start date is incomplete, it will be conservatively imputed 
to determine whether or not the medication was prior or concomitant. If the start date is 
missing, then it will be assumed to be concomitant. Imputation details for missing 
concomitant medication start and end date are presented in Appendix Section 12.2. 
All prior and concomitant medications will be listed by treatment and subject for the 
Safety Set. 
7.2. 
Study Treatments 
7.2.1. 
Extent of Exposure 
Study drug exposure will be calculated as the number of days from the first to last dose 
date of each period: 
Exposure = Date of last dose – Date of first dose + 1. 
If the date of first/last dose is missing, it will be imputed using the start/end date of the 
corresponding analysis window as described in Section 4.3.2. 
Descriptive summary statistics including the number of subjects, mean, standard deviation, 
median, minimum, and maximum for the study drug exposure (days) will be presented by 
treatment group and overall for the Safety Set for each period, and overall (i.e., across 
periods). 


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Subject counts and percentages for the duration of study drug exposure for the Placebo-
controlled Treatment Period will be summarized cumulatively and for the following 
categories: ≥1 to ≤14 days, >14 to ≤28 days, >28 days. Similarly, subject counts and 
percentages for the duration of study drug exposure for the Extension Period will be 
summarized cumulatively and for the following categories: ≥1 to ≤14 days, >14 to ≤28 
days, >28 to ≤56 days, >56 to ≤84 days, >84 to ≤112 days, >112 to ≤140 days, >140 days. 
Lastly, subject counts and percentages for the duration of study drug exposure over both 
treatment periods will be summarized cumulatively and for the following categories: ≥1 to 
≤14 days, >14 to ≤28 days, >28 to ≤56 days, >56 to ≤84 days, >84 to ≤112 days, >112 to 
≤140 days, >140 days to ≤168 days, >168 days. 
All study drug exposure data will be listed using the Safety Set. 
7.2.2. 
Treatment Compliance 
Treatment compliance for each period will be calculated as follows: 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (%) = 
𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒× 100 , where 
 
total expected capsules = (date of last dose for the period – date of first dose for the period) 
+1 
total capsules taken = total number of capsules dispensed for the period – total number of 
capsules returned 
For each period, if a subject has at least one kit not returned, the following imputation will 
be utilized: 
- 
if all dispensed kits are not returned, the compliance is imputed as 100% for the 
period 
- 
if only partial kits are returned, the missing capsules returned will be treated as 0 
and the compliance will be computed consequently 
- 
if a subject has a returned amount imputed for at least one kit which results to a 
treatment compliance of >120%, then the treatment compliance will be set to 100% 
instead for the period 
Each subject will be categorized as either compliant (compliance of ≥80% and ≤120%) or 
non-compliant (compliance of <80% or >120%).  
Compliance rate will be summarized by treatment group and overall for each period. 
Moreover, subject counts and percentages for the following compliance intervals (<80, ≥80 
- ≤100, >100 - ≤120, >120) will be summarized by treatment group and overall for each 
period.  
All compliance data will be listed using the Safety Set.  


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7.2.3. 
Diary Compliance 
A summary of the percentage of missing diaries in each period will be summarized by 
treatment group. A study day with no diary entry will be counted as two missing diary 
entries. A study day with only either the daytime or nighttime diary entry will be counted 
as one missing diary entry. The percentage will be calculated based on expected number of 
diary entries in the period, that is, the treatment duration in the period times two. 
8. EFFICACY ANALYSIS  
The overall type 1 error rate will be controlled at alpha=0.05 by utilizing a fixed sequence 
testing procedure. The comparisons will be performed in the following order until a test is 
not significant. Tests that are not significant based on this testing procedure for the primary 
and secondary endpoints will be considered purely nominal. 
 
Vonoprazan 20 mg vs. Placebo: % of days without daytime or nighttime heartburn over 
the Placebo-controlled Treatment Period as assessed by the daily diary 
 
 
Vonoprazan 10 mg vs. Placebo: % of days without daytime or nighttime heartburn over 
the Placebo-controlled Treatment Period as assessed by the daily diary 
 
 
Vonoprazan 20 mg vs. Placebo: percentage of days without rescue antacid use over the 
Placebo-controlled Treatment Period as assessed by the daily diary 
 
 
Vonoprazan 10 mg vs. Placebo: percentage of days without rescue antacid use over the 
Placebo-controlled Treatment Period as assessed by the daily diary 
 
No multiplicity adjustment will be performed for the exploratory endpoints. Each 
exploratory endpoint will be tested independently at an alpha level of 0.05. 
Comparisons will also be made between the vonoprazan dose groups for all endpoints with 
no multiplicity adjustment. 
8.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of the Estimand 1 (primary) is the percentage of days 
without daytime or nighttime heartburn over the Placebo-controlled Treatment Period as 
assessed by the daily diary. 


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8.1.1. 
Primary Analysis 
The percentage of days without daytime or nighttime heartburn over the Placebo-
controlled Treatment Period as assessed by the daily diary for each of the vonoprazan 
treatment groups will be compared to the placebo treatment group using a general linear 
model with treatment group as factor and severity and frequency of heartburn at baseline as 
covariates using the ITT Set.  
The severity and frequency of heartburn at baseline will be summarized as the mean 
severity and the number of days, respectively, from the daytime and nighttime heartburn 
symptoms reported in the daily diary during the last 7 days prior to Day -1 of the Placebo-
controlled Treatment Period.  
Descriptive summary statistics including the number of subjects, mean, standard deviation, 
median, Q1, Q3, minimum, and maximum percentage of days without daytime or 
nighttime heartburn will be presented. For each comparison of vonoprazan treatment group 
to placebo, the LS mean difference, 2-sided 95% CI, and p-value will also be presented. 
The percentage of subjects without daytime or nighttime heartburn by study day during the 
Placebo-controlled Treatment Period will be presented by treatment group in a figure. 
All efficacy data will be listed using the ITT Set. 
8.1.2. 
Derivation of the Primary Endpoint  
A diary day will be included in the denominator for the calculation of a subject’s 
percentage of days without daytime or nighttime heartburn if the following conditions are 
satisfied:  
• both the morning and evening diary for that day were completed 
• or if only one diary entry for that day was completed and this diary entry indicates 
the presence of heartburn.  
Diary days will not be included in the denominator if the subject missed both the morning 
and evening entries for that day or if the subject completed only one diary entry and this 
diary entry indicates the absence of heartburn. 
A diary day will be included in the numerator as a heartburn-free day if the following 
conditions are satisfied: 
• both the morning and evening diary for that day were completed and both entries 
indicate the absence of heartburn 
• no rescue antacid was used on that day 
• no H2RAs or PPIs were used on that day. 
For subjects who prematurely discontinue treatment during the Placebo-controlled 
Treatment Period, the percentage of days without daytime or nighttime heartburn after 
discontinuation up to Day 28 will be imputed using the percentage of heartburn-free days 


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during the Screening Period. The percentage of heartburn-free days during the Screening 
Period will be calculated using the same data handling rules for the percentage of 
heartburn-free days during the Placebo-controlled Treatment Period. For subjects who 
prematurely discontinue treatment prior to Day 7 of the Placebo-controlled Treatment 
Period and have less than 4 days of diary entries, the percentage of heartburn-free days will 
be imputed using the percentage of heartburn-free days during the Screening Period.  
 
