Conditions: Gastroesophageal Reflux
Keywords: Vonoprazan Gastroesophageal Reflux GERD Adolescents Pharmacokinetics
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the pharmacokinetic profile of vonoprazan in adolescent participants with symptomatic gastroesophageal reflux disease (GERD).

Detailed description:
This clinical trial information was submitted voluntarily under the applicable law and, therefore, certain submission deadlines may not apply. (That is, clinical trial information for this applicable clinical trial was submitted under section 402(j)(4)(A) of the Public Health Service Act and 42 CFR 11.60 and is not subject to the deadlines established by sections 402(j)(2) and (3) of the Public Health Service Act or 42 CFR 11.24 and 11.44.).

Arms:
arm 1: Participants will receive vonoprazan 10 mg once daily for 14 days. arm 2: Participants will receive vonoprazan 20 mg once daily for 14 days.

Interventions: intervention 1: Vonoprazan
Intervention descriptions: intervention 1: Oral Tablet

Protocol document:
Prot_000.pdf: 
Protocol Number: VPED-102 
Official Title: A Phase 1, Randomized, Parallel-group, Open-label, Multicenter Study to Evaluate 
the Pharmacokinetics, Pharmacodynamics and Safety of Vonoprazan (10 or 20 mg Once Daily) in 
Adolescents with Symptomatic Gastroesophageal Reflux Disease 
NCT Number: NCT05343364
Document Date: 16 September 2022 




Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 2 
Protocol Approval – Sponsor Signatory 
Study Title 
A Phase 1, Randomized, Parallel-group, Open-label, Multicenter Study to 
Evaluate the Pharmacokinetics, Pharmacodynamics and Safety of 
Vonoprazan (10 or 20 mg Once Daily) in Adolescents with Symptomatic 
Gastroesophageal Reflux Disease 
Protocol Number 
VPED-102 
Protocol Version 
and Date 
Version 3.0 
14 September 2022 
 
 
 




Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 4 
Protocol Approval – Principal/Coordinating Investigator 
Study Title 
A Phase 1, Randomized, Parallel-group, Open-label, Multicenter 
Study to Evaluate the Pharmacokinetics, Pharmacodynamics and 
Safety of Vonoprazan (10 or 20 mg Once Daily) in Adolescents with 
Symptomatic Gastroesophageal Reflux Disease 
Protocol Number VPED-102 
Protocol Version 
and Date 
Version 3.0 
14 September 2022 
 
Protocol accepted and approved by: 
Principal/Coordinating Investigator 
 
 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
14-Sep-2022


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 5 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 1, Randomized, 
Parallel-group, Open-label, Multicenter Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics and Safety of Vonoprazan (10 or 20 mg Once Daily) in Adolescents with 
Symptomatic Gastroesophageal Reflux Disease” and the accompanying investigator’s 
brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 3.0, dated 14 September 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 Board 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: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 6 
Summary of Changes 
Protocol Amendment History and Reasons for Amendment 
Version 
Date 
Reasons for Amendment 
Version 1.0 
01 November 2021 
Original Protocol 
Version 2.0 
(Protocol 
Amendment 1) 
11 April 2022 
• To clarify that subjects must be aged 12 to 
17 years, inclusive, at time of informed consent 
and throughout study participation. 
• To clarify that only select sites will perform 
gastric pH monitoring in subjects deemed 
clinically indicated by the principal 
investigator. 
• To add that all study drug doses be taken on an 
empty stomach.  
• To add that the time and content of any meals 
consumed prior to taking study drug on Day 6 
or Day 7 be recorded. 
• To add details for Day 7 dosing with respect to 
allowed water and meals.  
• To clarify that Day -1 assessments are only 
required for subjects undergoing gastric pH 
monitoring. 
• To clarify that Day 6 is an optional visit for 
subjects that check in to the clinic in the 
evening before starting Day 7 assessments.  
• Remove the Day 14 pharmacokinetic blood 
collection. 
• Remove morphology from electrocardiogram 
assessments.  
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 7 
Version 
Date 
Reasons for Amendment 
Version 3.0 
(Protocol 
Amendment 2) 
 
14 September 2022 
• Increased number of sites from 5 to 12 
• Updated information about vonoprazan  
• Removed duplicate entry for sucralfate 
under excluded medications and treatments  
• Removed gastrin and pepsinogen I and II 
assessments 
• Removed optional Day 6 visit  
• Modified strategy to estimate PK parameters 
to a population based approach; as a result 
adjusted PK sampling schedule on Day 7, 
added PK sampling on Day 14, provided 
information on when time of dosing and 
meals should be collected and remove Tmax,ss 
and t1/2z PK parameters.   
• Removed required overnight stay for PK 
sampling due to revised sampling schedule 
• Added details to the 24-hour gastric pH 
monitoring  
• Moved symptom assessments from Day 8 to 
Day 7 
• Updated Schedule of Events and Study 
Design to reflect above changes   
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 8 
Table of Contents 
Summary of Changes .................................................................................................................6 
Table of Contents .......................................................................................................................8 
List of Tables ............................................................................................................................ 11 
List of Figures ..........................................................................................................................12 
Protocol Synopsis.....................................................................................................................13 
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 GERD ...............19 
1.2.2 
Vonoprazan ..............................................................................................20 
1.3 
Justification for Dose ..............................................................................................22 
2 
Study Objectives and Endpoints ......................................................................................24 
3 
Investigational Plan ..........................................................................................................25 
3.1 
Study Design ...........................................................................................................25 
3.1.1 
Rationale of Study Design .......................................................................27 
4 
Subject Selection and Withdrawal Criteria ......................................................................29 
4.1 
Selection of Study Population .................................................................................29 
4.1.1 
Inclusion Criteria .....................................................................................29 
4.1.2 
Exclusion Criteria ....................................................................................30 
4.1.3 
Screen Failures .........................................................................................31 
4.1.4 
Lifestyle Considerations ..........................................................................32 
4.2 
Withdrawal of Subjects From Study Drug and/or the Study ..................................32 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................32 
4.2.2 
Handling of Withdrawals .........................................................................34 
4.2.3 
Lost to Follow-up.....................................................................................34 
4.2.4 
Replacements ...........................................................................................35 
5 
Study Drugs ......................................................................................................................36 
5.1 
Method of Assigning Subjects to Treatment Groups ..............................................36 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 9 
5.2 
Treatments Administered ........................................................................................36 
5.3 
Identity of Investigational Product..........................................................................37 
5.4 
Management of Clinical Supplies ...........................................................................37 
5.4.1 
Study Drug Packaging and Storage .........................................................37 
5.4.2 
Study Drug Accountability ......................................................................37 
5.5 
Overdose Management ...........................................................................................37 
5.5.1 
Treatment of Overdose ............................................................................38 
5.6 
Blinding...................................................................................................................38 
5.7 
Study Compliance ...................................................................................................38 
5.7.1 
Treatment Compliance .............................................................................38 
5.8 
Prior and Concomitant Therapy ..............................................................................38 
5.8.1 
Excluded Medications..............................................................................39 
6 
Study Assessments and Procedures ..................................................................................41 
6.1 
Pharmacokinetic and Pharmacodynamic Assessments ...........................................41 
6.1.1 
Pharmacokinetic Assessments .................................................................41 
6.1.2 
Pharmacodynamic Assessments ..............................................................43 
6.2 
Efficacy Assessments ..............................................................................................43 
6.2.1 
Pediatric Gastro-esophageal Symptom and Quality of Life 
Questionnaire-Adolescent-Short Form Questionnaire .............................43 
6.2.2 
GERD Symptom Assessment-Investigator ..............................................44 
6.3 
Safety Assessments .................................................................................................44 
6.3.1 
Pretreatment Events and Adverse Events ................................................44 
6.3.1.1 
Definitions ...............................................................................................44 
6.3.1.2 
Documenting Adverse Events ..................................................................51 
6.3.1.3 
Time Period and Frequency for Collecting AE and SAE Information ....53 
6.3.1.4 
Regulatory Reporting Requirements for SAEs ........................................56 
6.3.2 
Pregnancy.................................................................................................57 
6.3.3 
Laboratory Analyses ................................................................................58 
6.3.4 
Physical Examinations .............................................................................60 
6.3.5 
Vital Signs ................................................................................................60 
6.3.6 
Electrocardiograms ..................................................................................60 
6.4 
Safety Monitoring Committee ................................................................................60 
7 
Statistical and Analytical Plan ..........................................................................................61 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 10 
7.1 
Sample Size Calculations ........................................................................................61 
7.2 
Analysis Sets ...........................................................................................................61 
7.3 
Statistical Analysis Methodology ...........................................................................61 
7.3.1 
Pharmacokinetic Analyses .......................................................................61 
7.3.2 
Efficacy/Pharmacodynamic Analyses ......................................................61 
7.3.3 
Safety Analyses ........................................................................................62 
7.3.4 
Other Analyses .........................................................................................62 
7.3.5 
Interim Analyses ......................................................................................62 
8 
Data Quality Assurance ....................................................................................................63 
8.1 
Data Management ...................................................................................................63 
9 
Ethics ................................................................................................................................64 
9.1 
Institutional Review Board .....................................................................................64 
9.2 
Ethical Conduct of the Study ..................................................................................64 
9.3 
Subject Information and Consent............................................................................64 
10 Investigator’s Obligations ................................................................................................66 
10.1 Confidentiality ........................................................................................................66 
10.2 Financial Disclosure and Obligations .....................................................................66 
10.3 Investigator Documentation ....................................................................................67 
10.4 Study Conduct .........................................................................................................67 
10.5 Adherence to Protocol.............................................................................................68 
10.6 Adverse Events and Study Report Requirements ...................................................68 
10.7 Investigator’s Final Report .....................................................................................68 
10.8 Records Retention ...................................................................................................68 
10.9 Publications .............................................................................................................68 
11 Study Management ...........................................................................................................69 
11.1 Monitoring ..............................................................................................................69 
11.1.1 
External Data Monitoring Committee .....................................................69 
11.1.2 
Monitoring of the Study ...........................................................................69 
11.1.3 
Inspection of Records ..............................................................................69 
11.2 Management of Protocol Amendments and Deviations..........................................69 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 11 
11.2.1 
Modification of the Protocol ....................................................................69 
11.2.2 
Protocol Deviations..................................................................................70 
11.3 Study Termination ...................................................................................................70 
11.4 Final Report ............................................................................................................71 
12 Reference List...................................................................................................................72 
13 Appendices .......................................................................................................................75 
13.1 Appendix 1: Schedule of Events .............................................................................75 
13.2 Appendix 2: Contraceptive Guidance .....................................................................79 
13.3 Appendix 3: Liver Function Tests ...........................................................................81 
13.3.1 
Liver Function Test Monitoring ...............................................................81 
13.3.2 
Considerations for Temporary Discontinuation of Study Drug ...............81 
13.3.3 
Permanent Discontinuation of Study Drug ..............................................82 
13.3.4 
Re-initiation of Study Drug .....................................................................83 
13.4 Appendix 4: Questionnaires ....................................................................................84 
13.4.1 
Pediatric Gastro esophageal Symptom and Quality of Life Questionnaire 
Adolescent-Short Form Questionnaire ....................................................84 
13.4.2 
GERD Symptom Assessment-Investigator ..............................................87 
13.5 Appendix 5: Protocol Amendments ........................................................................88 
13.5.1 
Protocol Amendment 1 ............................................................................88 
13.5.2 
Protocol Amendment 2 ............................................................................95 
 
List of Tables 
Table 2-1 
Study Objectives and Endpoints ..................................................................... 24 
Table 5-1 
Excluded Medications and Treatments ........................................................... 40 
Table 6-1 
Pharmacokinetic Parameters to be Estimated using Vonoprazan Plasma 
Concentration Data ......................................................................................... 43 
Table 6-2 
Medically Significant Adverse Event List ...................................................... 46 
Table 6-3 
Adverse Events of Special Interest List .......................................................... 47 
Table 6-4 
Protocol-Required Safety Laboratory Assessments ........................................ 59 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 12 
Table 13-1 
Schedule of Events .......................................................................................... 76 
Table 13-2 
Abnormal Liver Function Criteria for Permanent Discontinuation of Study 
Drug ................................................................................................................ 82 
 
List of Figures 
Figure 3-1 
Study Scheme.................................................................................................. 26 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 13 
Protocol Synopsis 
 
Protocol Number: VPED-102 
Title: 
A Phase 1, Randomized, Parallel-group, Open-label, Multicenter Study 
to Evaluate the Pharmacokinetics, Pharmacodynamics and Safety of 
Vonoprazan (10 or 20 mg Once Daily) in Adolescents with 
Symptomatic Gastroesophageal Reflux Disease 
Sponsor:  
Phathom Pharmaceuticals, Inc. 
2150 East Lake Cook Road, Suite 800 
Buffalo Grove, IL 60089 USA 
Study Phase: 
1 
Study Sites: 
Approximately 12 sites in the United States 
Indication: 
Gastroesophageal reflux disease (GERD) 
Rationale: 
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 symptomatic non-erosive GERD, 
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 in 
adults 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. Two large studies in 
pediatric patients have reported that 18% experience weekly heartburn 
and 20% experience GERD symptoms. In addition, an analysis of 
1.2 million insurance claims found that the incidence rate of GERD in 
patients aged 12 to 17 years increased by 34% from 2000 to 2005. 
Vonoprazan belongs to a new class of acid-inhibitory agents called 
“potassium-competitive acid blockers”. In the United States, 
vonoprazan in combination with amoxicillin or in combination with 
amoxicillin and clarithromycin is approved for the treatment of 
Helicobacter pylori infection in adults. Vonoprazan is being developed 
in adults for the treatment of heartburn in patients with symptomatic 
non-erosive GERD, healing of all grades of EE and relief of heartburn 
and maintenance of healing of all grades of EE and relief of heartburn. 
The pediatric doses for this study were selected to approximate 
equivalent adult exposures following administration of vonoprazan 10 
or 20 mg QD and are age-based for adolescents 12 to 17 years of age. 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 14 
Objectives: 
Primary: 
• To evaluate the pharmacokinetic profile of vonoprazan (10 or 
20 mg once daily [QD]) in adolescent subjects with 
symptomatic GERD. 
Safety: 
• To evaluate the safety of vonoprazan (10 or 20 mg QD) in 
adolescent subjects with symptomatic GERD. 
Exploratory: 
• To evaluate symptom relief and pharmacodynamics of 
vonoprazan (10 or 20 mg QD) in adolescent subjects with 
symptomatic GERD. 
Study Population: Subjects 12 to 17 years of age, inclusive, with a medical history of 
symptoms of GERD for at least 3 months prior to screening. 
Study Design:  
This is a Phase 1, uncontrolled, randomized, open-label, parallel-group, 
multiple-dose study in adolescents aged 12 to 17 years with 
symptomatic GERD. Subjects will be screened for up to 28 days. 
Successfully screened subjects will be randomized to receive 10 or 
20 mg of vonoprazan QD for 14 days. A total of 18 subjects will be 
enrolled into the study. 
Blood samples for pharmacokinetic testing will be collected on Days 7 
and 14. Select sites will perform gastric pH monitoring in subjects 
deemed clinically indicated by the principal investigator.  
Subjects undergoing gastric pH monitoring will be confined to the 
clinic for testing. Gastric pH will be monitored for 24 hours beginning 
on Day -1 and on Day 7. 
The study will include 3 periods: 
Screening Period (≤4 weeks): Subjects will undergo screening 
assessments to determine study eligibility, and baseline assessments 
will be performed. If all eligibility criteria are met, the subject will be 
randomized and enter the Treatment Period. 
Treatment Period (Day 1 to Day 14): Subjects will be randomized to 
receive vonoprazan 10 mg or vonoprazan 20 mg QD. 
Follow-up Period: A safety follow-up phone call will occur 2 weeks 
after the last dose of study drug to assess adverse events (AEs). 
A subject will be considered to have completed the study if the subject 
completes the Treatment Period and the safety follow-up phone call. 
Following completion of study drug dosing or early discontinuation, 
the subject will be transitioned to local standard of care in accordance 
with each site’s prespecified process. 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 15 
Estimated Study 
Duration: 
The total duration of the study is up to 8 weeks. The Screening Period 
is up to 4 weeks, Treatment Period is 2 weeks, and safety follow-up 
phone call is 2 weeks after last study drug administration. 
Pharmacokinetic 
Assessments: 
The primary vonoprazan pharmacokinetic endpoints will include the 
following steady state parameters: 
• Maximum observed drug concentration at steady state (Cmax,ss) 
• Area under the plasma concentration-time curve during the 
dosing interval τ (AUCτ) 
• Apparent oral clearance (CL/F) 
• Apparent volume of distribution (Vz/F) 
Efficacy and 
Pharmacodynamic 
Assessments 
Efficacy and pharmacodynamic characteristics will be assessed by the 
following: 
• The severity of GERD symptoms at screening and Days 7 and 
14 as assessed by the investigator 
• The Pediatric Gastro-esophageal Symptom and Quality of Life 
Questionnaire-Adolescent-Short Form (PGSQ-A-SF) symptom 
and impact subscale as assessed by the adolescent at screening 
and Days 7 and 14 
• Mean pH and percentage of time above pH 4, 5, and 6 at 
Day -1 and Day 7 in the subset of subjects for whom 
intragastric pH monitoring is performed when clinically 
indicated per the investigator 
Safety 
Assessments: 
Safety will be assessed by the following: 
• AEs 
• Laboratory test values (hematology, serum chemistry, 
urinalysis) 
• Electrocardiograms 
• Vital signs 
Study Drug, 
Dosage, and Route 
of Administration: 
Open-label study drug (vonoprazan 10 mg or vonoprazan 20 mg) to be 
taken orally QD for 14 days (Day 1 through Day 14). All study drug 
doses are to be taken on an empty stomach with approximately 240 mL 
(8 oz) water between 7 and 10 am each day. 
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 16 
Sample Size: 
Approximately 18 subjects will be enrolled with 9 subjects in each dose 
group. Attempts will be made to enroll an equal number of subjects 
between 12 to 15 and 16 to 17 years of age. Because this is a 
pharmacokinetic and safety trial with no comparator, there is no power 
determination affecting the sample size. The sample size of approximately 
18 subjects is considered sufficient to assess the pharmacokinetics, safety, 
and tolerability of vonoprazan in a pediatric population aged 12 to 
17 years. Fewer subjects may be enrolled based on preliminary data, if 
considered sufficient to adequately characterize the PK profile. 
Statistical 
Methods: 
Pharmacokinetic Endpoints: 
Individual pharmacokinetic parameter estimates will be summarized 
descriptively by vonoprazan dose.  
Efficacy and Pharmacodynamic Endpoints: 
The severity of GERD symptoms at screening and Days 7 and 14, as 
assessed by the investigator, will be summarized overall and by 
vonoprazan dose. 
The change from baseline (ie, screening assessment) to Days 7 and 14 in 
the PGSQ-A-SF symptom and impact subscale, as assessed by the 
adolescent, will be summarized overall and by vonoprazan dose. 
Mean pH and the percentage of time above pH 4, 5, and 6 at baseline 
(Day -1) and Day 7 will be summarized for the subset of subjects for 
whom intragastric pH monitoring is available. 
Safety: 
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.  
Clinical laboratory tests, electrocardiograms, and vital signs will be 
summarized with descriptive statistics at each time point by treatment 
group. 
Version and 
Date of Protocol: 
Version 3.0 
14 September 2022 
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 17 
List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUCss 
area under the drug concentration-time curve at steady state 
CFR 
Code of Federal Regulations 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EE 
erosive esophagitis 
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 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LAR 
legally authorized representative 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCAB 
potassium-competitive acid blocker 
PGSQ-A-SF 
Pediatric Gastro-esophageal Symptom and Quality of Life 
Questionnaire-Adolescent-Short Form 
 