If there are more than 2% of ITT subjects who have been on treatment for at least 7 days 
and have less than 4 days of diary entries, multiple imputation will be used to compute the 
percentage of days without daytime or nighttime heartburn while on treatment, as the 
estimated percentage of days without heartburn may be unreliable for subjects with only a 
few completed diaries. The multiple imputation will be performed under a missing-at-
random (MAR) assumption using the Placebo-controlled Treatment Period treatment group 
and the severity and frequency of heartburn at baseline as variables in the model. The 
general linear model with treatment group as a factor and severity and frequency of 
heartburn at baseline as covariates will be run on each of 100 imputed datasets. The 
difference in the percentage of days without daytime or nighttime heartburn between 
treatment groups with 95% confidence intervals from each of the 100 imputed datasets will 
be combined using Rubin’s Method. For further details on the derivation of the diary-based 
endpoints, see Section 12.3.1. 
 
If less than 2% of ITT subjects require multiple imputation, the percentage of days without 
daytime or nighttime heartburn for all subjects with less than 4 days of diary entries will be 
imputed using the more conservative percentage of heartburn-free days during the 
Screening Period. 
8.1.3. 
Assumption Testing 
Since linear regression methods are generally robust to departures in normality for large 
sample sizes, testing of distributional assumption of the endpoint is not planned. 
8.1.4. 
Sensitivity/Supplementary Analyses 
To assess how intercurrent events in Section 4.5 affect the robustness of the primary 
analysis results for Estimand 1 (primary), the following analyses will be performed. See 
Section 12.5 for the detailed description of the estimand and planned primary and 
sensitivity/supplementary analyses. 
8.1.4.1. 
Non-parametric test 
The percentage of days without daytime or nighttime heartburn over the Placebo-
controlled Treatment Period as assessed by the daily diary for each of the vonoprazan 
treatment groups will be compared to the placebo treatment group using a Wilcoxon rank-
sum test using the ITT Set. 


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8.1.4.2. 
Use of acid reducing medications 
To explore how the use of acid reducing medications affects the primary analysis, the 
percentage of days without daytime or nighttime heartburn irrespective of rescue antacid, 
H2RA, and PPI over the Placebo-controlled Treatment Period will also be summarized. 
8.1.4.3. 
Imputation for missing diary entries 
To explore how missing data affects the robustness of the primary analysis on the 
percentage of days without daytime or nighttime heartburn over the Placebo-controlled 
Treatment Period, a sensitivity analysis will be performed in which days with missing 
diary entries (either no diary entries or only one diary entry) will be imputed as a day with 
heartburn for all subjects. In addition, for subjects who discontinue the Placebo-controlled 
Treatment Period prior to Day 28, days after discontinuation date will be imputed as 
having heartburn. The percentage of days without daytime or nighttime heartburn over the 
Placebo-controlled Treatment Period will be calculated based on the number of planned 
days in the Placebo-controlled Treatment Period, that is, 28 days.  
8.1.5. 
Subgroup Analysis 
The primary efficacy endpoint will be analyzed separately for the following subgroups per 
subgroup level in the ITT set using a general linear model with treatment group as a factor: 
• Age group 1 at Baseline (<45, ≥45 - <65, ≥65) 
• Sex (Male, Female)  
• BMI category (<25, ≥25 - <30, ≥30) 
• Mean severity of baseline daytime or nighttime heartburn (0, >0 - ≤ 1, > 1 - ≤ 2, 
> 2 - ≤ 3, >3 – 4) 
• Frequency (number of days) of baseline daytime or nighttime heartburn (0-3, 4-5, 
6-7)  
Severity and frequency of heartburn at baseline will be based on symptoms reported in the 
daily diary from the last 7 days prior to Day -1 of the Placebo-controlled Treatment Period. 
In addition, an analysis across each subgroup will be performed using a general linear 
model with factors for treatment group, subgroup level, and treatment by subgroup 
interaction. 
 
For the subgroup analyses of the primary efficacy endpoint, given the complexity of 
implementing multiple imputation within each subgroup, the percentage of days without 
daytime or nighttime heartburn for all subjects with less than 4 days of diary entries will be 
imputed using the more conservative imputation of the percentage of heartburn-free days 
during the Screening Period. Otherwise, the subgroup analyses for the percentage of days 
without daytime or nighttime heartburn will be summarized following the data handling 
methods for Estimand 1. 


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8.1.6. 
Supportive Analyses 
A supportive analysis of the primary endpoint (Estimand 2) will be conducted in the ITT 
set in which the percentage of days without daytime or nighttime heartburn over the 
Placebo-controlled Treatment Period will be summarized prior to treatment discontinuation 
and irrespective of rescue antacid, H2RA, and PPI use. 
In this analysis, the percentage of days without daytime or nighttime heartburn over the 
Placebo-controlled Treatment Period as assessed by the daily diary for each of the 
vonoprazan treatment groups will be compared to the placebo treatment group using the 
same statistical method as in the primary analysis, a general linear model with treatment 
group as a factor and severity and frequency of heartburn at baseline as covariates.  
 
A diary day will be included in the denominator for the calculation of the percentage of 
days without daytime or nighttime heartburn if at least one diary entry (either morning 
only, evening only, or both) was completed. Diary days will not be included in the 
denominator if the subject missed both the morning and evening entries for that day. 
For example, if the subject has at least one entry for 24 out of 28 days and has missed both 
the morning and evening diary entries for 4 days, then 24 days will be used as the 
denominator. Subjects with no available diary entries in the Placebo-controlled Treatment 
Period will not be included in the analysis. 
 
All entries on a day need to be heartburn-free for the day to be counted as a day with 
neither daytime nor nighttime heartburn. This will also apply if more than two diary entries 
are assigned to the same study day. If a subject has only one diary entry on a day and that 
entry does not indicate heartburn, the day will be considered heartburn-free for the 
analysis.  
8.2. 
Secondary Efficacy Endpoint 
For the secondary endpoint, the percentage of days without rescue antacid use over the 
Placebo-controlled Treatment Period as assessed by the daily diary, each vonoprazan 
treatment group will be compared to the placebo treatment group using a general linear 
model like that used for the primary endpoint. See Section 12.5 for the summary of 
estimand and associated statistical methods.  
The percentage of days without rescue antacid use will be obtained using all days with at 
least one diary entry (either morning only, evening only, or both) during the respective 
periods (Placebo-controlled Treatment, Extension, and Follow-up). That is, the study days 
in which the subject missed both the morning and evening entries will not be counted 
towards the denominator. For example, if the subject has at least one entry for 24 out of 28 
days and has missed the morning and evening diary entries for 4 days, then 24 days will be 
used as the denominator. In addition, a given day will be counted towards the numerator 
(days without rescue antacid use) if all entries for that study day indicate that rescue 
antacid was not used. This will also be applicable on days with more than two diary 