 
 


Phathom Pharmaceuticals, Inc. 
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Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 18 
 
Abbreviation 
Definition 
popPK 
population pharmacokinetic 
PPI 
proton pump inhibitor 
PTE 
pretreatment event 
QD 
once daily 
SAE 
serious adverse event 
SoE 
schedule of events 
SUSAR 
suspected unexpected serious adverse reaction 
Takeda 
Takeda Pharmaceutical Company Limited 
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: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 19 
1 
Introduction 
Vonoprazan belongs to a new class of acid-inhibitory agents called potassium-competitive 
acid blockers (PCABs). In the United States, vonoprazan in combination with amoxicillin or 
in combination with amoxicillin and clarithromycin is approved for the treatment of 
Helicobacter pylori infection in adults. Vonoprazan is being developed in adults for the 
treatment of heartburn in patients with symptomatic non-erosive GERD, healing of all grades 
of erosive esophagitis (EE) and relief of heartburn and maintenance of healing of all grades 
of EE and relief of heartburn. 
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 (Takeda) to develop, manufacture, and commercialize vonoprazan in the 
United States, Europe, and Canada. 
1.1 
Study Rationale 
The purpose of this study is to determine a dose of vonoprazan in adolescent subjects with 
symptomatic GERD that provides an exposure similar to the exposures in adults after 
administration of vonoprazan 10 mg or 20 mg once daily (QD). 
1.2 
Background 
1.2.1 
Epidemiology, Symptoms, and Current Treatments for GERD 
Gastroesophageal reflux disease 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]. Symptoms include heartburn, cough, epigastric pain, vomiting, and 
regurgitation. The term GERD covers a spectrum of conditions, including symptomatic 
non-erosive GERD, EE, and Barrett’s esophagus. 


Phathom Pharmaceuticals, Inc. 
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Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 20 
When defining GERD as the presence of at least weekly heartburn and/or regurgitation, 
epidemiological studies reported prevalence estimates in adults 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]. The prevalence of GERD symptoms has risen from 11.6% in 1995 to 1997 
to 17.1% in 2006 to 2009 [Ness-Jensen 2012], and awareness of GERD has concomitantly 
increased in pediatric and adolescent populations [Gold 2002, Nelson 2000]. Two large 
studies in pediatric patients have reported that 18% experience weekly heartburn and 20% 
experience GERD symptoms [Chen 2014, Guimaraes 2010, Locke 1997]. In addition, an 
analysis of 1.2 million insurance claims found that the incidence rate of GERD in patients 
aged 12 to 17 years increased by 34% from 2000 to 2005 [Nelson 2009]. 
Typically, management of GERD has included lifestyle changes (eg, diet, weight loss, or 
sleeping position), over-the-counter antacids, histamine-2 receptor antagonists (H2RAs), and 
more recently, proton pump inhibitors (PPIs). Proton pump inhibitors are considered superior 
to H2RAs for healing of EE and relief of GERD symptoms and have become the 
pharmacological mainstay for treatment of adult and adolescent GERD [Gold 2002, 
Rosen 2018]. 
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.  


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-102 Version 3.0 (Amendment 2) 
14 September 2022 
Page 21 
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 proton pumps: Vonoprazan inhibits acid secretion by competitively 
inhibiting the binding of potassium ions to the H+, K+-ATPase. Vonoprazan may 
selectively concentrate in the parietal cells in both the resting and stimulated states. It 
also binds to active pumps in a noncovalent and reversible manner. 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 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 [Jenkins 2015]. This is significantly 
longer than the half-life of conventional PPIs (<2 hours) [Shin 2013]. 
• Metabolism: Vonoprazan is metabolized by a combination of cytochrome P450 
(CYP) isoforms including CYP3A4/5, which does not have a high degree of genetic 
polymorphism as compared to 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, 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 8 short-term clinical studies in adults with EE (5 studies) and symptomatic 
non-erosive GERD (3 studies) with treatment durations of 2 to 8 weeks. In addition, Takeda 
conducted 3 studies of maintenance of healing of EE with treatment durations of 24 to 
52 weeks. Vonoprazan is approved in multiple countries outside the United States for the 
treatment of adults for reflux (erosive) esophagitis (for healing: vonoprazan 20 mg QD up to 
4 weeks or, if insufficient effect, 8 weeks; for maintenance: 10 mg QD or, if insufficient 
effect, 20 mg QD). 
The safety profile of vonoprazan in Phase 3 studies of adults across indications showed there 
was no evidence of a dose-related increase in adverse effects with vonoprazan from 5 mg to 
40 mg QD, and the safety profile of vonoprazan was similar to that of lansoprazole. As of 25 
December 2021, the global cumulative postmarketing patient exposure to vonoprazan is 
estimated to be approximately 70 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 
adolescents with GERD. 
1.3 
Justification for Dose 
The proposed pediatric doses are selected to approximate equivalent adult exposures 
following administration of vonoprazan 10 or 20 mg QD and are age-based for adolescents 
12 to 17 years of age. 
The proposed doses are based on simulations using a population pharmacokinetic (popPK) 
model. The 2-compartment linear popPK model for vonoprazan was developed with adult 


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data from 13 studies in healthy volunteers, 1 study in EE patients and 1 study in GERD 
patients. The final dataset consisted of 1,179 subjects (769 Asian and 410 Western). 
For the pediatric dose simulations, the popPK model for vonoprazan was updated to 
incorporate body size and maturation correction factors, appropriate to predict vonoprazan 
exposure in infants, children, and adolescents. Different model assumptions in terms of 
(i) the allometric weight scaling exponent (as estimated in the adult data or fixed at 0.75) and 
(ii) if or if not to correct for enzyme maturation in infants were compared. 
The resulting models were used to simulate posterior distributions of area under the drug 
concentration-time curve at steady state (AUCss) in both adults and pediatrics for a series of 
pediatric candidate doses. Matching pediatric doses were selected to limit the predicted 
percentage of pediatrics with an exposure exceeding the adult reference exposure (median 
AUCss) at 50 to 60%. 


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2 
Study Objectives and Endpoints 
Study objectives with corresponding endpoints are presented in Table 2-1. 
Table 2-1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate the pharmacokinetic profile of 
vonoprazan (10 or 20 mg QD) in adolescent 
subjects with symptomatic GERD. 
• 
Cmax,ss, AUCτ, CL/F, Vz/F  
Safety 
• To evaluate the safety of vonoprazan (10 or 
20 mg QD) in adolescent subjects with 
symptomatic GERD. 
• 
Adverse events 
• 
Laboratory test values (hematology, serum 
chemistry, urinalysis) 
• 
Electrocardiograms 
• 
Vital signs 
Exploratory 
• To evaluate symptom relief and 
pharmacodynamics of vonoprazan (10 or 20 mg 
QD) in adolescent subjects with symptomatic 
GERD. 
• 
The severity of GERD symptoms at screening 
and Days 7 and 14 as assessed by the 
investigator 
• 
The PGSQ-A-SF symptom and impact subscale 
as assessed by the adolescent at screening and 
Days 7 and 14 
• 
Mean pH and percentage of time above pH 4, 5, 
and 6 at Day -1 and Day 7 in the subset of 
subjects for whom intragastric pH monitoring is 
performed when clinically indicated per the 
investigator 
AUCτ: area under the plasma concentration-time curve during the dosing interval τ; CL/F: apparent oral 
clearance; Cmax,ss: maximum observed drug concentration at steady state; GERD: gastroesophageal reflux 
disease; PGSQ A-SF: Pediatric Gastro-esophageal Symptom and Quality of Life Questionnaire-Adolescent-
Short Form; QD: once daily; Vz/F: apparent volume of distribution 
 


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3 
Investigational Plan 
3.1 
Study Design 
This is a Phase 1, uncontrolled, randomized, open-label, parallel-group, multiple-dose study 
in adolescents aged 12 to 17 years with symptomatic GERD. Subjects will be screened for up 
to 28 days. Successfully screened subjects will be randomized to receive 10 or 20 mg of 
vonoprazan QD for 14 days. A total of 18 subjects will be enrolled into the study. 
Blood samples for pharmacokinetic testing will be collected on Days 7 and 14. Select sites 
will perform gastric pH monitoring in subjects deemed clinically indicated by the principal 
investigator. Subjects undergoing gastric pH monitoring will be confined to the clinic for 
testing. Gastric pH will be monitored for 24 hours beginning on Day -1 and on Day 7. 
A schematic diagram of the overall study design is presented in Figure 3-1. 
 




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The study will include 3 periods (see the schedule of events [SoE] in Section 13.1 for 
details): 
Screening Period (≤4 weeks): Subjects will undergo screening assessments to 
determine study eligibility, and baseline assessments will be performed. If all 
eligibility criteria are met, the subject will be randomized and enter the Treatment 
Period. 
Treatment Period (Day 1 to Day 14): Subjects will be randomized to receive 
vonoprazan 10 mg or vonoprazan 20 mg QD. 
Follow-up Period (2 weeks): A safety follow-up phone call will occur 2 weeks after 
the last dose of study drug to assess adverse events (AEs). 
A subject will be considered to have completed the study if the subject completes the 
Treatment Period and the safety follow-up phone call. 
Following completion of study drug dosing or early discontinuation, the subject will be 
transitioned to local standard of care in accordance with each site’s prespecified process. 
3.1.1 
Rationale of Study Design 
Blinding is not necessary in this study since the primary objective is to evaluate the 
pharmacokinetic profile of vonoprazan. The pharmacokinetic endpoints are objective and 
unlikely to be biased by the open-label design.  
A parallel-group, 2-dose design was selected to provide unbiased estimates of the vonoprazan 
pharmacokinetic and safety profile across doses likely to be efficacious. Dose justification is 
provided in Section 1.3. A placebo control group was not considered practical or ethical in 
the symptomatic, pediatric population. 
Pharmacokinetic studies with PPIs (dexlansoprazole, esomeprazole, lansoprazole, 
rabeprazole) in pediatric GERD patients were generally less than 7 days [Gunasekaran 2002, 
Gremse 2002, James 2007, Kukulka 2014, Kukulka 2012, Li 2006, Rosen 2018, 
Zannikos 2011, Zhao 2006]. Historical PPI data (esomeprazole, lansoprazole, pantoprazole) 
in pediatric GERD patients have shown benefit in terms of resolution of heartburn and other 
GERD symptoms within a week of treatment [Gold 2007, Gunasekaran 2002, Tolia 2006]. 


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The pharmacological profile of vonoprazan relative to PPIs would suggest that, if effective, 
the onset of resolution of heartburn in symptomatic GERD pediatric patients would be 
similar or potentially earlier than PPIs. 
This study may include patients with symptomatic GERD, with or without EE. The EE 
healing rate after 2 weeks of treatment with vonoprazan 20 mg QD was estimated from the 
results of Study TAK-438/CCT-002, which enrolled adult subjects with endoscopically 
confirmed EE of Los Angeles Classification Grades A to D. Of the 204 vonoprazan-treated 
subjects evaluated at Week 2, the majority (90.7%) were healed. Based on these data, the 
proposed 14-day treatment duration will provide clinical benefit to EE subjects, with a 
possibility of healing of EE. 


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4 
Subject Selection and Withdrawal Criteria 
4.1 
Selection of Study Population 
This study will be conducted at approximately 12 sites in the United States and will 
randomize 18 subjects (9 subjects per vonoprazan dose group) in the Treatment Period. 
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 12 to 17 years of age, inclusive, at the time of informed consent signing 
and throughout study participation. 
2. The subject has a body weight within the 5th through 95th percentile by age, inclusive, 
as determined by the National Center for Health Statistics. 
3. The subject has a medical history of symptoms of GERD for at least 3 months prior to 
screening, based on physical examination, current symptoms (eg, heartburn), or 
diagnostic tests (eg, pH or endoscopy). Notes in the medical records and/or other 
source documents such as prior endoscopies can be used to support the diagnosis. 
4. The subject has symptoms of at least moderate heartburn severity based on the GERD 
Symptom Assessment-Investigator scale performed at screening. 
5. The subject must be able to swallow study drug. 
6. Parent or legal guardian (ie, legally authorized representative [LAR]) is willing and 
able to complete the informed consent process and comply with study procedures and 
visit schedule. The participating subject will provide assent as applicable. 
7. A female subject of childbearing potential who is or may be sexually active with a 
nonsterilized male partner agrees to routinely use adequate contraception from the 
signing of informed consent until 2 weeks after the last dose of study drug as detailed 
in Section 13.2. 


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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 used prescription or non-prescription PPIs or H2RAs within 7 days 
prior to randomization or requires their use during the Treatment Period. 
2. The subject has used sucralfate or antacids within 1 day prior to randomization or 
requires their use during the Treatment Period. 
3. The subject has received other agents affecting digestive organs, including muscarinic 
antagonists (eg, hyoscyamine), prokinetics, oral anticholinergic agents, 
prostaglandins, bismuth from 30 days prior to Day 1 or requires their use during the 
course of the study. 
4. The subject has received atazanavir sulfate or rilpivirine hydrochloride from 5 days 
prior to Day 1 or requires their use during the course of the study. 
5. The subject has received any investigational compound (including vonoprazan) 
within 30 days prior to the start of the Screening Period. 
6. The subject is 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, child, sibling) or 
who may have consented under duress. 
7. The subject requires hospitalization or has surgery scheduled during the course of the 
study or has undergone major surgical procedures within 30 days prior to the 
Screening Period. 
8. The subject has undergone prior gastrointestinal surgeries such as fundoplication. 
9. The subject has any abnormal laboratory test values at the start of the Screening 
Period. 
10. The subject has a history of hypersensitivity or allergies to vonoprazan (including the 
formulation excipients: D-mannitol, microcrystalline cellulose, hydroxypropyl 


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cellulose, fumaric acid, croscarmellose sodium, magnesium stearate, hypromellose, 
macrogol 8000, and titanium oxide, or red or yellow ferric oxide). 
11. The subject used any prescription (excluding hormonal birth control) or 
over-the-counter medications (including CYP3A4 inducers), including herbal or 
nutritional supplements, within 14 days (or 5 half-lives) before the first dose of study 
drug or throughout the study. NOTE: Acid suppressive therapies are considered 
separately under exclusion criteria 1 and 2. 
12. The subject has consumed grapefruit or grapefruit juice, Seville orange or Seville 
orange-containing products (eg, marmalade), or other food products that may be 
CYP3A4 inhibitors (eg, vegetables from the mustard green family [kale, broccoli, 
watercress, collard greens, kohlrabi, Brussels sprouts, mustard] and charbroiled 
meats) within 7 days (or 5 half-lives) before the first dose of study drug or throughout 
the study. 
13. Female subject has a positive pregnancy test at screening or check in or is lactating. 
14. The subject has a positive urine drug or alcohol result at screening. 
15. The subject has positive results at screening for human immunodeficiency virus, 
hepatitis B surface antigen, or hepatitis C virus. 
16. In the opinion of the investigator, the subject is not suitable for entry into the study. 
4.1.3 
Screen Failures 
Screen failures are defined as subjects whose LAR signs the informed consent form (ICF) to 
participate in the clinical study but are not subsequently entered in the 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), AEs, and any serious adverse events (SAEs). 
Subjects may be allowed to be rescreened upon discussion with and approval by the medical 
monitor.  