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entries. Also, if a day only has one diary entry and the entry indicates that rescue antacid 
was not used, this day will be considered as a day without rescue antacid use. 
8.3. 
Exploratory Endpoints  
For all exploratory endpoints in which comparison between each vonoprazan treatment 
group and placebo is of interest, testing will be performed with no multiplicity adjustment 
to the alpha level. Each exploratory endpoint will be tested independently at an alpha level 
of 0.05. All exploratory endpoints will be analyzed using the ITT Set. 
8.3.1. 
Placebo-controlled Treatment Period 
The following exploratory endpoints will be compared between each vonoprazan treatment 
group and placebo using a general linear model like that used for the primary endpoint 
using the ITT Set except that the nighttime heartburn severity and frequency at baseline 
will be used as covariates for the percentage of days without nighttime heartburn over the 
Placebo-controlled Treatment Period and daytime heartburn severity and frequency at 
baseline will be used as covariates for the percentage of days without daytime heartburn 
over the Placebo-controlled Treatment Period endpoints respectively. 
• The percentage of days without nighttime heartburn over the Placebo-controlled 
Treatment Period as assessed by the daily diary. 
• The percentage of days without daytime heartburn over the Placebo-controlled 
Treatment Period as assessed by the daily diary. 
For the above exploratory endpoints, the percentage of days without nighttime heartburn or 
without daytime heartburn will be summarized two ways, following the data handling and 
analysis methods for both Estimand 1 and Estimand 2 for the primary endpoint.  
The following exploratory endpoints will be compared between each vonoprazan treatment 
group and placebo using a general linear model like that used for the primary endpoint 
using the ITT Set. 
• The percentage of days without daytime or nighttime heartburn over the last 7 days 
of the Placebo-controlled Treatment Period as assessed by the daily diary 
• The mean severity of daytime and nighttime heartburn over the Placebo-controlled 
Treatment Period as assessed by the daily diary 
• The mean severity of daytime heartburn over the Placebo-controlled Treatment 
Period as assessed by the daily diary 
• The mean severity of nighttime heartburn over the Placebo-controlled Treatment 
Period as assessed by the daily diary 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the PAGI-SYM questionnaire 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the PAGI-QoL questionnaire 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
the EQ-5D-5L 


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• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the N-GSSIQ 
• The change from baseline to the end of the Placebo-controlled Treatment Period for 
each subscale and the total score of the PSQI 
Cumulative incidences of the time to sustained resolution of heartburn during the Placebo-
controlled Treatment Period will be estimated using Kaplan-Meier method. For each 
comparison of vonoprazan treatment groups with placebo, the 95% CI will be presented, 
along with the p-value from the log-rank test. For details on endpoint derivation and 
censoring, see Section 12.3.3. Details of obtaining subscale and total scores for PAGI-
SYM, PAGI-QoL, EQ-5D-5L, N-GSSIQ, and PSQI are provided in Section 12.4.  
8.3.2. 
Extension Period 
The following exploratory endpoints will be summarized by treatment group. The 
extension period baseline is defined as the last visit during the Placebo-controlled 
Treatment Period prior to the first dose of study drug in the Extension Period. The first 
four endpoints related to the percentage of days without heartburn will be summarized two 
ways, following the data handling methods for both Estimand 1 and Estimand 2; however, 
for subjects who prematurely discontinue treatment during the Extension Period, there will 
be no imputation of the percentage of days without daytime or nighttime heartburn after 
discontinuation. 
• The percentage of days without daytime or nighttime heartburn over the Extension 
Period as assessed by the daily diary 
• The percentage of days without nighttime heartburn over the Extension Period as 
assessed by the daily diary 
• The percentage of days without daytime heartburn over the Extension Period as 
assessed by the daily diary 
• The percentage of days without daytime or nighttime heartburn from Week 4 to 
Week 8 in subjects re-randomized at Week 4 from placebo to either vonoprazan 10 
mg or 20 mg 
• The mean severity of daytime and nighttime heartburn over the Extension Period as 
assessed by the daily diary 
• The mean severity of daytime heartburn over the Extension Period as assessed by 
the daily diary 
• The mean severity of nighttime heartburn over the Extension Period as assessed by 
the daily diary 
• The percentage of days without rescue antacid use over the Extension Period as 
assessed by the daily diary 
• The change from baseline to Week 12 and Week 24 of the Extension Period for 
each subscale and the total score of the PAGI-SYM questionnaire 
• The change from baseline to Week 12 and Week 24 of the Extension Period for 
each subscale and the total score of the PAGI-QoL questionnaire 


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• The change from baseline to Week 12 and Week 24 of the Extension Period for the 
EQ-5D-5L 
• The change from baseline to Week 12 and Week 24 of the Extension Period for 
each subscale and the total score of the N-GSSIQ 
• The change from baseline to Week 12 and Week 24 of the Extension Period for 
each subscale and the total score of the PSQI 
For subjects who received vonoprazan throughout the study, the following exploratory 
endpoints will be summarized by treatment group across the Placebo-controlled Treatment 
and Extension Period of the study. The first three endpoints related to the percentage of 
days without heartburn will be summarized two ways, following the data handling methods 
for both Estimand 1 and Estimand 2; however, for subjects who prematurely discontinue 
treatment during the Extension Period, there will be no imputation of the percentage of 
days without daytime or nighttime heartburn after discontinuation. 
• The percentage of days without daytime or nighttime heartburn over both 
Treatment Periods as assessed by the daily diary 
• The percentage of days without nighttime heartburn over both Treatment Periods as 
assessed by the daily diary 
• The percentage of days without daytime heartburn over both Treatment Periods as 
assessed by the daily diary 
• The mean severity of daytime and nighttime heartburn over both Treatment Periods 
as assessed by the daily diary 
• The mean severity of daytime heartburn over both Treatment Periods as assessed 
by the daily diary 
• The mean severity of nighttime heartburn over both Treatment Periods as assessed 
by the daily diary 
• The percentage of days without rescue antacid use over both Treatment Periods as 
assessed by the daily diary 
In addition, the percentage of subjects without daytime or nighttime heartburn by study 
day across the Placebo-controlled Treatment and Extension Period will be presented by 
treatment group in a figure. 
8.3.3. 
Follow-up Period 
The following exploratory endpoints will be summarized by treatment group. The first 
endpoint of the percentage of days without daytime or nighttime heartburn will be 
summarized following the data handling methods for both Estimand 1 and Estimand 2.: 
• The percentage of days without daytime or nighttime heartburn during the Follow-
up Period as assessed by the daily diary 
• The percentage of days without rescue antacid use over the Follow-up Period as 
assessed by the daily diary 


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9. SAFETY ANALYSIS 
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 all safety 
analyses, baseline for the Placebo-controlled Treatment Period will be the last available 
assessment prior to the first dose of study drug. Baseline for the Extension period will be 
the last available assessment on the last visit during the Placebo-controlled Treatment 
Period prior to the first dose of study drug in the Extension Period. 
All safety analyses will be conducted for each treatment group and overall using the Safety 
Set. 
9.1. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 23.0.  
A treatment-emergent AE (TEAE) is defined as any event that occurs after the first dose of 
study drug in a period, or any event at baseline that worsens in either intensity or frequency 
after the first dose of study drug in a period.  
For subjects who did not enter the Extension Period, any AE that starts after more than 30 
days of the last dose of study drug in the Placebo-controlled Treatment Period will not be 
counted as TEAE in the Placebo-controlled Treatment Period. For subjects who did enter 
the Extension Period, any AE that starts after more than 30 days of the last dose of study 
drug in the Extension Period will not be counted as TEAE in the Extension Period.  
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 following AE summaries will be presented separately, using the Safety Set, for the 
Placebo-controlled Treatment Period and Extension Period using the treatment groups 
indicated in Section 4. Summaries will also be presented for subjects who received 
vonoprazan throughout the study across both treatment periods.   
• An overall summary of the number of events and the number of subjects with 
TEAEs in each treatment group will be presented, including TEAEs, serious 
TEAEs, study drug related TEAEs, study drug related serious TEAEs, TEAEs 
leading to treatment discontinuation, and TEAEs leading to death. 
• The number and percentage of subjects with TEAEs will be summarized in the 
following ways:  