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4.1.4 
Lifestyle Considerations 
Subjects will be instructed to maintain usual food intake, sleep habits, consistent activity, and 
caffeine intake throughout the study. 
Consumption of grapefruit or grapefruit juice, Seville orange or Seville orange-containing 
products (eg, marmalade), or other food products that may be CYP3A4 inhibitors (eg, 
vegetables from the mustard green family [kale, broccoli, watercress, collard greens, 
kohlrabi, Brussels sprouts, mustard] and charbroiled meats) within 7 days (or 5 half-lives) 
before the first dose of study drug and throughout the study will be prohibited. 
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 phone call performed 2 weeks after the 
last dose of study drug in the Treatment Period. 
4.2.1 
Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time (eg, Treatment Period, Follow-up Period) 
and for any reason without prejudice to their future medical care by the investigator or at the 
study site. Every effort should be made to keep subjects in the study. The primary reason for 
discontinuation or withdrawal of the subject from the study drug or the study should be 
recorded in the electronic case report form (eCRF). For screen failure subjects, refer to 
Section 4.1.3.  
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 


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criteria of liver function abnormalities for temporary and permanent discontinuation 
of study drug. 
3. Significant protocol deviation: The discovery post-randomization that the subject 
failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health. 
4. Lost to follow-up: The subject did not return to the clinic and attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented 
(3 documented telephone contact attempts and 1 certified letter, at a minimum) within 
6 weeks of the most recent planned visit. 
5. Voluntary withdrawal: The subject wishes to withdraw from the study. The reason for 
the withdrawal, if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be recorded 
(ie, withdrawal due to an AE or lack of efficacy). 
6. Study termination: The sponsor, Institutional Review Boards (IRBs), 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. 


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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. 
Following completion of study drug dosing or early discontinuation, the subject will be 
transitioned to local standard of care in accordance with each site’s prespecified process. 
Subjects who discontinue study drug or active participation in the study will no longer 
receive study drug. When a subject withdraws from the study drug or active participation in 
the study, the reason(s) for withdrawal shall be recorded by the investigator on the relevant 
page of the eCRF. Whenever possible, all subjects who discontinue study drug or withdraw 
from the study prematurely will undergo all end-of-study assessments. Subjects who fail to 
return for final assessments will be contacted by the site to make every attempt to comply 
with the protocol. 
It is vital to obtain follow-up data on any subject withdrawn because of an AE or SAE. In 
every case, efforts must be made to undertake protocol-specified 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 the LAR signs the ICF, the subject fails to 
return for scheduled visits during the Treatment Period or Follow-up Period, and the LAR is 
unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the LAR and reschedule the missed visit as soon as 
possible, counsel the subject and LAR on the importance of maintaining the assigned 


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visit schedule and ascertain whether or not the subject and LAR wish to and/or should 
continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the LAR (where possible, 3 telephone calls and, if 
necessary, a certified letter [or local equivalent methods] to the subject’s last known 
mailing address within 6 weeks of most recent planned visit). These contact attempts 
should be documented in the subject’s medical record. 
• Should the LAR continue to be unreachable, the subject will be considered to have 
withdrawn from the study due to being lost to follow-up. 
4.2.4 
Replacements 
Discontinued or withdrawn subjects will not be replaced. 
 


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5 
Study Drugs 
5.1 
Method of Assigning Subjects to Treatment Groups 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized in a 1:1 ratio to 1 of the following 2 groups during the Treatment Period: 
• Vonoprazan 10 mg QD for 14 days 
• Vonoprazan 20 mg QD for 14 days 
An interactive response technology (IRT) system will be used to administer the 
randomization schedule. Biostatistics will generate the randomization schedule using SAS 
software Version 9.4 or later (SAS Institute Inc, Cary, North Carolina) for IRT, which will 
link sequential subject randomization numbers to treatment codes. The randomization will 
also use an appropriate block size, which will not be revealed. 
5.2 
Treatments Administered 
Subjects will be instructed to take randomized study drug orally each morning between 7 and 
10 am on an empty stomach with approximately 240 mL (8 oz) water. Subjects will take 
study drug at the clinic on Days 1, 7, and 14; otherwise, study drug will be taken on an 
outpatient basis. Any missed doses should be noted by the subject and communicated to 
clinic staff to record in the eCRF.  
For the Days 6 and 13 dose, subjects will note the time it was taken and if they took the dose 
on an empty stomach. If the dose on Days 6 or 13 was not taken on an empty stomach, the 
subject is to note the time and content of any meal consumed prior to taking their study drug 
dose. Clinic staff will record this information in the eCRF. 
Subjects will be instructed not to eat any food or take study drug on the mornings of Days 7 
14 prior to their arrival at the clinic. If a subject consumes any food prior to arrival, the time 
and content of the meal is to be noted by the subject and recorded in the eCRF by clinic staff.  
On Days 7 and 14, subjects will take their study drug dose in the clinic. Water is permitted as 
desired, except for 1 hour before and 1 hour after administration (other than what is permitted 
for study drug dosing). Subjects will be provided a meal 30-60 minutes after study drug 
dosing per the clinic’s standard procedures. 


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5.3 
Identity of Investigational Product 
Vonoprazan study medication will be supplied as 10 mg and 20 mg tablets. 
 
 manufactures the vonoprazan drug 
substance and drug product. 
Study drug will be packaged in bottles for shipment to the investigational site. 
5.4 
Management of Clinical Supplies 
5.4.1 
Study Drug Packaging and Storage 
Vonoprazan tablets will be distributed in bottles and shipped by 
. 
Study supplies must be stored in a secure area (eg, a locked cabinet), protected from 
moisture, and kept at a controlled room temperature (20°C to 25°C [68°F to 77°F]; 
excursions allowed between 15°C and 30°C [59°F to 86°F]) until they are used or returned to 
the sponsor or designee for destruction. Study drug must be stored under the conditions 
specified on the label and remain in the original container until dispensed. 
Sites should refer to the Pharmacy Manual for reporting temperature excursions. 
5.4.2 
Study Drug 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. 
Sites should refer to the Pharmacy Manual and follow the accountability process described 
for this clinical study. 
5.5 
Overdose Management 
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. 


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Cases of overdose without manifested signs or symptoms are not considered AEs. Adverse 
events associated with an overdose will be documented on the 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. 
5.5.1 
Treatment of Overdose 
Vonoprazan is not removed from circulation by hemodialysis. In the event of drug overdose, 
the subject should be treated symptomatically. 
5.6 
Blinding 
This is an open-label study. 
5.7 
Study Compliance 
5.7.1 
Treatment Compliance 
Compliance with study drug is to be assessed as specified in the SoE (Section 13.1). 
Compliance will be assessed by direct questioning and counting returned tablets, which will 
be documented in the source documents and eCRF.  
A record of the number of study drug tablets 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. 
If subjects exhibit poor compliance as assessed by tablet counts, the LARs and subjects 
should be counseled on the importance of good compliance to the study dosing regimen. 
5.8 
Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of 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 
The LARs and subjects are to be instructed that the subject should not 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 will be collected.  
The medical monitor should be contacted if there are any questions regarding prior or 
concomitant therapy. 
5.8.1 
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  
phone call 
Antacids and sucralfate 
Day -1 (day before first 
dose of study drug) 
Day 14 (end of 
study drug dosing) 
H2RAs 
7 days prior to Day 1 
Day 14 (end of 
study drug dosing) 
PPIs 
7 days prior to Day 1 
Day 14 (end of 
study drug dosing) 
Strong inhibitors or inducers of CYP3A4 
(eg, itraconazole, ketoconazole, indinavir, nelfinavir, 
ritonavir, saquinavir, telithromycin) 
14 days prior to Day 1 
End of treatment 
CYP3A4 substrates with a narrow therapeutic index 
14 days prior to Day 1 
End of treatment 
Surgical procedures that could affect gastric acid 
secretion (eg, any form of partial gastrectomy, 
vagotomy) 
30 days prior to Day 1 
Follow-up  
phone call 
Other agents affecting digestive organs, including 
muscarinic antagonists (eg, hyoscyamine), prokinetics, 
oral anticholinergic agents, prostaglandins, bismuth 
30 days prior to Day 1 
Follow-up  
phone call 
Atazanavir sulfates; rilpivirine hydrochloride 
(contraindicated with vonoprazan) 
5 days prior to Day 1 
Follow-up  
phone call 
CYP: cytochrome P450 isoenzyme; H2RA: histamine-2 receptor antagonist; PPI: proton pump inhibitor 
Note: Following completion of study drug dosing or early discontinuation, the subject will be transitioned to local 
standard of care in accordance with each site’s prespecified process. 


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6 
Study Assessments and Procedures 
Prior to undergoing any protocol-specific procedures or assessments, all LARs of potential 
subjects must sign and date the ICF. Participating subjects will provide assent as applicable. 
Subjects and LARs will have the opportunity to have any questions answered before signing 
the ICF. The investigator must address all questions raised by the subject and LAR. 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. All safety concerns should be discussed immediately with the principal 
investigator and the medical monitor to determine if any active intervention is needed, 
including action taken with 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 
Pharmacokinetic and Pharmacodynamic Assessments 
6.1.1 
Pharmacokinetic Assessments 
Subjects (or parents/caregivers) will be asked to note the exact time they took their study 
drug dose on Days 6 and 13 and if they took the dose on an empty stomach. If the dose was 
not taken on an empty stomach, the subject is to note the time and content of any meal 
consumed prior to taking their study drug dose on Days 6 and 13. Clinic staff will record this 
information in the eCRF. 
Subjects will arrive in the morning on Days 7 and 14 for pharmacokinetic sampling. They 
should not eat or take the vonoprazan study medication before arriving to the clinic; the time 
and content of any meal consumed prior to arrival at the clinic is to be recorded in the eCRF 
by clinic staff. Subjects will be released from the clinic after pharmacokinetic sampling and 
study procedures are completed.  
Blood samples for pharmacokinetic analysis of vonoprazan in plasma will be collected on 
Days 7 and 14. On each of those days, one pre-dose sample will be collected prior to the 
morning administration of vonoprazan. Two additional samples will be collected after drug 


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administration: one between 0.5 and 2 hours post-dose and one between 2.5 and 4 hours post-
dose. The exact time of each pharmacokinetic sample should be recorded. 
Samples will be collected into appropriate blood collection tubes as specified by the 
bioanalytical laboratory. Details of blood collection, processing, storage and shipping will be 
contained in the Clinical Laboratory Manual.  
Bioanalytical Methods 
Plasma concentrations of vonoprazan will be measured at Labcorp Early Development 
Laboratories Inc. (Madison, WI) using a validated liquid chromatrography/mass spectrometry 
method with an analytical range of 0.1 to 100 µg/mL and will be used for the calculation of 
the plasma vonoprazan pharmacokinetic parameters. 
Depending on pace of enrollment, pharmacokinetic samples from a subset or subsets of 
subjects may be analyzed prior to the completion of enrollment. In any case, all of the 
pharmacokinetic samples collected from a given subject will be analyzed in the same 
bioanalytical batch.  
Pharmacokinetic Parameters 
Plasma pharmacokinetic parameters shown in Table 6-1 will be estimated using a non-linear 
mixed effects model and will be determined from the concentration-time data for all 
evaluable subjects. Actual sampling times, rather than scheduled or nominal sampling times, 
will be used in all computations using sampling time. Additional pharmacokinetic parameters 
may be estimated as appropriate. 


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Table 6-1 
Pharmacokinetic Parameters to be Estimated using Vonoprazan Plasma 
Concentration Data 
Parameter 
Definition 
Cmax,ss 
Maximum observed plasma concentration at steady state 
Cmax,ss/Dose 
Dose-normalized Cmax,ss (Cmax,ss divided by the administered dose in mg) 
AUCτ,ss 
Area under the plasma concentration-time curve during the dosing interval τ, where τ is 
the length of the dosing interval in hours, calculated using the linear trapezoidal rule 
AUCτ,ss/Dose Dose-normalized AUCτ,ss (AUCτ,ss divided by the administered dose in mg) 
λz 
Terminal elimination rate constant, calculated as the negative slope of the log-linear 
regression of the natural logarithm concentration-time curve during the terminal phase 
CL/F 
Apparent total plasma clearance after oral (extravascular) administration, calculated as 
Dose/ AUCτ,ss 
Vz/F 
Apparent volume of distribution during the terminal elimination phase after oral 
(extravascular) administration, calculated as (CL/F)/ λz 
 
6.1.2 
Pharmacodynamic Assessments 
If deemed clinically indicated by the principal investigator, gastric pH will be measured and 
recorded continuously for a 24-hour period on scheduled days as outlined in the SoE 
(Section 13.1) using a suitable pH probe and ambulatory pH recording system. All 
instruments will be calibrated prior to and following use. Gastric pH will be sampled and 
recorded every 5 seconds. The 24-hour continuous pH recording session will commence 30 
to 60 minutes prior to treatment administration. The reason for pH assessments, start time, 
stop time and any interruptions will be recorded in the source document and the case report 
form (CRF). To minimize the discomfort of probe insertion, administration of a topical 
anesthetic (lidocaine) will be permitted. After each 24-hour recording period, the flashcard 
will be removed from the recorder and the pH data will be transferred to the computer.  
6.2 
Efficacy Assessments  
6.2.1 
Pediatric Gastro-esophageal Symptom and Quality of Life 
Questionnaire-Adolescent-Short Form Questionnaire 
The Pediatric Gastro-esophageal Symptom and Quality of Life Questionnaire-Adolescent-
Short Form (PGSQ-A-SF) questionnaire will be administered at the times specified in 


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Table 13-1. Responses will be recorded 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 symptom subscale measures the number of days over the past 7 days on which subjects 
experience each individual symptom, where 1=0 days; 2=1 or 2 days; 3=3 or 4 days; 4=5 or 
6 days; and 5=every day (7 days). Mean symptom subscale score is the mean of the 
7 individual symptom item scores. The impact subscale measures the impact of symptoms on 
school, family, and social activities in the past 7 days, where 1=never; 2=almost never; 
3=sometimes; 4=almost always; and 5=always. Mean impact subscale score is the mean of 
the 4 individual impact item scores. A copy of the questionnaire is presented in 
Section 13.4.1. 
6.2.2 
GERD Symptom Assessment-Investigator 
The GERD Symptom Assessment-Investigator scale evaluates 5 symptoms of GERD: 
heartburn, acid regurgitation, dysphagia, belching and epigastric pain. The maximum severity 
of each GERD symptom occurring during the 7 days prior to the study visit will be assessed. 
The severity for each symptom will be recorded on the eCRF as either none, mild, moderate, 
severe or very severe. For consistency, the assessment should be performed by the same 
person throughout the study, if possible. Symptom and severity definitions are presented in 
Section 13.4.2. 
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 
whose informed consent to participate in a study has been signed, which has occurred prior to 
administration of any study drug; it does not necessarily have to have a causal relationship 
with study participation. 


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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. 
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:  
a. May require intervention to prevent items 1 through 5 above 
b. May include any event or symptoms described in the medically significant AE 
list (Table 6-2) 
c. 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 alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) value >3 × the upper limit of normal (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). 


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6.3.1.1.4 
Adverse Event of Special Interest 
An AE of special interest is a noteworthy event for the particular product or class of products 
that a sponsor may wish to monitor carefully. It could be serious or nonserious (eg, hair loss, 
loss of taste, impotence), and could include events that might be potential precursors or 
prodromes for more serious medical conditions in susceptible individuals. 
Adverse events of special interest include any event listed 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 
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. 


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Preplanned procedures:  
• Preplanned procedures that were scheduled prior to signing of informed consent are 
not considered PTEs or AEs. However, if a preplanned procedure is performed early 
(eg, as an emergency) due to a worsening of the pre-existing condition, the worsening 
of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned procedure should be reported as AEs. 
Elective surgeries or procedures:  
• Elective procedures performed where there is no change in the subject’s medical 
condition should not be recorded as PTEs or AEs but should be documented in the 
subject’s source documents. Complications resulting from an elective surgery should 
be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action should NOT be 
recorded as an AE. The investigator must make the distinction between exacerbation 
of pre-existing illness and lack of therapeutic efficacy. 
Overdose: 
• Any manifested side effects will be considered AEs and will be recorded on the AE 
page of the eCRF. 


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6.3.1.2 Documenting Adverse Events 
6.3.1.2.1 Assessment of Severity 
The severity or intensity of an AE refers to the extent to which an AE affects the subject’s 
daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual 
activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of onset and duration of each episode. 
6.3.1.2.2 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The relationship or association of each AE to study drug(s) will be assessed using the 
following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of study 
drug (including the course after withdrawal of the drug), or for which possible 
involvement of the drug cannot be ruled out, although factors other than the 
study drug, such as underlying diseases, complications, concomitant drugs, and 
concurrent treatments, may also be responsible. 
Not 
Related: 
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant drugs, and concurrent 
treatments. 
 


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6.3.1.2.3 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as not related. 
6.3.1.2.4 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the 
subject and/or physician. 
6.3.1.2.5 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved 
but with sequelae, or the subject died. 
6.3.1.2.6 Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of 
consecutive days are considered intermittent. All other events are considered continuous. 
6.3.1.2.7 Action Concerning Study Drug 
• Drug withdrawn: A study drug is stopped due to the particular AE. 
• Dose not changed: The particular AE did not require stopping a study drug. 
• Unknown: Only to be used if it has not been possible to determine what action has 
been taken. 
• Not applicable: A study drug was stopped for a reason other than the particular AE, 
eg, the study has been terminated, the subject died, or dosing with the study drug was 
already stopped before the onset of the AE. 
• Dose interrupted: The dose was interrupted/held due to the particular AE. 


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6.3.1.2.8 Outcome 
• Recovered/resolved: Subject returned to baseline status with respect to the AE/PTE. 
• Recovering/resolving: The intensity is lowered by one or more stages: the diagnosis 
or signs/symptoms have lessened/improved; the abnormal laboratory value improved 
but has not returned to the normal range or to baseline; or the subject died from a 
cause other than the particular AE/PTE with the condition remaining 
“recovering/resolving.” 
• Not recovered/not resolved: There is no change in the diagnosis, signs, or symptoms; 
the intensity of the diagnosis, signs/symptoms, or laboratory value on the last day of 
the observed study period has worsened from when it started; is an irreversible 
congenital anomaly; or the subject died from another cause with the particular 
AE/PTE state remaining “Not recovered/not resolved.” 
• Resolved with sequelae: Subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a 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 informed consent to participate in the 
study has been signed and will 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. 