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- 
by primary system organ class, preferred term, and treatment group 
- 
by primary system organ class, preferred term, maximum severity, and 
treatment group 
- 
by primary system organ class, preferred term, relationship to study drug, 
and treatment group 
• The number and percentage of subjects with TEAEs related to study drug will be 
summarized in the following ways:  
- 
by primary system organ class, preferred term, and treatment group 
- 
by primary system organ class, preferred term, maximum severity, and 
treatment group 
• The most common TEAEs (≥5% of subjects in any treatment group) and TEAEs 
related to study drug (≥2% of subjects in any treatment group) will be presented by 
preferred term in descending frequency starting from the most common event. The 
criteria for most common TEAEs may be adjusted as appropriate based on the 
number of TEAEs reported. 
• The most common non-serious AEs (>5% of subjects in any treatment group) will 
be presented by primary system organ class, preferred term and treatment group. 
• The number and proportion of subjects as well as the number of events (except for 
deaths) with the following types of events will be summarized by primary system 
organ class, preferred term and treatment group: 
- 
Adverse events leading to treatment discontinuation 
- 
Serious Adverse Events (SAEs) 
- 
Deaths 
- 
Adverse events of special interest (AESI) 
- 
Adverse Events leading to study discontinuation 
All adverse events data will be listed using the Safety Set for the Placebo-controlled 
Treatment Period and for the Extension Period. All adverse events over the Follow-up Period 
will also be listed using the Safety Set.  
For each period, separate listings will also be provided for the following using the Safety 
Set: 
• Deaths 
• SAEs (including serious pretreatment events) 
• Adverse events leading to treatment discontinuation 
• Adverse events of special interest 
• Adverse Events leading to study discontinuation 
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 7 will be summarized by AESI category, primary system 


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organ class and preferred term for each treatment group and overall. The search criteria 
that will be used to identify AESIs are specified in the table.  
 
Table 7. Adverse Events of Special Interest – Search Criteria 
Adverse Event of Special Interest 
Search Criteria 
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) 
Severe cutaneous adverse reactions 
• 
Severe cutaneous adverse reactions SMQ (Narrow) 
Clostridium difficile infections  
• 
Pseudomembranous colitis SMQ (Narrow) 
Gastric Cancer 
Gastric Neoplasms Malignant MedDRA High Level Term  
Bone fracture 
Bone Fracture Custom Query (PTs defined below) 
Acetabulum fracture      
Ilium fracture 
Ankle fracture  
                  Impacted fracture 
Atypical femur fracture  
Jaw fracture  
Atypical fracture  
                  Limb fracture  
Avulsion fracture  
                  Lower limb fracture 
Bone fissure  
                  Lumbar vertebral fracture 
Bone fragmentation                   Metaphyseal corner fracture 
Chance fracture  
                  Multiple fractures 
Clavicle fracture  
                  Open fracture 
Comminuted fracture      
Osteoporotic fracture 
Complicated fracture      
Patella fracture 
Compression fracture      
Pathological fracture 
Craniofacial fracture      
Pelvic fracture 
Epiphyseal fracture      
Pubis fracture 
Facial bones fracture      
Radius fracture 
Femoral neck fracture  
Rib fracture 
Femur fracture  
                  Sacroiliac fracture 
Fibula fracture  
                  Scapula fracture 
Foot fracture  
                  Skull fracture 
Forearm fracture  
                  Skull fractured base 
Fracture                                   Spinal compression fracture 
Fracture blisters  
                  Spinal fracture 
Fracture displacement  
Spinal fusion fracture 
Fracture malunion  
                  Sternal fracture 
Fracture nonunion  
                  Stress fracture 
Fracture of clavicle         
Subchondral insufficiency  
   due to birth trauma                       fracture 
Fractured coccyx  
                  Thoracic vertebral fracture 
Fractured ischium  
                  Tibia fracture 
Fractured sacrum                          Torus fracture                
Fractured skull depressed           Traumatic fracture   
Greenstick fracture                     Ulna fracture 
Hand fracture                              Upper limb fracture  
Hip fracture                                 Wrist fracture     
Humerus fracture                             
MedDRA: Medical Dictionary for Regulatory Activities; PT: preferred term; SMQ: Standardized MedDRA Queries. 
9.2. 
Clinical Laboratory Evaluations 
Descriptive statistics for clinical laboratory values (hematology, chemistry and urinalysis 
laboratory tests; in SI units and in US conventional units) and serum gastrin and 
pepsinogen I, pepsinogen II, and pepsinogen I/II ratio will be presented by treatment group 


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and overall for each period. Changes from baseline will also be presented for quantitative 
variables by treatment group and overall for each period. For categorical variables (ie, 
normal or abnormal findings, or qualitative clinical laboratory tests), shift tables for the 
change from baseline to each post-baseline time point will be presented by treatment group 
and overall for each treatment period.  
For each period, the number and percentage of subjects with at least one post-baseline 
serum gastrin value >500 ng/L and >1000 ng/L and with the test value higher 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. 
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, 
if available, will be presented by treatment group and overall. A supportive listing of 
subjects with such post-baseline elevations will be provided including the subject ID, 
baseline, and post-baseline values. 
• ALT > 3xULN 
• ALT > 5xULN 
• ALT > 10xULN 
• ALT > 3xULN and Total Bilirubin > 2xULN 
• AST > 3xULN 
• AST > 5xULN 
• AST > 10xULN 
• AST > 3xULN and Total Bilirubin > 2xULN 
• Total Bilirubin > 2xULN 
• AST > 3xULN or ALT > 3xULN 
• AST > 5xULN or ALT > 5xULN 
• AST > 10xULN or ALT > 10xULN 
• (AST > 3xULN or ALT > 3xULN) and Total Bilirubin > 2xULN 
• AST > 3xULN and ALT > 3xULN 
• AST > 5xULN and ALT > 5xULN 
• AST > 10xULN and ALT > 10xULN 
• AST > 3xULN and ALT > 3xULN and Total Bilirubin > 2xULN 
• Alkaline phosphatase > 1.5xULN 
• ALT > 3xULN and Alkaline phosphatase > 1.5xULN 
• AST > 3xULN and Alkaline phosphatase > 1.5xULN 
• Alkaline phosphatase > 3xULN 
• ALT > 3xULN and Alkaline phosphatase > 3xULN 
• AST > 3xULN and Alkaline phosphatase > 3xULN 


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All other laboratory parameters that correspond to FSH, serum HCG pregnancy test, 
serology (HIV antibody, HBsAg, and HCV antibody, hepatitis C viral load RNA 
[qualitative]), and urine drug screen including amphetamines (including 
methamphetamine), barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, 
methadone, and phencyclidine will be listed for the Safety Set. 
9.3. 
Vital Sign Measurements 
For each period, descriptive statistics for vital signs, including body temperature, systolic 
blood pressure, diastolic blood pressure and pulse rate, will be presented by treatment 
group and overall. Changes from baseline will also be presented by treatment group and 
overall. 
Abnormal vital sign values are defined as vital sign values that meet one of the criteria 
listed below. 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 by treatment group and overall. A supportive listing of subjects 
with such abnormal values will be provided including the subject ID, baseline, and post-
baseline values. 
• Systolic blood pressure (mmHg):  
o <50 
o >180 
• Diastolic blood pressure (mmHg):  
o <50 
o >100 
• Heart rate (bpm): 
o <50 
o >120 
9.4. 
Physical Examination 
All data collected from the physical examinations assessments must be available in the 
source documents but will not be added to the analysis database. 
9.5. 
Electrocardiogram 
Descriptive statistics for ECG parameters, including heart rate, RR interval, PR interval, 
QT interval, QTc Fridericia (QTcF), and QRS interval, will be presented by treatment 
group and overall for each period. All ECG assessment values and interpretations will be 
listed for all subjects in the Safety Set. Changes from baseline will also be presented for 
quantitative variables by treatment group and overall for each period.  


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For ECG interpretations (within normal limits, abnormal but not clinically significant, or 
abnormal and clinically significant), shift tables for the change from baseline to each post-
baseline time point will be presented by treatment group and overall.  
Abnormal QTcF values are defined as ECG values that meet at least one of the criteria 
listed below. The number and percentage of subjects with at least one of the post-baseline 
abnormal values and with post-baseline value higher than baseline value, if available, will 
be presented by treatment group and overall for each period. A supportive listing of 
subjects with such post-baseline elevations will be provided including the subject ID, 
baseline, and post-baseline values. 
• 
Absolute QTcF interval prolongation: 
o QTc interval > 450 
o QTc interval > 480  
o QTc interval > 500  
• Change from baseline in QTcF interval: 
o QTc interval increases from baseline >30  
o QTc interval increases from baseline >60 
o QTc interval > 450 with increase from baseline >30  
10. INTERIM ANALYSIS/OTHER ANALYSES 
10.1. 
Interim Analysis 
An analysis of the Placebo-controlled Treatment Period data may be performed after all 
subjects have completed the Placebo-controlled Treatment Period. The data for the 
Placebo-controlled Treatment Period would be locked and the blind broken to perform this 
analysis. This analysis would be conducted after all randomized subjects have completed 
the Placebo-controlled Treatment Period and no changes to the conduct of the Extension 
Period would be made based on the results from the Placebo-controlled Treatment Period.  
Following the interim analysis, Phathom and PPD would be unblinded to the treatment 
assignment of individual subjects during the Placebo-controlled Treatment Period to 
perform this analysis. The treatment assignment would remain blinded to the investigative 
site. 
10.2. 
Coronavirus Pandemic 
In accordance with guidance issued by regulatory agencies, study data collection will 
document missed/delayed visits due to COVID-19-related reasons and assessments 
completed via alternative method due to COVID-19-related reasons. 
The COVID-19 impact on individual subjects collected on the COVID-19 eCRF pages will 
be listed for the Randomized Set. Protocol deviations related to COVID-19 will be marked 
in the protocol deviation listing for the Randomized Set. COVID-19 infection history and 
vaccine information will also be listed for the Randomized Set. 


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The anticipated impact of COVID-19 is widely regarded as unknown. If the impact of 
COVID-19 on the conduct of this study is observed to be significant, further summaries 
and listings of the impact will be explored. 
11. REFERENCES 
1. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh sleep 
quality index: A new instrument for psychiatric practice and research. Ireland: 
Elsevier Ireland Ltd Psychiatry research, 1989; 28(2): 193-213. 
 
2. Spiegel BM, Roberts L, Mody R, Harding G, Kothari-Talwar S, Kahrilas PJ, 
Camilleri ML, Dabbous O, Revicki DA. The development and validation of a 
Nocturnal Gastro-oesophageal Reflux Disease Symptom Severity and Impact 
Questionnaire for adults. Alimentary Pharmacology and Therapeutics, 2010; 32(4): 
591-602. 
12. APPENDICIES 
 








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e 
If menopause is suspected and is required only for confirmation of postmenopausal females as defined in Section 13.2 of the protocol. 
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.  
f 
Performed after the subjects have been free from antibiotics and bismuth for ≥4 weeks and free from proton pump inhibitors and 
histamine-2 receptor antagonists for ≥2 weeks. The test will be performed locally, using an approved testing method as per local standard 
of care. 
g 
See Section 6.3.3 of the protocol for all required laboratory assessments. Glucose should be obtained after an 8-hour fast at Visit 1 and at 
any unscheduled visit.  
h 
Gastrin results at Visit 2 will not be blinded and will be reported to investigative sites. Gastrin at Visits 4, 6, 9, 10 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.  
i 
Only female subjects with childbearing potential.   
j 
Subjects should be instructed to complete the electronic diary every morning upon waking (for nighttime symptoms) and every evening 
before bedtime (for daytime symptoms) on each day of the study during all periods. Subjects (including screen failures) are expected to 
promptly return the electronic diary to the investigational site upon completion/termination from the study.  
k 
The Screening endoscopy can be performed any time during the Screening Period (Day -35 to Day -2); however, it should be performed 
after the subject has fulfilled Inclusion Criterion 6 (ie, heartburn reported on 4 or more days during any consecutive 7-day period of the 
Screening Period as recorded in the electronic diary).  
l 
Following completion of the Placebo-controlled Treatment Period at Week 4, all subjects will be assigned study drug for the Extension 
Period by the interactive response technology system. Subjects randomized to placebo during the Placebo-controlled Treatment Period 
will be re-randomized to receive vonoprazan 10 mg or vonoprazan 20 mg once daily for the 20-week Extension Period. Subjects 
randomized to 1 of the 2 vonoprazan treatment groups during the Placebo-controlled Treatment Period will continue to receive the same 
vonoprazan dose during the Extension Period. The first dose of study drug for the Extension Period will be taken the day after the Week 4 
visit. The first dose of study drug for the Extension Period will be taken the day after the Week 4 visit. 
 
 


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12.2. 
Imputation Rules for Missing Date Information 
12.2.1. 
Rules for Concomitant Medication Start Date Imputation 
The following rules will be applied to impute the missing (numerical) start dates. 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. 
If the start date is completely missing or the year of the start date is missing, then the start 
date will be imputed as the date of the first dose of study drug. 
Missing day and month 
• If the year of the partial start date is the same year as 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 used to impute the missing day and month. 
• If the year of the partial start date is before the year of the date of the first dose of 
study drug, then the missing month and day will be imputed as December 31. 
• If the year of the partial start date is after the year of the date of the first dose of 
study drug, then the missing month and day will be imputed as January 01. 
Missing month only 
If only the month of the partial date is provided, then the day will also be treated as 
missing, and the rules above will be applied.  
Missing day only 
• If the month and year of the partial 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 used to impute the missing day. 
• If the year of the partial date is same as the year of the date of the first dose of 
study drug but the month of the partial date is before the month of the date of the 
first dose of study drug or if the year of the partial date is before the year of the 
date of the first dose of study drug, then the missing day will be imputed as the last 
day of the month. 
• If the year of the partial date is same as the year of the date of the first dose of 
study drug but the month of the partial date is after the month of the date of the 
first dose of study drug or if the year of the partial date is after the year of the date 
of the first dose of study drug, then the missing day will be imputed as the first day 
of the month. 
12.2.2. 
Rules for Concomitant Medication End Date Imputation 
The following rules will be applied to impute the missing (numerical) end dates. If the date 
of the last dose of study drug is missing, then the last visit date will be used instead. If the 


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imputed stop date is before the start date (either imputed or non-imputed), then the stop 
date will be set to be the same as the start date. 
Missing day and month 
• If the year of the partial stop date is the same year as 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 
used to impute the missing day and month. 
• If the year of the partial stop date is before the year of the date of the last dose of 
study drug, then the missing month and day will be imputed as December 31. 
• If the year of the partial start date is after the year of the date of the last dose of 
study drug, then the missing month and day will be imputed as January 01. 
Missing month only 
If only the month of the partial date is provided, then the day will also be treated as 
missing, and the rules above will be applied.  
Missing day only 
• If the month and year of the partial 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 used to impute the missing day. 
• If the year of the partial date is the same as the year of the date of the last dose of 
study drug but the month of the partial date is before the month of the date of the 
last dose of study drug or if the year of the partial date is before the year of the 
date of the last dose of study drug, then the missing day will be imputed as the last 
day of the month. 
• If the year of the partial date is the same as the year of the date of the last dose of 
study drug but the month of the partial date is after the month of the date of the last 
dose of study drug or if the year of the partial date is after the year of the date of 
the last dose of study drug, then the missing day will be imputed as the first day of 
the month. 
12.2.3. 
Rules for AE Start Date Imputation 
For AEs, incomplete (ie., partially missing) start dates will be imputed in the same manner 
as described in Section 12.2.1. Partial stop dates will not be imputed. 
12.3. 
Morning and Evening Diary 
12.3.1. 
Diary Data Handling 
Subjects will document the presence (yes/no) and maximum severity (1=Mild, 
2=Moderate, 3=Severe, or 4=Very Severe; definitions provided in table below) of daytime 
and nighttime heartburn symptoms and use of rescue antacid (yes/no) twice daily in their 
diary.  
 