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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. 
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 


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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 
• 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 
. 
 
 24-Hour Safety Contact Information 
 
SAE Hotline: 
 
SAE Fax: 
 or 
 
 
Any SAE spontaneously reported to the investigator following the AE collection period 
should be reported to the sponsor if considered related to study participation. 


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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. 
6.3.1.3.4 Safety Reporting to Investigators, IRBs and Regulatory 
Authorities 
The sponsor designee (contract research organization) will be delegated the responsibility for 
reporting all suspected unexpected serious adverse reactions (SUSARs) and any other 
applicable SAEs to regulatory authorities and the IRB, as applicable. 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. 
The sponsor designee will also prepare an expedited report for other safety issues that might 
materially alter the current benefit-risk assessment of an investigational medicinal product or 
that would be sufficient to consider changes in the investigational medicinal products. 
6.3.1.4 Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor/sponsor designee of an SAE is 
essential so that legal obligations and ethical responsibilities toward the safety of subjects 
and the safety of a study drug under clinical investigation are met. 


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The sponsor/sponsor designee has a legal responsibility to notify the regulatory agencies 
about the safety of a study drug under clinical investigation. The sponsor/sponsor designee 
will comply with regulatory requirements relating to safety reporting to the regulatory 
authority, IRB, and investigators. 
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for SUSARs according to 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, if appropriate, according to local requirements. 
If there is an increase in unexpected SAEs or if there is a change in the frequency and 
character of expected SAEs based on the known safety profile of vonoprazan, further 
evaluation will be conducted to characterize these events and any impact on benefit/risk. 
Health authorities will be consulted to agree upon the appropriate action to be taken 
regarding the conduct of the study, including no change to the protocol, revision of the safety 
monitoring plan, suspension of enrollment, or discontinuation of the study. 
6.3.2 
Pregnancy 
If any subject is found to be pregnant during the study, she should be withdrawn, and any 
sponsor-supplied drug (vonoprazan active) should be immediately discontinued. If the 
pregnancy occurs during administration of active study drug, eg, after Visit 2 or within 
4 weeks of the last dose of active study drug, the pregnancy should be reported immediately, 
using a pregnancy notification form, to the contact listed in Section 6.3.1.3.2. 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. All pregnancies 
will be reported using the pregnancy form and will be followed up to final outcome. The 
outcome, including any premature termination, must be reported to the sponsor. An 
evaluation after the birth of the child will also be conducted. 


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6.3.3 
Laboratory Analyses 
See Table 6-4 for the list of clinical laboratory tests to be performed and the SoE 
(Section 13.1) for the timing and frequency. 
• The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. Note that laboratory tests at screening may be used to assess for alternative 
etiologies of a subject’s symptoms. The laboratory reports must be filed with the 
source documents. Abnormal laboratory findings that are expected with the 
underlying disease should not be considered clinically significant unless judged by 
the investigator to be more severe than expected for the subject’s condition. 
• All laboratory tests with abnormal values considered clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the 
sponsor notified. 
o All protocol-required laboratory assessments, as defined in Table 6-4, must be 
conducted in accordance with the laboratory manual and the SoE. 
 If laboratory values from non–protocol-specified laboratory 
assessments performed at the institution’s local laboratory require a 
change in subject management or are considered clinically significant 
by the investigator (eg, SAE, AE, or dose modification), then the 
results must be recorded in the unscheduled laboratory eCRF. 
All samples will be collected in accordance with acceptable laboratory procedures. Details of 
these procedures and required safety monitoring will be provided in the laboratory manual. 
Total volume of blood to be collected during the study will be documented in the ICF. 
All study-required laboratory assessments will be performed by a central laboratory. 
Investigators must document their review of each laboratory safety report. 


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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) 
Other 
screening tests 
• 
Urine drug screen including amphetamines (including methamphetamine), 
barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, methadone, and 
phencyclidine per site’s standard procedures 
• 
Urine alcohol per site’s standard procedures 
• 
hCG pregnancy test c 
• 
Serology (HIV antibody, HBsAg, and HCV antibody; hepatitis C, viral load RNA d 
[qualitative])  
ALT: alanine aminotransferase; AST: aspartate aminotransferase; 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. 
c 
Only female subjects with childbearing potential will have urine hCG; if positive, confirm with serum 
hCG. 
d 
Reflex - if hepatitis C positive. 
 
 
 
 
 


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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 body 
weight will also be measured. 
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 systolic and diastolic blood pressure, pulse rate, respiratory rate, and 
temperature.  
6.3.6 
Electrocardiograms 
Refer to the SoE (Section 13.1) for the timing and frequency of ECG assessments.  
A single, standard 12-lead ECG recordings will be made after the subject has been in the 
supine position for at least 5 minutes. A single repeat measurement is permitted at screening 
for eligibility determination. Measurements of the following intervals will be reported: 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. Assessments should include comments on whether the tracings are normal or 
abnormal (if abnormal, whether clinically significant or not clinically significant); rhythm; 
the presence of arrhythmia or conduction defects; any evidence of myocardial infarction; and 
ST-segment, T-wave, and U-wave abnormalities. 
6.4 
Safety Monitoring Committee 
A Safety Monitoring Committee is not planned for this study. 


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7 
Statistical and Analytical Plan 
7.1 
Sample Size Calculations 
Approximately 18 subjects will be enrolled with 9 subjects in each dose group. Attempts will 
be made to enroll an equal number of subjects between 12 to 15 and 16 to 17 years of age. 
Because this is a pharmacokinetic and safety trial with no comparator, there is no power 
determination affecting the sample size. The sample size of approximately 18 subjects is 
considered sufficient to assess the pharmacokinetics, safety, and tolerability of vonoprazan in 
a pediatric population aged 12 to 17 years. Fewer subjects may be enrolled based on 
preliminary data, if considered sufficient to adequately characterize the PK profile. 
7.2 
Analysis Sets 
The pharmacokinetic population will include subjects who receive at least 1 dose of study 
drug and have sufficient concentration data to support accurate estimation of at least 
1 pharmacokinetic parameter.  
The pharmacodynamic population will include subjects who receive at least 1 dose of study 
drug and have sufficient pH data to support calculation of pharmacodynamic parameters. 
The safety population will include all subjects who receive at least 1 dose of study drug. 
7.3 
Statistical Analysis Methodology 
Details of all statistical analyses will be described in a separate statistical analysis plan. 
7.3.1 
Pharmacokinetic Analyses 
The individual pharmacokinetic parameter estimates in Table 6-1 will be summarized 
descriptively by vonoprazan dose. 
7.3.2 
Efficacy/Pharmacodynamic Analyses 
The severity of GERD symptoms at baseline and Days 7 and 14, as assessed by the 
investigator, will be summarized overall and by vonoprazan dose. 
The change from baseline to Days 7 and 14 in the PGSQ-A-SF symptom and impact 
subscale, as assessed by the adolescent, will be summarized overall and by vonoprazan dose. 


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Mean pH and the percentage of time above pH 4, 5, and 6 at baseline (Day -1) and Day 7 will 
be summarized for the subset of subjects for whom intragastric pH monitoring is available. 
7.3.3 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent 
AEs will be summarized by vonoprazan dose and overall, as well as by severity and 
relationship to study drug.  
Actual values and changes from baseline to each visit for clinical laboratory test results, vital 
sign measurements, and 12-lead ECG results will be summarized by vonoprazan dose at each 
time point using descriptive statistics (number of subjects, mean, standard deviation, median, 
minimum, and maximum). Shift tables will be generated for clinical laboratory test results. 
7.3.4 
Other Analyses 
Baseline demographic variables will be summarized overall for all subjects. The number of 
subjects who enroll in the study and the number and percentage of subjects who complete the 
study will be presented. The frequency and percentage of subjects who withdraw or 
discontinue from the study and the reason for withdrawal or discontinuation will also be 
summarized. 
7.3.5 
Interim Analyses 
No formal interim analyses will be performed in this study. 


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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 
Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an IRB 
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 and/or LAR must 
be approved by the IRB. Documentation of all IRB approvals and of the IRB 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 approvals should be signed by the IRB chairperson or designee and must identify the 
IRB 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. The 
investigator must promptly supply the sponsor or its designee, the IRB, 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 regulatory authority regulations shall be 
obtained from each subject’s LAR before entering the subject in the study or performing any 
unusual or nonroutine procedure that involves risk to the subject. Participating subjects will 
provide assent as applicable. 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 and assent materials should be reviewed by the 
sponsor or its designee or both before IRB submission. Once reviewed, the consent and 
assent materials will be submitted by the investigator to his or her IRB for review and 


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


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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 
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. 
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: 
• IRB approval 
• Original investigator-signed investigator agreement page of the protocol 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 for United States sites 
• Curriculum vitae for the investigator and each subinvestigator listed on Form 
FDA 1572 
• Financial disclosure information to allow the sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR 54. In addition, 
the investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study. 
• IRB-approved informed consent and assent (if applicable), 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 and LAR 
• 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 according to the timeline and method outlined in the protocol. In 
addition, the investigator agrees to submit annual reports to the study site IRB 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 with a summary of the study’s 
outcome and the sponsor and regulatory authority(ies) with any reports required. 
10.8 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
10.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The sponsor has final approval authority over all 
such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 


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11 Study Management 
11.1 Monitoring 
11.1.1 External Data Monitoring Committee 
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 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 
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 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 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 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 the 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 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 LARs and study subjects, as appropriate.  


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children 1 to 11 years old with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 
2011;52(6):691-701. 
Zhao J, Li J, Hammer-Maansson JE, et al. Pharmacokinetic properties of esomeprazole in 
children aged 1 to 11 years with symptoms of gastroesophageal reflux disease: a randomized, 
open-label study. Clin Ther 2006;28(11):1868-76. 


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13 Appendices 
13.1 Appendix 1: Schedule of Events  
 




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a 
Visit 2 and Visit 5 only required for subjects undergoing gastric pH monitoring at select sites.  
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 
Informed consent will be signed by the subject’s legally authorized representative prior to any activity in the study. Subject assent (if applicable) may be obtained 
as required per site guidelines. 
d 
A complete physical examination will be performed at screening (at minimum, assessment of skin, cardiovascular, respiratory, gastrointestinal, and neurological 
systems). A brief physical examination will be performed at other visits (at minimum, assessment of skin, cardiovascular, respiratory, and gastrointestinal 
systems). Interim physical examinations may be performed at the discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. 
e 
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and temperature. 
f 
Height collected only at screening. 
g 
Hepatitis B surface antigen, hepatitis C virus antibody, and HIV type 1 and 2 antibodies. 
h 
Urine drug/alcohol screen will occur at screening per the site standard procedures. 
i 
Clinical laboratory testing will include hematology, serum chemistry, and urinalysis. Glucose will be obtained after an 8-hour fast at all visits. Blood draws should 
follow vital signs or electrocardiograms. 
j 
Only female subjects with childbearing potential will have urine hCG; if positive, confirm with serum hCG.  
k 
Single 12-lead electrocardiogram recordings will be made after the subject has been in the supine position for at least 5 minutes at screening. A single repeat 
measurement is permitted at screening for eligibility determination. Measurements of the following intervals will be reported: PR interval, RR interval, QRS 
interval, and QT 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. Assessments should include comments on whether the tracings are normal or abnormal (if abnormal, whether clinically significant or not clinically 
significant); rhythm; the presence of arrhythmia or conduction defects; any evidence of myocardial infarction; and ST-segment, T-wave, and U-wave 
abnormalities. 
l 
Subject will be randomized to study treatment after all eligibility criteria have been met. 
m 
Subjects will self-administer study drug, possibly with assistance from the parent/caregiver. Study drug will be dispensed and administered in the clinic on 
Days 1, 7, and 14. Study drug for at-home administration will be dispensed on Day 1 (to be taken on Days 2-6) and Day 7 (to be taken on Days 8-13). Study drug 
should be taken every day between 7 and 10 am on an empty stomach. The exact time of dosing on Day 6 and Day 13, if the dose was taken on an empty stomach 
should be noted by the subject or parent/caregiver and recorded by clinic staff upon arrival at the clinic. Subjects will be instructed not to eat any food or take 
study drug on the morning of Days 7 and 14 prior to their arrival at the clinic. If a subject consumes any food prior to the dose on Days 6 and 13 or prior to arrival 
at the clinic on Days 7 or 14, the time and content of the meal is to be noted and recorded in the eCRF by clinic staff. On Days 7 and 14, water is permitted as 
desired except for the period 1 hour before and 1 hour after administration of study drug (other than as permitted for study drug dosing). Subjects will be provided 
a meal 30-60 minutes after study drug dosing on Days 7 and 14 per the clinic’s standard procedures. 
n 
Check in on Day -1 and Check out on Day 1 and Check in on Day 7 and Check out on Day 8 (as determined by PI) is only for subjects who will undergo 24-hour 
gastric pH monitoring.   
o 
Gastric pH monitoring on Day -1 for 24 hours and on Day 7 for 24 hours; only if clinically indicated. 
p 
Blood samples for PK analysis of vonoprazan in plasma will be collected on Days 7 and 14. On both days, one pre-dose sample will be collected prior to the 
morning administration of vonoprazan and two additional samples will be collected after drug administration: one between 0.5 and 2 hours post-dose and one 
between 2.5 and 4 hours post-dose. The exact time of each pharmacokinetic sample should be recorded in the source and eCRF. 


Phathom Pharmaceuticals, Inc. 
 
  
 
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q 
Collection of pretreatment events will start after the informed consent form has been signed. Adverse events will be assessed from time of informed consent 
signing until the follow-up visit and should be followed until they are resolved, stable, or judged by the investigator to be not clinically significant. 
 


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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 2 weeks after 
the last dose of study drug, female subjects of childbearing potential* who are sexually active 
with a nonsterilized male partner** must use adequate contraception. In addition, they must 
be advised not to donate ova during this period. 
*Females NOT of childbearing potential are defined as those who are premenarchal, 
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 level >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. 
Note: If the childbearing potential of a subject changes after start of the study (eg, a 
premenarchal female subject experiences menarche) or the risk of pregnancy changes (eg, a 
female subject who is not heterosexually active becomes active), the participant must discuss 
this with the investigator, who should determine if the female subject must begin a highly 
effective method of contraception or a male participant must use a condom. 
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 


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• Progesterone T PLUS condom or spermicide 
Hormonal Contraceptives 
• Implants 
• 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 normal 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 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 
 
 
 
24-Hour Safety Contact Information 
SAE Hotline: 
 
SAE Fax: 
 or 
 
 
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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13.4.2 GERD Symptom Assessment-Investigator 
The following 5 symptoms of GERD will be evaluated. 
Symptom 
Definition 
Heartburn 
A burning feeling in the mid-epigastric area and/or chest 
Acid regurgitation 
Flow of sour or bitter fluid into the mouth 
Dysphagia 
Difficulty in swallowing 
Belching 
The voiding of gas from the stomach through the mouth, which 
may have been associated with acid regurgitation 
Epigastric pain 
Central upper abdominal pain 
 
The maximum severity of each GERD symptom occurring during the 7 days prior to the 
study visit will be assessed as detailed below. 
Severity 
Definition 
None 
No symptom 
Mild 
Symptom did not last long and was easily tolerated 
Moderate 
Symptom caused discomfort and/or interrupted usual activities 
(including sleep) 
Severe 
Symptom caused great interference with usual activities and may 
have been incapacitating (including sleep) 
Very severe 
Symptom caused intense and constant discomfort and/or marked 
interference with usual activities (including sleep) 


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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 
Synopsis (Study Population) 
Subjects 12 to 17 years of age, inclusive, with a medical history of symptoms of GERD for at 
least 3 months prior to screening. 
Synopsis (Study Design) 
Subjects will be confined to the clinic for pharmacokinetic testing. Blood samples for 
pharmacokinetic testing will be collected on Day 7 for 24 hours. Select sites will perform 
gastric pH monitoring in subjects if deemed clinically indicated by the principal investigator,. 
gGastric pH may will be monitored for 24 hours beginning on Day -1 and on Day 7. 
Synopsis (Study Drug, Dosage, and Route of Administration) 
Open-label study drug (vonoprazan 10 mg or vonoprazan 20 mg) to be taken orally QD for 
14 days (Day 1 through Day 14). All study drug doses are to be taken on an empty stomach 
with approximately 240 mL (8 oz) water between 7 and 10 am each day. 
Study Design (Section 3.1) 
Subjects will be confined to the clinic for pharmacokinetic testing. Blood samples for 
pharmacokinetic testing will be collected on Day 7 for 24 hours. Select sites will perform 
gastric pH monitoring in subjects if deemed clinically indicated by the principal investigator,. 
gGastric pH may will be monitored for 24 hours beginning on Day -1 and on Day 7. 




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Inclusion Criteria (Section 4.1.1) 
1. The subject is 12 to 17 years of age, inclusive, at the time of informed consent signing 
and throughout study participation. 
Lifestyle Considerations (Section 4.1.4) 
Consumption of grapefruit or grapefruit juice, Seville orange or Seville orange-containing 
products (eg, marmalade), or other food products that may be CYP3A4 inhibitors (eg, 
vegetables from the mustard green family [kale, broccoli, watercress, collard greens, 
kohlrabi, Brussels sprouts, mustard] and charbroiled meats) within 7 days (or 5 half-lives) 
before the first dose of study drug and throughout the study will be prohibited. 
Treatments Administered (Section 5.2) 
Subjects will be instructed to take randomized study drug orally each morning between 7 and 
10 am on an empty stomach with approximately 240 mL (8 oz) water between 7 and 10 am 
daily. Subjects will take study drug at the clinic on Days 1, 7, 8, and 14; otherwise, study 
drug will be taken on an outpatient basis. Any missed doses should be noted by the subject 
and communicated to clinic staff to record in the eCRF.  
For the Day 6 dose, subjects will note the time it was taken and if they took the dose on an 
empty stomach. If the dose was not taken on an empty stomach, the subject is to note the 
time and content of any meal consumed prior to taking their study drug dose on Day 6. Clinic 
staff will record this information in the eCRF. 
Subjects who do not check in to the clinic on the optional Day 6 visit will be instructed not to 
eat any food or take study drug on the morning of Day 7 prior to their arrival at the clinic. If a 
subject consumes any food prior to arrival, the time and content of the meal is to be noted by 
the subject and recorded in the eCRF by clinic staff.  
On Day 7, subjects will take their study drug dose in the clinic. Water is permitted as desired, 
except for 1 hour before and 1 hour after administration (other than is permitted for study 
drug dosing). Subjects will be provided a meal 30-60 minutes after study drug dosing per the 
clinic’s standard procedures. 
 