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Table 8. Definitions of Heartburn Severity (Daytime/Nighttime)  
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 electronic diary is completed every morning upon waking to record the previous 
evening's maximum heartburn severity rating, and every evening before bedtime to record 
that day's maximum heartburn severity rating. Thus, for analysis purposes, the diary entries 
will be assigned to a study day based on the start of the collection interval in which the 
collection interval consists of an evening entry for the daytime and a morning entry for the 
nighttime. For example, the diary entries for Day 1 would include the evening diary 
completed on Day 1 and the morning diary completed on Day 2, the diary entries for Day 2 
would include the evening diary completed on Day 2 and the morning diary completed on 
Day 3, and so on. If the presence of heartburn is answered as “no” in a diary, the question 
of maximum severity will not be answered, and the maximum severity will be considered 
as 0 (0=None) in the analysis. Only evening diaries will be used for assessing daytime 
heartburn, and only morning diaries will be used for assessing nighttime heartburn. 
 
12.3.2. 
Derivation of Severity of Heartburn Exploratory Endpoints 
For each period, the mean severity of daytime and nighttime heartburn will be obtained by 
taking the mean of the daily average maximum severity across all days that have at least 
one morning or evening diary entry. The daily average maximum severity will be obtained 
by first identifying separately the highest recorded severity across morning entries and 
across evening entries within the day, then taking the average of the morning maximum 
severity and evening maximum severity.  
For each period, the mean severity of daytime heartburn will be obtained by first 
identifying the highest recorded severity across evening diary entries within a day for all 
the days within a period. Then the average of the severity across all days with at least one 
evening diary entry within a period will be obtained. Similarly, the mean severity of 
nighttime heartburn will be obtained by first identifying the highest recorded severity 
across morning diary entries within a day for all the days within a period. Then the average 
of the severity across all days with at least one morning diary entry within a period will be 
obtained. 


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12.3.3. 
Sustained Resolution of Heartburn 
Sustained resolution of heartburn will be defined as at least seven consecutive days with no 
daytime or nighttime heartburn during a particular period. The seven consecutive days 
should have at least one diary entry (either morning only, evening only, or both). Thus, 
seven consecutive days of missing diary data will not count as sustained resolution of 
heartburn.  
The time to sustained resolution of heartburn is defined as the time to the first occurrence 
of sustained resolution, specifically the time from the first dose of study drug to the first 
day of the first onset of seven consecutive days with no daytime or nighttime heartburn 
within a period. Subjects who do not achieve sustained resolution of heartburn will be 
censored on the first day of the last sequence of seven days during the period. To illustrate, 
for a subject who does not have sustained resolution of heartburn and has the last diary 
entry on Day 28, the last sequence of seven days would be Day 22 to Day 28 and thus, the 
censoring time would be Day 22. Subjects who prematurely discontinue the study before 
they have completed at least 7 days of the diary will be censored at Day 1. 
12.4. 
Questionnaire Scoring 
12.4.1. 
PAGI-SYM Questionnaire 
The PAGI-SYM questionnaire includes questions that ask about the severity of symptoms 
the subject may have related to his/her gastrointestinal problem. The questionnaire consists 
of 20 items, each with response options based on a 6-point Likert scale (0=None, 1=Very 
Mild, 2=Mild, 3=Moderate, 4=Severe, 5=Very Severe) and with a recall period of the 
previous 2 weeks. The items are grouped into 6 subscales and a total score, which are 
described below.  


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PAGI-SYM Subscale 
Items on PAGI-SYM eCRF 
Nausea/Vomiting 
Question 1: Nausea 
Question 2: Retching 
Question 3: Vomiting 
Fullness/Early Satiety 
Question 4: Stomach fullness 
Question 5: Not able to finish a normal-sized meal 
Question 6: Feeling excessively full after meal 
Question 7: Loss of appetite 
Bloating 
Question 8: Bloating  
Question 9: Stomach or belly visibly larger 
Upper Abdominal Pain 
Question 10: Upper abdominal pain  
Question 11: Upper abdominal discomfort 
Lower Abdominal Pain 
Question 12: Lower abdominal pain  
Question 13: Lower abdominal discomfort 
Heartburn/Regurgitation 
Question 14: Heartburn during the day 
Question 15: Heartburn when lying down 
Question 16: Feeling of discomfort inside chest during the day  
Question 17: Feeling of discomfort inside chest at night 
Question 18: Regurgitation or reflux during the day 
Question 19: Regurgitation or reflux during when lying down 
Question 20: Bitter, acid or sour taste in mouth 
PAGI-SYM Total Score 
Mean of PAGI-SYM Subscale Scores 
 
The subscale scores are obtained by taking the average of the responses on the 
corresponding non-missing items for each subscale. If there are missing responses for 
items within a subscale, the half-scale rule will be implemented, that is, the subscale score 
will only be calculated if the rate of missing items is at most 50%. Otherwise, the subscale 
score will be set to missing. The PAGI-SYM total score is calculated by taking the mean of 
the subscale scores. If at least one subscale score is missing, the total score will be set to 
missing. Higher scores indicate worse symptoms. Thus, a negative change from baseline 
for a score indicates improvement.  
12.4.2. 
PAGI-QoL Questionnaire 
The PAGI-QoL questionnaire includes questions that ask about how some of the 
gastrointestinal problems the subject may have experienced may have affected his/her 
quality of life. The questionnaire consists of 30 items, each with response options based 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, 5=All of the time) and with a recall period of the 
previous 2 weeks. The items are grouped into 5 subscales and a total score which are 
described below.  