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Pharmacokinetic Assessments (Section 6.1.1) 
Subjects (or parents/caregivers) will be asked to record note the exact time they took their 
study drug dose on Day 6 and if they took the dose on an empty stomach. If the dose was not 
taken on an empty stomach, the subject is to note the time and content of any meal consumed 
prior to taking their study drug dose on Day 6. Clinic staff will record this information in the 
eCRF. 
Subjects may either return to the clinic in the evening of Day 6 or in the morning on Day 7 
(before 7 am) for pharmacokinetic sampling on Day 7. If subjects return to the clinic in the 
morning on Day 7, they should not eat or take the vonoprazan study medication before 
returning to the clinic; the time and content of any meal consumed prior to arrival at the 
clinic is to be recorded in the eCRF by clinic staff. Subjects will be released from the clinic 
on Day 8 after pharmacokinetic sampling and study procedures are completed. On Day 14, 
subjects will return to the clinic between 7 and 10 am for a predose pharmacokinetic sample. 
Blood samples for pharmacokinetic analysis of vonoprazan in plasma will be collected on 
Day 7 within 30 minutes prior to the morning administration of vonoprazan and at 0.25, 0.5, 
0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours after drug administration. for the 
assessment of steady state. On Day 14, a single pharmacokinetic sample will be collected 
within 30 minutes prior to the morning administration of vonoprazan. Pharmacokinetic 
sampling should be timed to occur last and as close to the scheduled time window as 
possible. 
Electrocardiograms (Section 6.3.6) 
A single, standard 12-lead ECG recordings will be made after the subject has been in the 
supine position for at least 5 minutes. A single repeat measurement is permitted at screening 
for eligibility determination. Measurements of the following intervals will be reported: 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. Assessments should include comments on whether the tracings are normal or 
abnormal (if abnormal, whether clinically significant or not clinically significant); rhythm; 
the presence of arrhythmia or conduction defects; morphology; any evidence of myocardial 
infarction; and ST-segment, T-wave, and U-wave abnormalities. 




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a 
Visit 2 (Day -1) is only required for subjects undergoing gastric pH monitoring at select sites.  
b 
Visit 4 (Day 6) is an optional visit for subjects that check in to the clinic in the evening before starting Day 7 assessments. 
ac 
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. 
bd Informed consent will be signed by the subject’s legally authorized representative prior to any activity in the study. Subject assent (if applicable) may be obtained as required 
per site guidelines. 
ce 
A complete physical examination will be performed at screening (at minimum, assessment of skin, cardiovascular, respiratory, gastrointestinal, and neurological systems). A 
brief physical examination will be performed at other visits (at minimum, assessment of skin, cardiovascular, respiratory, and gastrointestinal systems). Interim physical 
examinations may be performed at the discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. 
df 
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and temperature. 
eg 
Height collected only at screening. 
fh 
Hepatitis B surface antigen, hepatitis C virus antibody, and HIV type 1 and 2 antibodies. 
gi 
Urine drug/alcohol screen will occur at screening per the site standard procedures. 
hj 
Clinical laboratory testing will include hematology, serum chemistry, and urinalysis. Glucose will be obtained after an 8-hour fast at all visits. Blood draws should follow vital 
signs or electrocardiograms. 
ik 
Subject should be fasting for 12 hours. Blood sample for gastrin will be collected prior to study drug dosing.  
jl 
Only female subjects with childbearing potential will have urine hCG; if positive, confirm with serum hCG.  
km Single 12-lead electrocardiogram recordings will be made after the subject has been in the supine position for at least 5 minutes at screening. A single repeat measurement is 
permitted at screening for eligibility determination. Measurements of the following intervals will be reported: PR interval, RR interval, QRS interval, and QT 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. Assessments should include comments on 
whether the tracings are normal or abnormal (if abnormal, whether clinically significant or not clinically significant); rhythm; the presence of arrhythmia or conduction 
defects; morphology; any evidence of myocardial infarction; and ST-segment, T-wave, and U-wave abnormalities. 
ln 
Subject will be randomized to study treatment after all eligibility criteria have been met. 
mo Subjects will self-administer study drug, possibly with assistance from the parent/caregiver. Study drug will be dispensed and administered in the clinic on Days 1, 7, 8 and 
14. Study drug for at-home administration will be dispensed on Day 1 (to be taken on Days 2-6) and Day 8 (to be taken on Days 9-13). Study drug should be taken every day 
between 7 and 10 am on an empty stomach. The exact time of dosing on Day 6 and if the dose was taken on an empty stomach should be noted by the subject or 
parent/caregiver and recorded by clinic staff upon arrival at the clinic. Subjects who do not check in to the clinic on the optional Day 6 visit will be instructed not to eat any 
food or take study drug on the morning of Day 7 prior to their arrival at the clinic. If a subject consumes any food prior to the dose on Day 6 or prior to arrival at the clinic on 
Day 7, the time and content of the meal is to be noted and recorded in the eCRF by clinic staff. On Day 7, water is permitted as desired except for the period 1 hour before and 
1 hour after administration of study drug (other than as permitted for study drug dosing). Subjects will be provided a meal 30-60 minutes after study drug dosing on Day 7 per 
the clinic’s standard procedures. 
np Check in on Day -1 is only for subjects who will undergo 24-hour gastric pH monitoring. Subjects may check in on Day 6 or Day 7 (as determined by site). Day 7 check in 
must occur no later than 7 am.  
oq Gastric pH monitoring on Day -1 for 24 hours and on Day 7 for 24 hours; only if clinically indicated. 


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pr 
Blood samples for PK analysis of vonoprazan in plasma will be collected on Day 7 within 30 minutes prior to the morning administration of vonoprazan and at 0.25, 0.5, 0.75, 
1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours after drug administration for the assessment of steady state. On Day 14, a single PK sample within 30 minutes prior to the 
morning administration of vonoprazan. PK sampling should be timed to occur last and as close to the scheduled time window as possible. 
qs 
Collection of pretreatment events will start after the informed consent form has been signed. Adverse events will be assessed from time of informed consent signing until the 
follow-up visit and should be followed until they are resolved, stable, or judged by the investigator to be not clinically significant. 
 


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13.5.2 Protocol Amendment 2 
Synopsis (Study Sites) 
Approximately 5 12 sites in the United States 
Synopsis (Rationale) 
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 symptomatic non-erosive GERD, 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 in adults 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. Two large studies in pediatric patients have reported that 18% experience 
weekly heartburn and 20% experience GERD symptoms. In addition, an analysis of 
1.2 million insurance claims found that the incidence rate of GERD in patients aged 12 to 
17 years increased by 34% from 2000 to 2005. 
Vonoprazan belongs to a new class of acid-inhibitory agents called “potassium-competitive 
acid blockers”. In the United States, vonoprazan in combination with amoxicillin or in 
combination with amoxicillin and clarithromycin is approved for the treatment of 
Helicobacter pylori infection in adults. Vonoprazan is being developed in adults for the 
treatment of heartburn in patients with symptomatic non-erosive GERD, healing of all grades 
of EE and relief of heartburn, and maintenance of healing of all grades of EE and relief of 
heartburn, and treatment of Helicobacter pylori infection. 
The pediatric doses for this study were selected to approximate equivalent adult exposures 
following administration of vonoprazan 10 or 20 mg QD and are age-based for adolescents 
12 to 17 years of age. 
Synopsis (Study Design) 
This is a Phase 1, uncontrolled, randomized, open-label, parallel-group, multiple-dose study 
in adolescents aged 12 to 17 years with symptomatic GERD. Subjects will be screened for up 
to 28 days. Successfully screened subjects will be randomized to receive 10 or 20 mg of 
vonoprazan QD for 14 days. A total of 18 subjects will be enrolled into the study. 
Subjects will be confined to the clinic for pharmacokinetic testing. Blood samples for 
pharmacokinetic testing will be collected on Days 7 and 14 for 24 hours. Select sites will 
perform gastric pH monitoring in subjects deemed clinically indicated by the principal 
investigator.  
Subjects undergoing gastric pH monitoring will be confined to the clinic for testing. Gastric 
pH will be monitored for 24 hours beginning on Day -1 and on Day 7. 


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The study will include 3 periods: 
Screening Period (≤4 weeks): Subjects will undergo screening assessments to determine 
study eligibility, and baseline assessments will be performed. If all eligibility criteria are met, 
the subject will be randomized and enter the Treatment Period. 
Treatment Period (Day 1 to Day 14): Subjects will be randomized to receive vonoprazan 
10 mg or vonoprazan 20 mg QD. 
Follow-up Period: A safety follow-up phone call will occur 2 weeks after the last dose of 
study drug to assess adverse events (AEs). 
A subject will be considered to have completed the study if the subject completes the 
Treatment Period and the safety follow-up phone call. 
Following completion of study drug dosing or early discontinuation, the subject will be 
transitioned to local standard of care in accordance with each site’s prespecified process. 
Synopsis (Study Pharmacokinetic Assessments) 
The primary vonoprazan pharmacokinetic endpoints will include the following steady state 
parameters measured on Day 7: 
• Maximum observed drug concentration at steady state (Cmax,ss) 
• Area under the plasma concentration-time curve during the dosing interval τ (AUCτ) 
• Time at steady state to reach Cmax,ss (Tmax,ss) 
• Terminal elimination half life (t1/2z) 
• Apparent oral clearance (CL/F) 
• Apparent volume of distribution (Vz/F) 
Synopsis (Efficacy and Pharmacodynamic Assessments) 
Efficacy and pharmacodynamic characteristics will be assessed by the following: 
• The severity of GERD symptoms at screening and Days 87 and 14 as assessed by the 
investigator 
• The Pediatric Gastro-esophageal Symptom and Quality of Life 
Questionnaire-Adolescent-Short Form (PGSQ-A-SF) symptom and impact subscale 
as assessed by the adolescent at screening and Days 87 and 14 
• Mean pH and percentage of time above pH 4, 5, and 6 at Day -1 and Day 7 in the 
subset of subjects for whom intragastric pH monitoring is performed when clinically 
indicated per the investigator 
Synopsis (Safety Assessments) 
Safety will be assessed by the following: 


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• AEs 
• Laboratory test values (hematology, serum chemistry, urinalysis) 
• Serum gastrin and pepsinogen I and II levels 
• Electrocardiograms  
• Vital sign 
Synopsis (Sample Size) 
Approximately 18 subjects will be enrolled with 9 subjects in each dose group. Attempts will 
be made to enroll an equal number of subjects between 12 to 15 and 16 to 17 years of age. 
Because this is a pharmacokinetic and safety trial with no comparator, there is no power 
determination affecting the sample size. The sample size of approximately 18 subjects is 
considered sufficient to assess the pharmacokinetics, safety, and tolerability of vonoprazan in 
a pediatric population aged 12 to 17 years. Fewer subjects may be enrolled based on 
preliminary data, if considered sufficient to adequately characterize the PK profile. 
Synopsis (Statistical Methods) 
Pharmacokinetic Endpoints: 
Individual pharmacokinetic parameters on Day 7 parameter estimates will be summarized 
descriptively by vonoprazan dose. Descriptive statistics will include number of subjects, 
arithmetic mean, standard deviation, coefficient of variation, geometric mean, geometric 
coefficient of variation, median, minimum, and maximum, as appropriate. 
Efficacy and Pharmacodynamic Endpoints: 
The severity of GERD symptoms at screening and Days 87 and 14, as assessed by the 
investigator, will be summarized overall and by vonoprazan dose. 
The change from baseline (ie, screening assessment) to Days 87 and 14 in the PGSQ-A-SF 
symptom and impact subscale, as assessed by the adolescent, will be summarized overall and 
by vonoprazan dose. 
Mean pH and the percentage of time above pH 4, 5, and 6 at baseline (Day -1) and Day 7 will 
be summarized for the subset of subjects for whom intragastric pH monitoring is available. 
Safety: 
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.  
Clinical laboratory tests, gastrin and pepsinogen I and II levels, electrocardiograms, and vital 
signs will be summarized with descriptive statistics at each time point by treatment group. 


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Introduction (Section 1) 
Vonoprazan belongs to a new class of acid-inhibitory agents called potassium-competitive 
acid blockers (PCABs). In the United States, vonoprazan in combination with amoxicillin or 
in combination with amoxicillin and clarithromycin is approved for the treatment of 
Helicobacter pylori infection in adults. Vonoprazan is being developed in adults for the 
treatment of heartburn in patients with symptomatic non-erosive GERD, healing of all grades 
of erosive esophagitis (EE) and relief of heartburn, and maintenance of healing of all grades 
of EE and relief of heartburn, and treatment of Helicobacter 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 (Takeda) to develop, manufacture, and commercialize vonoprazan in the 
United States, Europe, and Canada. 
Vonoprazan (Section 1.1.1) 
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 may selectively concentrates in the parietal cells in both the resting and 
stimulated states,. It also binds to the active pumps in a noncovalent and reversible 
manner, 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 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 [Jenkins 2015]. This is significantly 
longer than the half-life of conventional PPIs (<2 hours) [Shin 2013]. 
• Metabolism: Vonoprazan is predominantly metabolized by a combination of 
cytochrome P450 (CYP) isoforms including CYP3A4/5, which does not have lacks a 
high degree of genetic polymorphism as compared withto 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, 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 8 short-term clinical studies in adults with EE (5 studies) and symptomatic 
non-erosive GERD (3 studies) with treatment durations of 2 to 8 weeks. In addition, Takeda 
conducted 3 studies of maintenance of healing of EE with treatment durations of 24 to 
52 weeks. Vonoprazan is approved in multiple countries outside the United States for the 
treatment of adults for reflux (erosive) esophagitis (for healing: vonoprazan 20 mg QD up to 
4 weeks or, if insufficient effect, 8 weeks; for maintenance: 10 mg QD or, if insufficient 
effect, 20 mg QD). 
The safety profile of vonoprazan in Phase 3 studies of adults across indications showed there 
was no evidence of a dose-related increase in adverse effects with vonoprazan from 5 mg to 
40 mg QD, and the safety profile of vonoprazan was similar to that of lansoprazole. As of 
16 June25 December 2021, the global cumulative postmarketing patient exposure to 
vonoprazan is estimated to be over 6870 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 
adolescents with GERD. 
 
 


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Study Objectives and Endpoints (Section 2) 
Study objectives with corresponding endpoints are presented in Table 2-1. 
Table 2-1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate the pharmacokinetic profile of 
vonoprazan (10 or 20 mg QD) in adolescent 
subjects with symptomatic GERD. 
• 
Cmax,ss, AUCτ, Tmax,ss, t1/2z, CL/F, Vz/F on Day 7 
Safety 
• To evaluate the safety of vonoprazan (10 or 
20 mg QD) in adolescent subjects with 
symptomatic GERD. 
• 
Adverse events 
• 
Laboratory test values (hematology, serum 
chemistry, urinalysis) 
• 
Serum gastrin and pepsinogen I and II levels 
• 
Electrocardiograms 
• 
Vital signs 
Exploratory 
• To evaluate symptom relief and 
pharmacodynamics of vonoprazan (10 or 20 mg 
QD) in adolescent subjects with symptomatic 
GERD. 
• 
The severity of GERD symptoms at screening 
and Days 87 and 14 as assessed by the 
investigator 
• 
The PGSQ-A-SF symptom and impact subscale 
as assessed by the adolescent at screening and 
Days  87 and 14 
• 
Mean pH and percentage of time above pH 4, 5, 
and 6 at Day -1 and Day 7 in the subset of 
subjects for whom intragastric pH monitoring is 
performed when clinically indicated per the 
investigator 
AUCτ: area under the plasma concentration-time curve during the dosing interval τ; CL/F: apparent oral 
clearance; Cmax,ss: maximum observed drug concentration at steady state; GERD: gastroesophageal reflux 
disease; PGSQ A-SF: Pediatric Gastro-esophageal Symptom and Quality of Life Questionnaire-Adolescent-
Short Form; QD: once daily; t1/2z: terminal elimination half life; Tmax,ss: time at steady state to reach Cmax,ss; 
Vz/F: apparent volume of distribution 
 
Study Design (Section 3.1)  
This is a Phase 1, uncontrolled, randomized, open-label, parallel-group, multiple-dose study 
in adolescents aged 12 to 17 years with symptomatic GERD. Subjects will be screened for up 
to 28 days. Successfully screened subjects will be randomized to receive 10 or 20 mg of 
vonoprazan QD for 14 days. A total of 18 subjects will be enrolled into the study. 


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Subjects will be confined to the clinic for pharmacokinetic testing. Blood samples for 
pharmacokinetic testing will be collected on Days 7 and 14for 24 hours. Select sites will 
perform gastric pH monitoring in subjects deemed clinically indicated by the principal 
investigator. Subjects undergoing gastric pH monitoring will be confined to the clinic for 
testing. Gastric pH will be monitored for 24 hours beginning on Day -1 and on Day 7. 
A schematic diagram of the overall study design is presented in Figure 3-1. 
 