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PAGI-QoL Subscale 
Items on PAGI-QoL eCRF 
Daily Activities 
Question 1: depending on others to do daily activities 
Question 2: avoided performing daily activities 
Question 3: difficulty concentrating 
Question 4: longer than usual to perform daily activities 
Question 5: felt tired 
Question 6: lost desire to participate in social activities 
Question 7: worried about having stomach symptoms in public 
Question 8: avoided performing physical activities or sports 
Question 9: avoided traveling 
Question 10: felt frustrated about not being able to do what one wanted to do 
Clothing 
Question 11: felt constricted in the clothes one is wearing 
Question 12: felt frustrated about not being able to dress as wanted to  
Diet and Food Habits 
Question 13: felt concerned about what can and cannot eat  
Question 14: avoided certain types of foods 
Question 15: restricted eating at restaurant or at someone’s home 
Question 16: felt less enjoyment in food than usual 
Question 17: felt concerned that change of food habits could trigger symptoms 
Question 18: felt frustrated about not being able to choose the wanted food  
Question 19: felt frustrated about not being able to choose wanted type of 
beverage  
Relationship 
Question 20: relationship with spouse or partner been disturbed  
Question 21: relationship with children or relatives been disturbed 
Question 22: relationship with friends been disturbed 
Psychological  
Well-being and Distress 
Question 23: been in bad mood  
Question 24: felt depressed 
Question 25: felt anxious 
Question 26: felt angry 
Question 27: felt irritable 
Question 28: felt discouraged 
Question 29: been stressed 
Question 30: felt helpless 
PAGI-QoL Total Score 
Mean of PAGI-QoL Subscale Scores 
 
The subscale scores are obtained by taking the average of the responses on the 
corresponding non-missing items for each subscale after reversing the item scores. If there 
are missing responses for items within a subscale, the half-scale rule will be implemented, 
that is, the subscale score will only be calculated if the rate of missing items is at most 
50%. Otherwise, the subscale score will be set to missing. The PAGI-QoL total score is 
calculated by taking the mean of the subscale scores. If at least one subscale score is 
missing, the total score will be set to missing. A positive change from baseline score 
indicates improved quality of life.  


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12.4.3. 
EQ-5D-5L Questionnaire 
The EQ-5D-5L is a standardized instrument developed by the EuroQol Group as a measure 
of health-related quality of life. The EQ-5D-5L consists of a descriptive system and a 
visual analogue scale. The descriptive system comprises 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. The visual analogue scale records 
the subject’s self-rated health on a vertical scale (0 to 100). 
The EQ-5D-5L will be converted into a single index value. The summary index can be 
derived from the EQ-5D-5L descriptive system and using the crosswalk link function of 
the US value sets. Documents containing information on the crosswalk project, tables for 
values for all 3125 health states and the EQ-5D-5L Crosswalk Index Value Calculator can 
be downloaded from the EuroQol website. The EQ-5D-5L index score is on a scale from 0 
(worst imaginable health state) to 1 (best imaginable health state). 
12.4.4. 
PSQI Questionnaire 
The PSQI1 is a self-reported questionnaire which assesses sleep quality and disturbances 
over a 1-month recall period. The PSQI has 19 self-rated items organized into 7 subscales, 
each of which has a range of 0 to 3 points. The subscale measures consist of subjective 
sleep quality, sleep latency (how long it takes to fall asleep), sleep duration, habitual sleep 
efficiency (the percentage of time in bed that one is asleep), sleep disturbances, use of 
sleeping medication, and daytime dysfunction. The 7 subscale scores are then added to 
produce a global score. Overall scores range from 0 to 21 with a lower score indicating 
better sleep quality. The subscales and global scores are described below: 


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PSQI Subscale 
Items on PSQI eCRF 
Rule 
Subscale score 
Sleep quality 
Question 6: sleep quality overall 
Assign score as: 
“very good” = 0 
“fairly good” = 1 
“fairly bad” = 2 
“very bad” = 3 
Score of Question 6 
Sleep latency 
Question 2: how long (in minutes) 
usually taken to fall asleep each night 
Assign score as: 
≤15 minutes = 0 
16-30 minutes = 1 
31-60 minutes = 2 
>60 minutes =3 
Assign subscale score 
based on sum of 
Questions 2 and 5a as: 
Sum is 0 = 0 
Sum is 1-2 = 1 
Sum is 3-4 = 2 
Sum is 5-6 = 3 
Question 5a: cannot get to sleep within 
30 minutes 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three of more times a week” = 3 
Sleep duration 
Question 4: hours of actual sleep get at 
night 
 
Assign score as follows: 
≥7 hours = 0 
≥6-<7 hours = 1 
≥5-<6 hours = 2 
<5 hours = 3 
Score of Question 4 
Habitual sleep 
efficiency 
Question 4: hours of actual sleep get at 
night 
Question 3: time usually gotten up in 
the morning 
Question 1: time usually gone to bed at 
night 
- Calculate “number of hours 
spent in bed” from Question 3 
and Question 1 
- Calculate 
“habitual sleep efficiency (%)” = 
(no. of hours slept / no. of hours 
spent in bed) × 100 
Assign subscale score 
based on “habitual sleep 
efficiency (%)” as: 
>85% = 0 
75-84% = 1 
65-74% = 2 
<65% = 3 
Sleep disturbances 
Question 5b: wake up in the middle of 
night or early morning 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three or more times a week” = 3 
Assign subscale score 
based on sum of 
Questions 5b, 5c, 5d, 
5e, 5f, 5g, 5h, 5i, 5j as: 
Sum is 0 = 0 
Sum is 1-9 = 1 
Sum is 10-18 = 2 
Sum is 19-27 = 3 
Question 5c: have to get up to use the 
bathroom 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three or more times a week” = 3 
Question 5d: cannot breathe 
comfortably 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three or more times a week” = 3 
Question 5e: cough or snore loudly 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three or more times a week” = 3 


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Question 5f: feel too cold 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three or more times a week” = 3 
Question 5g: feel too hot 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three or more times a week” = 3 
Question 5h: had bad dreams 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three or more times a week” = 3 
Question 5i: have pain 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three or more times a week” = 3 
Question 5j: other reason(s) 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three or more times a week” = 3 
 
If comment is null or Question 5j is 
null, assign a score of 0 
Use of sleeping 
medication 
Question 7: how often have taken 
medicine to help sleep 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three or more times a week” = 3 
Score of Question 7 
Daytime dysfunction Question 8: how often have trouble 
staying awake while driving, eating 
meals, or engaging in social activity 
Assign score as: 
“not during the past month” = 0 
“less than once a week” = 1 
“once or twice a week” = 2 
“three or more times a week” = 3 
Assign subscale score 
based on sum of 
Questions 8 and 9 as: 
Sum is 0 = 0 
Sum is 1-2 = 1 
Sum is 3-4 = 2 
Sum is 5-6 = 3 
Question 9: how much problems has it 
been to keep enough enthusiasm to get 
things done 
Assign score as: 
“no problem at all” = 0 
“only a very slight problem” = 1 
“somewhat of a problem” = 2 
“a very big problem” = 3 
PSQI Total Score 
Sum of PSQI Subscale Scores 
 
 
If response is missing to any of the questions 1 through 9 (except for 5j), then the 
corresponding subscale score that is calculated using the missing response will be set to 
missing. Moreover, the PSQI total score will also be set to missing. 


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12.4.5. 
N-GSSIQ Questionnaire 
The N-GSSIQ2 is a validated instrument to assess the severity and impact of nocturnal 
GERD symptoms over the past 2 weeks. The questionnaire is comprised of 20 items 
covering 3 subscales: Nocturnal GERD Symptom Severity (13 items; score range of 0 to 
65), Morning Impact of Nocturnal GERD (2 items; score range of 0 to 10), and Concern 
about Nocturnal GERD (5 items; score range of 0 to 20). The subscale scores are 
calculated as the sum of the corresponding items for the subscale. If there are missing 
responses for items within a subscale, the half-scale rule will be implemented, that is, the 
subscale score will only be calculated if the rate of missing items is at most 50% in which 
the missing item’s score will be set to the average of the non-missing item scores. The total 
N-GSSIQ score is calculated as the mean of the subscale scores for the Nocturnal GERD 
Symptom Severity and Morning Impact of Nocturnal GERD only with higher scores 
representing greater severity of symptoms, greater symptom impact, and greater concern. If 
either the subscale score for the Nocturnal GERD Symptom Severity or subscale score for 
Morning Impact of Nocturnal GERD is missing, the total N-GSSIQ score will be set to 
missing. Details of the subscale and total score are provided below: 
 