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The study will include 3 periods (see the schedule of events [SoE] in Section 13.1 for 
details): 
Screening Period (≤4 weeks): Subjects will undergo screening assessments to 
determine study eligibility, and baseline assessments will be performed. If all 
eligibility criteria are met, the subject will be randomized and enter the Treatment 
Period. 
Treatment Period (Day 1 to Day 14): Subjects will be randomized to receive 
vonoprazan 10 mg or vonoprazan 20 mg QD. 
Follow-up Period (2 weeks): A safety follow-up phone call will occur 2 weeks after 
the last dose of study drug to assess adverse events (AEs). 
A subject will be considered to have completed the study if the subject completes the 
Treatment Period and the safety follow-up phone call. 
Following completion of study drug dosing or early discontinuation, the subject will be 
transitioned to local standard of care in accordance with each site’s prespecified process. 
Selection of Study Population (Section 4.1) 
This study will be conducted at approximately 512 sites in the United States and will 
randomize 18 subjects (9 subjects per vonoprazan dose group) in the Treatment Period. 
Exclusion Criteria (Section 4.1.2) 
3. The subject has received other agents affecting digestive organs, including muscarinic 
antagonists (eg, hyoscyamine), prokinetics, oral anticholinergic agents, 
prostaglandins, bismuth, sucralfate from 30 days prior to Day 1 or requires their use 
during the course of the study. 
Treatments administered (Section 5.2) 
Subjects will be instructed to take randomized study drug orally each morning between 7 and 
10 am on an empty stomach with approximately 240 mL (8 oz) water. Subjects will take 
study drug at the clinic on Days 1, 7, 8, and 14; otherwise, study drug will be taken on an 


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outpatient basis. Any missed doses should be noted by the subject and communicated to 
clinic staff to record in the eCRF.  
For the Days 6 and 13 dose, subjects will note the time it was taken and if they took the dose 
on an empty stomach. If the dose was not taken on an empty stomach, the subject is to note 
the time and content of any meal consumed prior to taking their study drug dose on Day 6. 
Clinic staff will record this information in the eCRF. 
Subjects who do not check in to the clinic on the optional Day 6 visit will be instructed not to 
eat any food or take study drug on the mornings of Days 7 and 14 prior to their arrival at the 
clinic. If a subject consumes any food prior to arrival, the time and content of the meal is to 
be noted by the subject and recorded in the eCRF by clinic staff.  
On Days 7 and 14, subjects will take their study drug dose in the clinic. Water is permitted as 
desired, except for 1 hour before and 1 hour after administration (other than what is permitted 
for study drug dosing). Subjects will be provided a meal 30-60 minutes after study drug 
dosing per the clinic’s standard procedures. 
Excluded Medications (Section 5.8.1) 
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  
phone call 
Antacids and sucralfate 
Day -1 (day before first 
dose of study drug) 
Day 14 (end of 
study drug dosing) 
H2RAs 
7 days prior to Day 1 
Day 14 (end of 
study drug dosing) 
PPIs 
7 days prior to Day 1 
Day 14 (end of 
study drug dosing) 
Strong inhibitors or inducers of CYP3A4 
(eg, itraconazole, ketoconazole, indinavir, nelfinavir, 
ritonavir, saquinavir, telithromycin) 
14 days prior to Day 1 
End of treatment 
CYP3A4 substrates with a narrow therapeutic index 
14 days prior to Day 1 
End of treatment 
Surgical procedures that could affect gastric acid 
secretion (eg, any form of partial gastrectomy, 
vagotomy) 
30 days prior to Day 1 
Follow-up  
phone call 
Other agents affecting digestive organs, including 
muscarinic antagonists (eg, hyoscyamine), prokinetics, 
oral anticholinergic agents, prostaglandins, bismuth, 
sucralfate 
30 days prior to Day 1 
Follow-up  
phone call 
Atazanavir sulfates; rilpivirine hydrochloride 
(contraindicated with vonoprazan) 
5 days prior to Day 1 
Follow-up  
phone call 
CYP: cytochrome P450 isoenzyme; H2RA: histamine-2 receptor antagonist; PPI: proton pump inhibitor 
Note: Following completion of study drug dosing or early discontinuation, the subject will be transitioned to local 
standard of care in accordance with each site’s prespecified process. 
 
Pharmacokinetic Assessments (Section 6.1.1) 
Subjects (or parents/caregivers) will be asked to note the exact time they took their study 
drug dose on Days 6 and 13 and if they took the dose on an empty stomach. If the dose was 
not taken on an empty stomach, the subject is to note the time and content of any meal 
consumed prior to taking their study drug dose on Days 6 and 13. Clinic staff will record this 
information in the eCRF. 
Subjects may either return to the clinic in the evening of Day 6 or will arrive in the morning 
on Days 7 and 14 (before 7 am) for pharmacokinetic sampling. on Day 7. If subjects return to 


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the clinic in the morning on Day 7, they They should not eat or take the vonoprazan study 
medication before arriving returning to the clinic; the time and content of any meal consumed 
prior to arrival at the clinic is to be recorded in the eCRF by clinic staff. Subjects will be 
released from the clinic on Day 8 after pharmacokinetic sampling and study procedures are 
completed.  
Blood samples for pharmacokinetic analysis of vonoprazan in plasma will be collected on 
Days 7 and 14. within 30 minutes On each of those days, one pre-dose sample will be 
collected prior to the morning administration of vonoprazan and at 0.25, 0.5, 0.75, 1, 1.5, 2, 
3, 4, 6, 8, 10, 12, 16, and 24 hours after drug administration. Pharmacokinetic sampling Two 
additional samples will be collected after drug administration: one between 0.5 and 2 hours 
post-dose and one between 2.5 and 4 hours post-dose. The exact time of each 
pharmacokinetic sample should be recorded. timed to occur last and as close to the scheduled 
time window as possible. 
Samples will be collected into appropriate blood collection tubes as specified by the 
bioanalytical laboratory. Details of blood collection, processing, storage and shipping will be 
contained in the Clinical Laboratory Manual. 
Bioanalytical Methods 
Plasma concentrations of vonoprazan will be measured at Labcorp Early Development 
Laboratories Inc. (Madison, WI) using a validated liquid chromatrography/mass spectrometry 
method with an analytical range of 0.1 to 100 µg/mL and will be used for the calculation of 
the plasma vonoprazan pharmacokinetic parameters. 
Depending on pace of enrollment, pharmacokinetic samples from a subset or subsets of 
subjects may be analyzed prior to the completion of enrollment. In any case, all of the 
pharmacokinetic samples collected from a given subject will be analyzed in the same 
bioanalytical batch.  
Pharmacokinetic Parameters 
Plasma pharmacokinetic parameters shown in Table 6-1 will be derived estimated using a 
non-linear mixed effects model compartmental analysis methods and will be determined from 
the concentration-time data for all evaluable subjects. Actual sampling times, rather than 


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scheduled or nominal sampling times, will be used in all computations using sampling time. 
Additional pharmacokinetic parameters may be calculated estimated as appropriate. 
Table 6-1 
Pharmacokinetic Parameters to be Calculated Estimated using 
Vonoprazan Plasma Concentration time Data 
Parameter 
Definition 
Cmax,ss 
Maximum observed plasma concentration at steady state 
Cmax,ss/Dose 
Dose-normalized Cmax,ss (Cmax,ss divided by the administered dose in mg) 
AUCτ,ss 
Area under the plasma concentration-time curve during the dosing interval τ, where τ is 
the length of the dosing interval in hours, calculated using the linear trapezoidal rule 
AUCτ,ss/Dose Dose-normalized AUCτ,ss (AUCτ,ss divided by the administered dose in mg) 
Tmax 
Time to reach Cmax 
t1/2z 
Terminal elimination half life, calculated as ln(2)/λz 
λz 
Terminal elimination rate constant, calculated as the negative slope of the log-linear 
regression of the natural logarithm concentration-time curve during the terminal phase 
CL/F 
Apparent total plasma clearance after oral (extravascular) administration, calculated as 
Dose/ AUCτ,ss 
Vz/F 
Apparent volume of distribution during the terminal elimination phase after oral 
(extravascular) administration, calculated as (CL/F)/ λz 
 
Pharmacodynamic Assessments (Section 6.1.2) 
If deemed clinically indicated by the principal investigator, gastric pH will be determined 
measured and recorded continuously for a 24-hour period on scheduled days as outlined in 
the SoE (Section 13.1) using a suitable pH probe and ambulatory pH recording system. All 
instruments will be calibrated prior to and following use. Gastric pH will be monitored for 24 
hours, as outlined in the SoE (Section 13.1) sampled and recorded every 5 seconds. The 24-
hour continuous pH recording session will commence 30 to 60 minutes prior to treatment 
administration. The reason for pH assessments, start time, stop time and any interruptions 
will be recorded in the source document and the case report form (CRF). To minimize the 
discomfort of probe insertion, administration of a topical anesthetic (lidocaine) will be 
permitted. After each 24-hour recording period, the flashcard will be removed from the 
recorder and the pH data will be transferred to the computer. 
 
 


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Adverse Event of Special Interest (Section 6.3.1.1.4) 
An AE of special interest is a noteworthy event for the particular product or class of products 
that a sponsor may wish to monitor carefully. It could be serious or nonserious (eg, hair loss, 
loss of taste, impotence), and could include events that might be potential precursors or 
prodromes for more serious medical conditions in susceptible individuals. 
Adverse events of special interest include any event listed 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 
 
Laboratory Analyses (Section 6.3.3) 


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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 as safety/pharmacodynamic biomarkers at Days 1 (prior to study drug 
dosing), 8, and 14 after fasting for 12 hours.  
Other 
screening tests 
• 
Urine drug screen including amphetamines (including methamphetamine), 
barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, methadone, and 
phencyclidine per site’s standard procedures 
• 
Urine alcohol per site’s standard procedures 
• 
hCG pregnancy test c 
• 
Serology (HIV antibody, HBsAg, and HCV antibody; hepatitis C, viral load RNA d 
[qualitative])  
ALT: alanine aminotransferase; AST: aspartate aminotransferase; 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. 
c 
Only female subjects with childbearing potential will have urine hCG; if positive, confirm with serum 
hCG. 
d 
Reflex - if hepatitis C positive. 
 


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Sample Size Calculation (Section 7.1) 
Approximately 18 subjects will be enrolled with 9 subjects in each dose group. Attempts will 
be made to enroll an equal number of subjects between 12 to 15 and 16 to 17 years of age. 
Because this is a pharmacokinetic and safety trial with no comparator, there is no power 
determination affecting the sample size. The sample size of approximately 18 subjects is 
considered sufficient to assess the pharmacokinetics, safety, and tolerability of vonoprazan in 
a pediatric population aged 12 to 17 years. Fewer subjects may be enrolled based on 
preliminary data, if considered sufficient to adequately characterize the PK profile. 
Pharmacokinetic Analyses (Section 7.3.1) 
Plasma concentration data will be summarized by time point for each vonoprazan dose using 
the following descriptive statistics: number of subjects, arithmetic mean, standard deviation, 
coefficient of variation, geometric mean, geometric coefficient of variation, median, 
minimum, and maximum, as appropriate.  
The individual pharmacokinetic parameter estimates parameters in Table 6-1 will be 
summarized descriptively by vonoprazan dose. 
Efficacy/Pharmacodynamic Analyses (Section 7.3.2) 
The severity of GERD symptoms at baseline and Days 87 and 14, as assessed by the 
investigator, will be summarized overall and by vonoprazan dose. 
The change from baseline to Days  87 and 14 in the PGSQ-A-SF symptom and impact 
subscale, as assessed by the adolescent, will be summarized overall and by vonoprazan dose. 
Mean pH and the percentage of time above pH 4, 5, and 6 at baseline (Day -1) and Day 7 will 
be summarized for the subset of subjects for whom intragastric pH monitoring is available. 
Schedule of Events (Section 13.1) 
 
 




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a 
Visit 2 (Day -1) and Visit 5 is only required for subjects undergoing gastric pH monitoring at select sites.  
b 
Visit 4 (Day 6) is an optional visit for subjects that check in to the clinic in the evening before starting Day 7 assessments. 
cb 
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. 
dc 
Informed consent will be signed by the subject’s legally authorized representative prior to any activity in the study. Subject assent (if applicable) may be obtained as required 
per site guidelines. 
ed 
A complete physical examination will be performed at screening (at minimum, assessment of skin, cardiovascular, respiratory, gastrointestinal, and neurological systems). A 
brief physical examination will be performed at other visits (at minimum, assessment of skin, cardiovascular, respiratory, and gastrointestinal systems). Interim physical 
examinations may be performed at the discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. 
fe 
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and temperature. 
gf 
Height collected only at screening. 
hg Hepatitis B surface antigen, hepatitis C virus antibody, and HIV type 1 and 2 antibodies. 
ih 
Urine drug/alcohol screen will occur at screening per the site standard procedures. 
ji 
Clinical laboratory testing will include hematology, serum chemistry, and urinalysis. Glucose will be obtained after an 8-hour fast at all visits. Blood draws should follow vital 
signs or electrocardiograms. 
k 
Subject should be fasting for 12 hours. Blood sample for gastrin will be collected prior to study drug dosing.  
lj 
Only female subjects with childbearing potential will have urine hCG; if positive, confirm with serum hCG.  
mk  Single 12-lead electrocardiogram recordings will be made after the subject has been in the supine position for at least 5 minutes at screening. A single repeat measurement is 
permitted at screening for eligibility determination. Measurements of the following intervals will be reported: PR interval, RR interval, QRS interval, and QT 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. Assessments should include comments on 
whether the tracings are normal or abnormal (if abnormal, whether clinically significant or not clinically significant); rhythm; the presence of arrhythmia or conduction 
defects; any evidence of myocardial infarction; and ST-segment, T-wave, and U-wave abnormalities. 
nl 
Subject will be randomized to study treatment after all eligibility criteria have been met. 
om Subjects will self-administer study drug, possibly with assistance from the parent/caregiver. Study drug will be dispensed and administered in the clinic on Days 1, 7, 8 and 
14. Study drug for at-home administration will be dispensed on Day 1 (to be taken on Days 2-6) and Day 87 (to be taken on Days 89-13). Study drug should be taken every 
day between 7 and 10 am on an empty stomach. The exact time of dosing on Day 6 and Day 13 and if the dose was taken on an empty stomach should be noted by the subject 
or parent/caregiver and recorded by clinic staff upon arrival at the clinic. Subjects who do not check in to the clinic on the optional Day 6 visit will be instructed not to eat any 
food or take study drug on the morning of Days 7 and 14 prior to their arrival at the clinic. If a subject consumes any food prior to the dose on Days 6 and 13 or prior to arrival 
at the clinic on Days 7 and 14, the time and content of the meal is to be noted and recorded in the eCRF by clinic staff. On Days 7 and 14, water is permitted as desired except 
for the period 1 hour before and 1 hour after administration of study drug (other than as permitted for study drug dosing). Subjects will be provided a meal 30-60 minutes after 
study drug dosing on Days 7 and 14 per the clinic’s standard procedures. 
pn Check in on Day -1 and Check out on Day 1 and Check in on Day 7 and Check out on Day 8 (as determined by PI) is only for subjects who will undergo 24-hour gastric pH 
monitoring. Subjects may check in on Day 6 or Day 7 (as determined by site). Day 7 check in must occur no later than 7 am.  
qo Gastric pH monitoring on Day -1 for 24 hours and on Day 7 for 24 hours; only if clinically indicated. 


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rp 
Blood samples for PK analysis of vonoprazan in plasma will be collected on Days 7 and 14. within 30 minutes prior to the morning administration of vonoprazan and at 0.25, 
0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours after drug administration. PK sampling should be timed to occur last and as close to the scheduled time window as 
possible. On both days, one pre-dose sample will be collected prior to the morning administration of vonoprazan and two additional samples will be collected after drug 
administration: one between 0.5 and 2 hours post-dose and one between 2.5 and 4 hours post-dose. The exact time of each pharmacokinetic sample should be recorded in the 
source and eCRF. 
sq 
Collection of pretreatment events will start after the informed consent form has been signed. Adverse events will be assessed from time of informed consent signing until the 
follow-up visit and should be followed until they are resolved, stable, or judged by the investigator to be not clinically significant. 
 
 

SAP_001.pdf: 
Protocol Number: VPED-102 
Official Title: A Phase 1, Randomized, Parallel-group, Open-label, Multicenter Study to Evaluate 
the Pharmacokinetics, Pharmacodynamics and Safety of Vonoprazan (10 or 20 mg Once Daily) in 
Adolescents with Symptomatic Gastroesophageal Reflux Disease 
NCT Number: NCT05343364
Document Date: 31 January 2023 


Phathom Pharmaceuticals, Inc.                                                                       
Statistical Analysis Plan, Version 2.0
VPED-102                                                                                                                          
Date Issued: 31JAN2023
 
 
Phathom Pharmaceuticals, Inc 
 
VPED-102 
 
A Phase 1, Randomized, Parallel-group, Open-label, Multicenter Study 
to Evaluate the Pharmacokinetics, Pharmacodynamics and Safety of 
Vonoprazan (10 or 20 mg Once Daily) in Adolescents with Symptomatic 
Gastroesophageal Reflux Disease 
 
31JAN2023 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Prepared by: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
3 
 
Summary of Changes  
 
The VPED-102 protocol was amended on 14 September 2022 (Version 3.0, Amendment 2).  
Changes in that amendment are reflected in this document with a summary of the relevant 
protocol changes which precipitated modifications in the Statistical Analysis Plan presented 
below.  The actual changes to the analyses are reflected in the respective sections in this 
document. 
 
Amendment History and Reasons for Amendment  
Version  
Date  
Reasons for Amendment  
Version 1.0  
01 November 2021  
Original Statistical Analysis Plan 
Version 2.0  
(Based on 
Protocol 
Amendment 2) 
31 January 2023  
 
Modified strategy to estimate PK parameters to 
a population based approach; as a result 
adjusted PK sampling schedule on Day 7, 
added PK sampling on Day 14, provided 
information on when time of dosing and meals 
should be collected and removed Tmax,ss and t1/2z 
PK parameters.    
 
Moved symptom assessments and completion 
of PGSQ-A-SF questionnaire from Day 8 to 
Day 7  
 
Updated Schedule of Events and Study Design 
to reflect above changes    
 
 
 
 


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
4 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..............................................................................................6 
1. 
INTRODUCTION ....................................................................................................7 
2. 
OBJECTIVES ...........................................................................................................7 
2.1. PRIMARY OBJECTIVE ................................................................................................ 7 
2.2. SAFETY OBJECTIVE ................................................................................................... 7 
2.3. EXPLORATORY OBJECTIVE ........................................................................................ 7 
3. 
INVESTIGATIONAL PLAN ..................................................................................8 
3.1. OVERALL STUDY DESIGN AND PLAN ........................................................................ 8 
3.2. STUDY ENDPOINTS .................................................................................................... 8 
3.2.1. 
Pharmacokinetic Assessments ........................................................................... 8 
3.2.2. 
Efficacy and Pharmacodynamic Assessments ................................................... 8 
3.2.3. 
Safety Assessments ............................................................................................ 9 
3.3. TREATMENTS ............................................................................................................ 9 
3.3.1. 
Treatments Administered ................................................................................... 9 
4. 
GENERAL STATISTICAL CONSIDERATIONS ...............................................9 
4.1. SAMPLE SIZE ........................................................................................................... 10 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING ............................................... 10 
4.3. STUDY DAY AND STUDY START DATE .................................................................... 10 
4.4. ANALYSES SET ........................................................................................................ 11 
4.4.1. 
Screened Set .................................................................................................... 11 
4.4.2. 
Enrolled Set ..................................................................................................... 11 
4.4.3. 
Pharmacokinetic Set ........................................................................................ 11 
4.4.4. 
Pharmacodynamic Set ..................................................................................... 11 
4.4.5. 
Safety Set ......................................................................................................... 11 
4.5. VISIT WINDOWS ...................................................................................................... 11 
5. 
SUBJECT DISPOSITION .....................................................................................11 
5.1. DISPOSITION ........................................................................................................... 11 
5.2. PROTOCOL DEVIATIONS .......................................................................................... 12 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ..........................12 
6.1. DEMOGRAPHICS ...................................................................................................... 12 
6.2. MEDICAL HISTORY ................................................................................................. 12 
6.3. INCLUSION AND EXCLUSION CRITERIA ................................................................... 12 
7. 
TREATMENTS AND MEDICATIONS ..............................................................13 
7.1. PRIOR AND CONCOMITANT MEDICATIONS .............................................................. 13 
7.1.1. 
Prior Medications ........................................................................................... 13 
7.1.2. 
Concomitant Medications ............................................................................... 13 


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
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7.2. STUDY DRUG .......................................................................................................... 13 
7.3. STUDY TREATMENTS .............................................................................................. 13 
7.3.1. 
Extent of Exposure .......................................................................................... 13 
7.3.2. 
Treatment Compliance .................................................................................... 14 
8. 
EFFICACY ANALYSIS ........................................................................................14 
8.1. PHARMACOKINETIC ANALYSES ............................................................................... 14 
8.1.1. 
Plasma Concentrations ................................................................................... 14 
8.2. EXPLORATORY ANALYSES....................................................................................... 15 
8.2.1. 
GERD Symptom Assessment ........................................................................... 15 
8.2.2. 
PGSQ-A-SF ..................................................................................................... 15 
8.2.3. 
Pharmacodynamic Assessment ....................................................................... 15 
9. 
SAFETY ANALYSIS .............................................................................................15 
9.1. ADVERSE EVENTS ................................................................................................... 16 
9.1.1. 
Adverse Events of Special Interest (AESI) ...................................................... 17 
9.2. CLINICAL LABORATORY EVALUATIONS .................................................................. 19 
9.2.1. 
Clinical chemistry ........................................................................................... 19 
9.2.2. 
Urinalysis ........................................................................................................ 20 
9.3. VITAL SIGN MEASUREMENTS ................................................................................. 20 
9.4. PHYSICAL EXAMINATION ........................................................................................ 21 
9.5. ELECTROCARDIOGRAM RESULTS ............................................................................. 21 
9.6. PREGNANCY TEST ................................................................................................... 21 
10. 
INTERIM ANALYSIS/OTHER ANALYSIS ......................................................21 
10.1. 
INTERIM ANALYSIS .............................................................................................. 21 
10.2. 
CORONAVIRUS PANDEMIC ................................................................................... 22 
11. 
CHANGES IN THE PLANNED ANALYSIS ......................................................22 
12. 
APPENDICES ........................................................................................................23 
12.1. 
APPENDIX 1:  IMPUTATION ALGORITHM FOR PARTIAL AND MISSING DATES ....... 23 
12.1.1. 
Rules for Concomitant Medication Start Date Imputation .......................... 23 
12.1.2. 
Rules for Concomitant Medication End Date Imputation ........................... 24 
12.1.3. 
Rules for Prior Medication Start Date Imputation ...................................... 25 
12.1.4. 
Rules for AE Start Date Imputation ............................................................. 25 
12.2. 
APPENDIX 2: SCHEDULE OF EVENTS .................................................................... 26 
12.3. 
APPENDIX 3: GERD SYMPTOM ASSESSMENT-INVESTIGATOR ............................. 29 
 
 
 
 
 


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
6 
 
List of Abbreviations 
AE 
AESI 
ALT 
AST 
AUC 
BLQ 
CRF 
CV 
CYP 
adverse event 
adverse event of special interest 
alanine aminotransferase 
aspartate aminotransferase 
area under the curve 
below the limit of quantification 
Case Report Form 
coefficient of variation 
cytochrome P450 
ECG 
eCRF 
EE 
GERD 
GGT 
H+, K+-ATPase 
H2RA 
hCG 
electrocardiogram 
electronic case report form 
erosive esophagitis 
gastroesophageal reflux disease 
gamma-glutamyl transferase 
hydrogen, potassium adenosine triphosphatase 
histamine-2 receptor antagonist 
human chorionic gonadotropin 
IRT 
LFT 
MedDRA 
interactive response technology 
liver function test 
medical Dictionary for Regulatory Activities 
PGSQ-A-SF 
 
PK 
popPK 
PPI 
PT 
PTE 
QD 
SAE 
SAP 
SD 
SoE 
 Pediatric Gastro-esophageal Symptom and Quality of Life 
Questionnaire-Adolescent-Short Form 
pharmacokinetic 
population pharmacokinetic 
proton pump inhibitor 
preferred Term 
pretreatment event 
once daily 
serious adverse event 
statistical analysis plan 
standard deviation 
schedule of events 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
 
 
 
 
 
 
 
 


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
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1. Introduction 
  
Vonoprazan belongs to a new class of acid-
-
heartburn in subjects with symptomatic non-erosive GERD, healing of all grades of EE 
and relief of heartburn, maintenance of healing of all grades of EE and relief of heartburn, 
and treatment of Helicobacter pylori infection. 
 
The purpose of this study is to determine a dose of vonoprazan in adolescent subjects with 
symptomatic GERD that provides an exposure similar to the exposures in adults after 
administration of vonoprazan 10 mg or 20 mg once daily (QD).  
 
The pediatric doses for this study were selected to approximate equivalent adult exposures 
following administration of vonoprazan 10 or 20 mg QD and are age-based for adolescents 
12 to 17 years of age. 
 
This document outlines the statistical methods to be implemented in the analysis of data 
collected within the scope of Phathom Pharmaceuticals, Inc., Protocol VPED-102 (A 
Phase 1, Randomized, Parallel-group, Open-label, Multicenter Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics and Safety of Vonoprazan (10 or 20 mg Once 
Daily) in Adolescents with Symptomatic Gastroesophageal Reflux Disease). 
 
The purpose of this statistical analysis plan (SAP) is to define the planned statistical 
methods consistent with the study objectives. This plan should be read in conjunction with 
the study protocol version 3.0 (14 September 2022) and the case report forms (CRFs) 
version 1.0 (Date: 16 November 2022). All analyses will be conducted using SAS® 
Version 9.4 or higher. 
2. Objectives 
2.1. Primary Objective 
To evaluate the pharmacokinetic profile of vonoprazan (10 or 20 mg QD) in adolescent 
subjects with symptomatic GERD. 
2.2. Safety Objective  
To evaluate the safety of vonoprazan (10 or 20 mg QD) in adolescent subjects with 
symptomatic GERD. 
2.3. Exploratory Objective  
To evaluate symptom relief and pharmacodynamics of vonoprazan (10 or 20 mg QD) in 
adolescent subjects with symptomatic GERD. 


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
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3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is a Phase 1, uncontrolled, randomized, open-label, parallel-group, multiple-dose 
study in adolescents aged 12 to 17 years with symptomatic GERD. Subjects will be 
screened for up to 28 days. Successfully screened subjects will be randomized to receive 
10 or 20 mg of vonoprazan QD for 14 days. A total of 18 subjects will be enrolled into the 
study. Blood samples for pharmacokinetic testing will be collected on Days 7 and 14. If 
deemed clinically indicated by the principal investigator, gastric pH may be monitored for 
24 hours on Day -1 and Day 7. The study will include 3 periods: 
 
Screening Period (
4 weeks): Subjects will undergo screening assessments to determine 
study eligibility, and baseline assessments will be performed. If all eligibility criteria are 
met, the subject will be randomized and enter the Treatment Period. 
Treatment Period (Day 1 to Day 14): Subjects will be randomized to receive vonoprazan 
10 mg or vonoprazan 20 mg QD. 
Follow-up Period (2 weeks): A safety follow-up phone call will occur 2 weeks after the 
last dose of study drug to assess adverse events (AEs).  
 
A subject will be considered to have completed the study if the subject completes the 
Treatment Period and the safety follow-up phone call. Following completion of study drug 
dosing or early discontinuation, the subject will be transitioned to local standard of care in 
 
 
The total duration of the study is up to 8 weeks. The Screening Period is up to 4 weeks, 
Treatment Period is 2 weeks, and safety follow-up phone call is 2 weeks after last study 
drug administration.  
3.2. Study Endpoints 
3.2.1. Pharmacokinetic Assessments  
The primary vonoprazan pharmacokinetic endpoints will include the following parameters 
for each subject estimated from a population PK model: 
 Maximum observed drug concentration at steady state (Cmax,ss) 
 Area under the plasma concentration-time curve during the dosing interval 
 (AUC ) 
 Apparent oral clearance (CL/F) 
 Apparent volume of distribution (Vz/F) 
3.2.2. Efficacy and Pharmacodynamic Assessments 
Efficacy and pharmacodynamic characteristics will be assessed by the following: 
 The severity of GERD symptoms at screening and Days 7 and 14 as 
assessed by the investigator. 


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
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 The Pediatric Gastroesophageal Symptom and Quality of Life 
Questionnaire-Adolescent-Short Form (PGSQ-A-SF) symptom and impact 
subscale as assessed by the adolescent at screening and Days 7 and 14. 
 Mean pH and percentage of time above pH 4, 5, and 6 at Day -1 and Day 7 
in the subset of subjects for whom intragastric pH monitoring is performed 
when clinically indicated per the investigator. 
3.2.3. Safety Assessments 
Safety will be assessed by the following: 
 AEs 
 Laboratory test values (hematology, serum chemistry, urinalysis) 
 Electrocardiograms 
 Vital signs 
 
3.3. Treatments   
The pediatric doses for this study were selected to approximate equivalent adult exposures 
following administration of vonoprazan 10 or 20 mg QD and are age-based for adolescents 
12 to 17 years of age. Subjects who meet all of the inclusion criteria and none of the 
exclusion criteria will be randomized in a 1:1 ratio to 1 of the following 2 groups during 
the Treatment Period: 
 Vonoprazan 10 mg QD for 14 days 
 Vonoprazan 20 mg QD for 14 days 
3.3.1. Treatments Administered 
Subjects will be instructed to take randomized study drug orally each morning between 7 
and 10 am on an empty stomach with approximately 240 mL (8 oz) water. Subjects will 
take study drug at the clinic on Days 1, 7, 8, and 14; otherwise, study drug will be taken on 
an outpatient basis. Vonoprazan study medication will be supplied as 10 mg and 20 mg 
tablets. 
4. General Statistical Considerations 
In general, descriptive statistics will be presented by treatment group and by visit, as 
applicable. Continuous data will be summarized using descriptive statistics (i.e., n, mean, 
standard deviation (SD), median, minimum, and maximum). Categorical data will be 
summarized using the subject count and percentage in each category. Non-zero 
percentages will be rounded to one decimal place, except 100% will be displayed without 
any decimal places. For the summary statistics of all numerical variables unless otherwise 
specified, minimum and maximum will be displayed to the same level of precision as 
reported up to a maximum of 3 decimal places. Mean and median will be displayed to one 
level of precision greater than the data collected up to a maximum of 3 decimal places. 
Standard deviation and standard error (SE) will be displayed to two levels of precision 


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
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greater than the data collected up to a maximum of 3 decimal places. When count data are 
presented, the percentage will be suppressed when the count is zero to draw attention to the 
non-
specified on the shells to account for dropouts and missing values. The denominator for all 
percentages will be the number of subjects in that treatment within the population of 
interest, unless otherwise specified. Refer to Appendix 1 for imputation rules for partial 
and missing AE onset dates as well as partial and missing prior/concomitant medication 
start and end dates. Data will be displayed in all listings sorted by treatment group. 
4.1. Sample Size 
Approximately 18 subjects will be enrolled with 9 subjects in each dose group. Attempts 
will be made to enroll an equal number of subjects between 12 to 15 and 16 to 17 years of 
age. Because this is a pharmacokinetic and safety trial with no comparator, there is no 
power determination affecting the sample size. The sample size of approximately 18 
subjects is considered sufficient to assess the pharmacokinetics, safety, and tolerability of 
vonoprazan in a pediatric population aged 12 to 17 years. Fewer subjects may be enrolled 
based on preliminary data, if considered sufficient to adequately characterize the PK 
profile. 
4.2. Randomization, Stratification, and Blinding 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized in a 1:1 ratio to 1 of the following 2 groups during the Treatment Period: 
 Vonoprazan 10 mg QD for 14 days 
 Vonoprazan 20 mg QD for 14 days 
An interactive response technology (IRT) system will be used to administer the 
randomization schedule. Randomization schedule will be generated 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. 
 
This is an open-label study. 
4.3. Study Day and Study Start Date 
The screening period for the study will be from Day -28 to Day -1. The treatment period 
will be from Day 1 to Day 14 where the final Visit will be on Day 14. The Safety Follow 
Up period will be from Day 15 to Day 28.  
 
For this study, randomization is to occur on Day 1, as well as the first dose of study drug. 
For assessments done on or after Day 1, study day is defined as assessment/event date - 
Day 1 + 1. For assessments done before Day 1, study day is defined as assessment/event 
date - Day 1.  


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
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4.4. Analyses set 
4.4.1. Screened Set  
The screened set will include all subjects who signed the study informed consent. 
4.4.2. Enrolled Set 
The enrolled set will include all subjects who signed the study informed consent and have 
been randomized. 
4.4.3. Pharmacokinetic Set 
The pharmacokinetic (PK) set will include all subjects who had at least one measurable 
concentration result. Where subjects experience issues which may affect exposure to study 
drug (e.g., emesis, dosing errors, etc.), data will be reviewed by the study 
pharmacokineticist and evaluated for exclusion from the PK population on a case-by-case 
basis.  All subjects excluded from the PK population will be documented in the data 
listings. 
4.4.4. Pharmacodynamic Set 
The pharmacodynamic (PD) set will include subjects who receive at least 1 dose of study 
drug and have sufficient pH data to support calculation of pharmacodynamic parameters.  
4.4.5. Safety Set  
The safety set will include all subjects who receive at least 1 dose of study drug. 
4.5. Visit Windows 
All data summarized by visit will be based on the nominal visit name collected on the 
eCRF page. For data from unscheduled visits, these will be listed but not included in any 
by-visit summaries or analyses. 
5. Subject Disposition 
5.1. Disposition 
Disposition will be summarized for all enrolled subjects by treatment and overall. The 
number and percentage of subjects who have been enrolled, have been treated (i.e., Safety 
Set), have completed the study treatment, have completed the study, have discontinued 
from the study treatment, have discontinued from the study, as well as the primary reason 
for study treatment discontinuation and study discontinuation (if applicable) will be 
tabulated.  
 
Screen failures are defined as subjects whose legally authorized representative signs the 
informed consent form to participate in the clinical study but are not subsequently entered 
in the Treatment Period of the study. The number and percentage of screened, enrolled, 
and screen failure subjects, as well as the primary reason for screen failure will be 


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
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tabulated for all screened subjects. Subjects who fail screening and the reasons for screen 
failure will be listed for all screen failure subjects.  
 
Additionally, a summary of the analysis sets will be provided to include the number and 
percentage of subjects in each analysis set by treatment group and overall. Subject 
disposition and analysis sets will also be presented in a listing. 
5.2. Protocol Deviations 
Protocol deviations will be recorded within the 
 Clinical Trial Management System 
(CTMS) and undergo cross-functional team review prior to database lock. In addition, 
protocol deviation classification (i.e., significant vs. not significant) as determined by 
Phathom Pharmaceuticals, Inc. prior to database lock will be documented in CTMS.  
 