N-GSSIQ Subscale 
Items on N-GSSIQ eCRF 
Nocturnal GERD 
Symptom Severity 
Question 1: Heartburn after going to bed at night 
Question 2: Regurgitation or reflux after going to bed at night 
Question 3: Nausea after going to bed at night 
Question 4: Burping or belching after going to bed at night 
Question 5: Feeling of discomfort inside chest after going to bed at night 
Question 6: Difficulty swallowing back liquid after going to bed at night 
Question 7: Bubbling or gurgling in the throat after going to bed at night 
Question 8: Gagging or choking feeling in the throat after going to bed at night  
Question 9: Waking up with food or liquid in the mouth during the night 
Question 10: Pain or burning in the stomach, chest or throat upon awakening in 
the morning 
Question 11: Trouble falling asleep because of your heartburn/reflux 
Question 12: Wake up at night because of heartburn/reflux 
Question 13: Go to bed later than would have liked because of heartburn/reflux 
Morning Impact of 
Nocturnal GERD 
Question 14: Wake up in the morning feeling tired  
Question 15: Wake up in the morning feeling irritable 
Concern about Nocturnal 
GERD 
Question 16: Something serious may be wrong because of heartburn/reflux after 
going to bed at night 
Question 17: Heartburn/reflux after going to bed at night may result in serious 
damage to the throat or stomach 
Question 18: Heartburn/reflux could get worse at night 
Question 19: Must carefully watch what to eat before bedtime because of 
heartburn/reflux 
Question 20: Heartburn/reflux after going to bed at night impacts everyday life  
N-GSSIQ Total Score 
Mean of Nocturnal GERD Symptom Severity and Morning Impact of Nocturnal 
GERD Subscale Scores 
 


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12.5. 
Estimands and Sensitivity/Supplementary Analysis 
 
Table 9. Summary of Statistical Methods and Sensitivity Analyses 


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Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity/Supplementary Analysis 
Analysis 
Set 
Imputation/Data/Censo
ring Rules 
Analysis Model/Method 
Estimand 1 
(Primary) 
Difference in the mean 
percentage of days without 
daytime or nighttime 
heartburn over the Placebo-
controlled Treatment Period 
between each dose of 
vonoprazan and placebo 
(10mg QD – placebo and 
20mg QD - placebo) in 
subjects with NERD, where a 
heartburn-free day is a day for 
which all entries are 
heartburn-free with no use of 
rescue antacid, H2RAs, and 
PPIs and assuming the 
percentage of heartburn-free 
days after treatment 
discontinuation is the 
percentage of heartburn-free 
days during the screening 
period, irrespective of rescue 
antacid, H2RAs, and PPIs 
used after treatment  
discontinuation. 
 
 
ITT [1] 
See Section 8.1.2.  
The point estimate and 2-
sided 95% CI of the 
difference in mean 
percentage of days without 
daytime or nighttime 
heartburn over the Placebo-
controlled Treatment Period 
between each dose of 
vonoprazan and placebo (10 
mg QD – placebo and 20 mg 
QD - placebo) will be 
obtained through a linear 
contrast of the least square 
(LS) means comparing the 
mean percentage of days 
without daytime or nighttime 
heartburn over the Placebo-
controlled Treatment Period 
for each vonoprazan dose 
with placebo using the 
general linear model with 
treatment group as factor, and 
severity and frequency of 
heartburn at baseline as 
covariates. 
1. Nonparametric test (i.e., 
Wilcoxon rank-sum test) 
2. Same as the primary analysis 
but the percentage of days 
without daytime or nighttime 
heartburn irrespective of use of 
rescue antacid, H2RAs, or 
PPIs over the Placebo-
controlled Treatment Period 
will be calculated.  
3. Imputation of missing data due 
to any reason. The days after 
treatment discontinuation will 
be imputed as having 
heartburn on those days. Also, 
days with missing diary entries 
prior to treatment 
discontinuation (either no 
entries on the day, or with only 
one diary entry on the day) 
will be imputed as having 
heartburn on those days. 


Phathom Pharmaceuticals, Inc. 
Statistical Analysis Plan, Version 1.0 
NERD-301 
 
Date Issued: 29Sep2022 
 
 
 
58 
Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity/Supplementary Analysis 
Analysis 
Set 
Imputation/Data/Censo
ring Rules 
Analysis Model/Method 
Estimand 2 
(Primary 
Supportive) 
Difference in the mean 
percentage of days without 
daytime or nighttime 
heartburn over the Placebo-
controlled Treatment Period 
as assessed by the daily diary 
between each dose of 
vonoprazan and placebo 
(10mg QD – placebo and 
20mg QD - placebo) in 
subjects with NERD whose 
response to treatment is of 
interest only while on study 
drug, i.e., prior to study drug 
discontinuation due to any 
reason and irrespective of 
excluded/rescue medications 
and treatments.   
 
ITT [1] 
See Section 8.1.6.  
The point estimate and 2-
sided 95% CI of the 
difference in mean 
percentage of days without 
daytime or nighttime 
heartburn over the Placebo-
controlled Treatment Period 
between each dose of 
vonoprazan and placebo 
(10mg QD – placebo and 
20mg QD - placebo) will be 
obtained through a linear 
contrast of the least square 
(LS) means comparing the 
mean percentage of days 
without daytime or nighttime 
heartburn over the Placebo-
controlled Treatment Period 
for each vonoprazan dose 
with placebo using the 
general linear model with 
treatment group as factor, and 
severity and frequency of 
heartburn at baseline as 
covariates. 
 
 
 
 
 
 
 
 
 


Phathom Pharmaceuticals, Inc. 
Statistical Analysis Plan, Version 1.0 
NERD-301 
 
Date Issued: 29Sep2022 
 
 
 
59 
Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity/Supplementary Analysis 
Analysis 
Set 
Imputation/Data/
Censoring Rules 
Analysis Model/Method 
Estimand 3  
(Secondary) 
Difference in the percentage 
of days without rescue 
antacid use over the 
Placebo-controlled 
Treatment Period as 
assessed by the daily diary 
between each dose of 
vonoprazan and placebo 
(10mg QD – placebo and 
20mg QD - placebo) in 
subjects with NERD whose 
response to treatment is of 
interest only while on study 
drug, i.e., prior to study 
drug discontinuation due to 
any reasons and irrespective 
of excluded (non-rescue) 
medications and treatments.   
 
ITT [1] 
See Section 8.2.  
The point estimate and 2-sided 
95% CI of the difference in mean 
percentage of days without rescue 
antacid use over the Placebo-
controlled Treatment Period 
between each dose of vonoprazan 
and placebo (10mg QD – placebo 
and 20mg QD - placebo) will be 
obtained through a linear contrast 
of the least square (LS) means 
comparing the mean percentage of 
days without rescue antacid use 
over the Placebo-controlled 
Treatment Period for each 
vonoprazan dose with placebo 
using the general linear model with 
treatment group as factor, and 
severity and frequency of 
heartburn at baseline as covariates. 
 
 
 
 
 
 
 
Abbreviation: ITT = Intent-to-treat; NERD = Non-Erosive Gastroesophageal Reflux Disease.  
Refer to Table 4 for specific intercurrent event definitions.  
[1] ITT set for the Placebo-controlled Treatment Period will be defined as all subjects randomized into the Placebo-controlled Treatment Period who receive at 
least one dose of study drug during the Placebo-controlled Treatment Period.