The number and percentage of subjects with significant protocol deviations will be 
summarized by CTMS activity subtype, treatment group and overall using the Safety set.   
Individual subject protocol deviations, both significant and non-significant, will be 
presented in a data listing using the Enrolled set. 
6. Demographics and Baseline Characteristics 
6.1. Demographics 
Baseline demographics will be summarized by treatment and overall, for all subjects in the 
Safety Set. Baseline demographic data to be evaluated will include age, sex, race, ethnicity, 
fertility status, height (cm), weight (kg), body mass index (BMI) (kg/m2), smoking status 
and alcohol use. Descriptive statistics will be presented for age, height and weight. Sex, 
race, ethnicity, smoking status, alcohol use, body mass index and fertility status will be 
summarized categorically. Demographic and baseline characteristics data will be listed for 
all subjects in the Safety Set. 
6.2. Medical History 
Medical history will be summarized by treatment and overall, for all subjects in the Safety 
Set. Medical history data will be summarized by Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class (SOC) and preferred term (PT). The dictionary 
version used for reporting the study will be described in the relevant table and listing 
footnotes. Percentages will be calculated based on the number of subjects in the safety 
population. Medical history will be coded using MedDRA Version 23.0 or higher. 
 
Medical history data including specific details will be presented in a listing. 
6.3. Inclusion and Exclusion Criteria 
The details of Inclusion and Exclusion criteria are listed in Section 4.1.1 and 4.1.2 of the 
protocol. All inclusion/exclusion criteria related information for enrolled subjects will be 
presented in a data listing. The listing will include those failed inclusion/exclusion criteria. 


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
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7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary. 
The WHO Drug Dictionary version used for reporting the study will be described in the 
relevant table and listing footnotes. If the medication start or end date is missing, it will be 
imputed before summary as described in Appendix 1. If the start date of a medication is 
completely missing and the end date is before dosing of study drug on Day 1, it will be 
counted as a prior medication. If the start date of a medication is completely missing and 
the end date is after dosing of study drug on Day 1, it will be counted as both a prior and 
concomitant medication. If the start date of a medication is on or after the dose of study 
drug on Day 1 and the end date of the medication is completely missing, it will be counted 
as a concomitant medication. Prior and concomitant medications will be summarized and 
listed based on the Safety Set. 
7.1.1. Prior Medications  
Prior medications are defined as those medications with a recorded end date before dosing 
of study drug on Day 1. The total number of prior medications will be summarized. The 
number and percentage of subjects with at least one prior medication will be summarized 
overall and by Anatomical Therapeutic Chemical (ATC) level 4 term and PT. Prior 
medications will be presented by treatment and overall using the Safety Set. PTs will be 
sorted in descending order of frequency within each ATC level 4 term based on counts in 
the overall column. 
7.1.2. Concomitant Medications  
Concomitant medications are defined as those medications that are taken after the first 
dose of study drug on Day 1. The total number of concomitant medications will be 
summarized in a table. The number and percentage of subjects with at least one 
concomitant medication will be summarized by ATC level 4 term and PT. Concomitant 
medications will be presented by treatment and overall using the Safety Set. PTs will be 
sorted in descending order of frequency within each ATC level 4 term based on counts in 
the overall column. 
7.2. Study Drug 
The study drug details related to study drug administration will be listed for each subject in 
the Safety Set.  
7.3. Study Treatments 
7.3.1. Extent of Exposure 
Duration of exposure is defined as the total number of days a subject is exposed to any 
study drug and will be presented as the total number of days from the first dose date and 
time (Day 1) to the last dose date and time (date of last known study drug administration 


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
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minus the date and time of first dose + 1) as recorded on the Study 
Completion/Termination page on the eCRF. If the last dose date and time on the Study 
Completion/Termination page is missing, then the last dose date and time recorded on the 
Exposure page on the eCRF will be used. Duration of exposure will be categorized into 
time intervals and frequency counts and percentages will be presented for the number (%) 
of subjects in each interval. Percentages will be computed from the number of subjects in 
the Safety population. All summaries will be based on the Safety population. A listing on 
Extent of Exposure will also be presented based on Safety population. 
7.3.2. Treatment Compliance 
Subjects will be instructed to take randomized study drug orally between 7 and 10 am 
daily. Subjects will take study drug at the clinic on Days 1, 7, and 14; otherwise, study 
drug will be taken on an outpatient basis. 
 
Treatment compliance overall and by treatment will be summarized using descriptive 
statistics. For each subject, the compliance will be calculated as the total number of actual 
doses divided by the total number of planned doses.  
 
8. Efficacy Analysis 
8.1.  Pharmacokinetic analyses 
A population PK model will be used to analyze the plasma concentration data, estimate 
pharmacokinetic parameters, and address the primary objective of this study. The planned 
analyses will be included in a separate document. 
8.1.1. Plasma Concentrations 
Blood samples will be collected at the following time points for PK assessment using a 
population PK approach:  
 
 Day 7: Pre-dose (within 30 mins prior to morning administration of Vonoprazan) 
and at, 0.5 to 2, and 2.5 to 4, hours after drug administration. 
 Day 14: Pre-dose (within 30 mins prior to morning administration of Vonoprazan) 
and at 0.5 to 2 and 2.5 to 4 hours after drug administration  
 
Subjects enrolled prior to amendment 2 of the protocol had intensive blood collections 
intended to be used for Non-compartmental PK analyses.  Those samples were collected at 
different scheduled times than described above but will still be used in the population PK 
analyses. 
 
Individual plasma concentrations will be presented in data listings with their scheduled 
collection times based on the protocol under which they were enrolled. 


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
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8.2. Exploratory analyses 
GERD Symptom Assessment and PGSQ-A-SF will be presented using the Safety Set. The 
Pharmacodynamic assessment will be analyzed with Pharmacodynamic Set.   
 
Prior to Protocol Amendment 2, the GERD Symptom Assessment and PGSQ-A-SF were 
scheduled for Day 8.  Amendment 2 changed the schedule for these assessments to Day 7.  
Summaries and analyses will be presented together as Day 7/8.  
8.2.1. GERD Symptom Assessment 
The GERD Symptom Assessment-Investigator scale evaluates 5 symptoms of GERD: 
heartburn, acid regurgitation, dysphagia, belching and epigastric pain. The maximum 
severity of each GERD symptom occurring during the 7 days prior to the study visit will 
be assessed. The severity for each symptom will be recorded as either none, mild, 
moderate, severe or very severe. The severity of GERD symptoms at baseline and Days 7 
and 14 as assessed by the investigator will be summarized overall and by vonoprazan dose.  
8.2.2. PGSQ-A-SF 
The symptom subscale measures the number of days over the past 7 days on which 
subjects experience each individual symptom, where 1=0 days; 2=1 or 2 days; 3=3 or 4 
days; 4=5 or 6 days; and 5=every day (7 days). Mean symptom subscale score is the mean 
of the 7 individual symptom item scores. The impact subscale measures the impact of 
symptoms on school, family, and social activities in the past 7 days, where 1=never; 
2=almost never; 3=sometimes; 4=almost always; and 5=always. Mean impact subscale 
score is the mean of the 4 individual impact item scores. 
 
The change from baseline to Days 7 and 14 in the PGSQ-A-SF symptom and impact 
subscale, as assessed by the adolescent will be summarized overall and by vonoprazan 
dose.  
8.2.3. Pharmacodynamic Assessment 
Mean pH and percentage of time above pH 4, 5, and 6 at Day -1 and Day 7 will be 
summarized for the subset of subjects for whom intragastric pH monitoring is performed 
when clinically indicated per the investigator. 
 
The investigator reported clinical criteria that supported the need for 24-hour gastric pH 
monitoring in individual subjects will be presented in a data listing. 
9. Safety Analysis 
Safety will be assessed based on AEs, SAEs, physical examination findings, vital sign 
measurements, ECG results, and clinical laboratory evaluations (clinical chemistry, 
hematology, and urinalysis All safety analyses will be conducted for the Safety Set.  


Phathom Pharmaceuticals, Inc.                                                                                                
Statistical Analysis Plan, Version 2.0
VPED-102                                                           
Date Issued: 31JAN2023
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9.1. Adverse Events 
Adverse events will be coded using Version 24.0 or higher of the Medical Dictionary for 
Regulatory Activities (MedDRA). An AE can be any unfavorable and unintended sign 
(e.g., 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. 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. A PTE is defined as any untoward medical 
occurrence in a clinical investigation subject whose informed consent to participate in a 
study has been signed, which has occurred prior to administration of any study drug; it 
does not necessarily have to have a causal relationship with study participation.   
 
Overall AEs will be summarized separately, for the following adverse events. 
 Treatment-Emergent Adverse Event 
 Serious Treatment-Emergent Adverse Event 
 Study Drug-Related Treatment-Emergent Adverse Event 
 Study Drug-Related Treatment-Emergent Serious Adverse Event 
 Treatment-Emergent Adverse Event Leading to Treatment Discontinuation 
 Treatment-Emergent Adverse Event Leading to Study Discontinuation 
 Adverse Event Leading to Death 
 
A subject with multiple adverse events within a primary SOC or preferred term will only 
be 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 SOC, 
then the subject will be counted only once with the greatest severity or relationship at the 
 
 
The number and percentage of subjects with TEAEs will be summarized by treatment in 
the following ways:  
 by primary SOC and preferred term 
 by primary SOC, preferred term and maximum severity 
 by primary SOC, preferred term and relationship to study drug 
 
The number and percentage of subjects with TEAEs related to study drug will be 
summarized by treatment in the following ways: 
 by primary SOC and preferred term 
 by primary SOC, preferred term and maximum severity 
 


Phathom Pharmaceuticals, Inc.                                                                                                
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The number and proportion of subjects as well as the number of events (except deaths) 
with the following types of events will be summarized by primary SOC, preferred term and 
treatment group: 
 Adverse events leading to treatment discontinuation 
 Adverse events leading to study discontinuation 
 Serious Adverse Events (SAEs) 
 Deaths 
 Adverse events of special interest (AESI) 
 
All adverse events will be included in a listing using the safety set. Pre-treatment AEs and 
Serious AEs will be listed using the Screened set. In addition, the following select adverse 
events will be displayed in separate listings: 
 Deaths 
 Serious adverse events 
 Adverse events leading to treatment discontinuation 
 Adverse events leading to study discontinuation 
 Adverse events of special interest 
9.1.1. Adverse Events of Special Interest (AESI) 
The number and percentage of subjects with TEAEs and SAEs that are in one of the AESI 
categories presented in Table 1 will be summarized by AESI category, primary SOC and 
preferred term. The search criteria that will be used to identify AESIs are specified in the 
table.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Phathom Pharmaceuticals, Inc.                                                                                                
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9.2. Clinical Laboratory Evaluations 
Safety lab parameters, including clinical chemistry, hematology and urinalysis will be 
presented at Screening, Day 7 and 14.  
 
Descriptive statistics for clinical laboratory values (hematology, chemistry and urinalysis 
laboratory tests) will be presented. Changes from baseline will also be presented for 
quantitative variables. For categorical variables (i.e., normal or abnormal findings, or 
qualitative clinical laboratory tests), shift tables for the change from baseline to the end of 
study will be presented. Results of clinical laboratory values will be categorized as low, 
normal, or high according to laboratory range specifications. Shifts from baseline to each 
scheduled post-baseline time point will be presented to show the number and percentage of 
subjects in each category by parameter.  
9.2.1. Clinical chemistry 
Abnormal liver function tests are defined as liver test values that meet at least one of the 
criteria listed below. The number and percentage of subjects with at least one post-baseline 
abnormal liver function test and with the test value higher than baseline value, if available, 
will be presented. A supportive listing of subjects with such post-baseline elevations will 
be provided including the subject ID, baseline, and post baseline values. 
 
 ALT > 3xULN  
 ALT > 5xULN  
 ALT > 10xULN  
 ALT > 3xULN and Total Bilirubin > 2xULN  
 
 AST > 3xULN  
 AST > 5xULN  
 AST > 10xULN  
 AST > 3xULN and Total Bilirubin > 2xULN  
 
 Total Bilirubin > 2xULN  
 
 AST > 3xULN or ALT > 3xULN  
 
 AST > 5xULN or ALT > 5xULN  
 
 AST > 10xULN or ALT > 10xULN  
 
 (AST > 3xULN or ALT > 3xULN) and Total Bilirubin > 2xULN  
 
 AST > 3xULN and ALT > 3xULN  
 
 AST > 5xULN and ALT > 5xULN  


Phathom Pharmaceuticals, Inc.                                                                                                
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 AST > 10xULN and ALT > 10xULN  
 
 AST > 3xULN and ALT > 3xULN and Total Bilirubin > 2xULN  
 
 Alkaline phosphatase > 1.5xULN  
 ALT > 3xULN and Alkaline phosphatase > 1.5xULN  
 AST > 3xULN and Alkaline phosphatase > 1.5xULN  
 
 Alkaline phosphatase > 3xULN  
 ALT > 3xULN and Alkaline phosphatase > 3xULN  
 AST > 3xULN and Alkaline phosphatase > 3xULN  
 
 ALT or AST >3xULN and a 2-fold increase above baseline for subjects with 
normal baseline ALT or AST levels  
 ALT or AST > 8xULN for subjects with normal baseline ALT or AST levels 
9.2.2. Urinalysis  
 Microscopic urinalysis results will be listed only. All laboratory data test results will be 
included in data listings.  
9.3. Vital Sign Measurements 
Summary tables will be presented by treatment for vital sign data, including height (cm), 
weight (kg), heart rate (beats/min), sitting systolic blood pressure (mmHg), sitting diastolic 
blood pressure (mmHg), respiratory rate (breaths/min), and temperature (C) (and route 
used to measure temperature i.e., Oral, Tympanic or Temporal) in the Safety Set. Observed 
results and change from baseline to each scheduled post-baseline time point will be 
presented. Change from baseline will only be calculated for subjects having non-missing 
baseline and post-baseline measurements. The height assessment will only be done at the 
Screening visit. All vital signs data will be presented in a listing. 
 
Abnormal vital sign values are defined as vital sign values that meet one of the criteria 
listed below. The number and percentage of subjects with at least one post-baseline 
abnormal vital sign value and with the value worse than the baseline value, if available, 
will be presented. A supportive listing of subjects with such post-baseline elevations will 
be provided including the subject ID, baseline, and post-baseline values. 
 
 Systolic blood pressure (mmHg):  
o <50 
o >180 
 Diastolic blood pressure (mmHg):  
o <50 
o >100 
 Heart rate (bpm): 


Phathom Pharmaceuticals, Inc.                                                                                                
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o <50 
o >120 
9.4. Physical examination 
All data collected from physical examinations assessment must be available in the source 
documents but will not be added to the analysis database. 
9.5. Electrocardiogram results 
An overall 12-lead ECG interpretation (Normal, Abnormal  Not Clinically Significant, 
Abnormal Clinically Significant) will be available based on central reading of ECG data. 
Shifts from baseline to each scheduled post-baseline time point will be presented to show 
the number and percentage of subjects in each category by treatment for subjects in the 
Safety Set.   
 
Abnormal QTcF values are defined as ECG values that meet at least one of the criteria 
listed below. The number and percentage of subjects with at least one of the post-baseline 
abnormal values and with post-baseline value higher than baseline value, if available, will 
be presented using the Safety set. A supportive listing of subjects with such post-baseline 
elevations will be provided including the subject ID, baseline, and post-baseline values. 
 Absolute QTcF interval prolongation: 
o QTc interval > 450 msec 
o QTc interval > 480 msec  
o QTc interval > 500 msec  
 Change from baseline in QTcF interval: 
o QTc interval increases from baseline >30 msec 
o QTc interval increases from baseline >60 msec 
o QTc interval > 450 msec with increase from baseline >30 msec 
 
Results for heart rate, R-R interval, P-R Interval, QRS Interval, QT Interval, QTcF 
Interval, Rhythm, Arrhythmia or Conduction defects, Evidence of Myocardial Infarction, 
ST-segment abnormality, T-wave abnormality, and U-wave will be listed only. 
9.6. Pregnancy test 
Pregnancy test results will be presented in a listing for the Safety Set.  
10. Interim Analysis/Other Analysis 
10.1. 
Interim Analysis 
No formal interim analyses will be performed in this study. 


Phathom Pharmaceuticals, Inc.                                                                                                
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10.2. 
Coronavirus Pandemic 
In accordance with guidance issued by regulatory agencies, study data collection will 
document visits missed/delayed due to COVID-19 related reasons and assessments 
completed via alternative method due to COVID-19 related reasons. 
 
The COVID-19 impacts on individual subjects collected on the COVID-19 CRF pages will 
be listed for the Enrolled Set. Protocol deviations related to COVID-19 will be marked in 
the protocol deviation listing for the Enrolled Set.  
 
The anticipated impact of COVID-19 is widely regarded as unknown. If the impact of 
COVID-19 on the conduct of this study is observed to be significant, further summaries 
and listings of the impact will be explored. 
11. Changes in the Planned Analysis 
Not Applicable 
 
 


Phathom Pharmaceuticals, Inc.                                                                                                
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12. Appendices 
12.1. 
Appendix 1:  Imputation Algorithm for Partial and Missing Dates 
12.1.1. Rules for Concomitant Medication Start Date Imputation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Phathom Pharmaceuticals, Inc.                                                                                                
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12.1.2. Rules for Concomitant Medication End Date Imputation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Phathom Pharmaceuticals, Inc.                                                                                                
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12.1.3. Rules for Prior Medication Start Date Imputation 
 
12.1.4. Rules for AE Start Date Imputation 
 
 
 
 
 
 


Phathom Pharmaceuticals, Inc.                                                                                                
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12.2. 
Appendix 2: Schedule of Events 
 
 
 
Screening Period 
Treatment Period 
 Final Visit 
Safety FU 
 
Timing 
Day -28 to 
Day -2 
Day-1 a 
Day 1 
Day 7 
Day 8 a 
ET 
Day 14 
Phone Call 
Day 28 
Unscheduled 
Visit b 
Visit Number: 
1 
2 
3 
4 
5 
6 
7 
 
Informed consent c 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
Demographic and medical 
history 
X 
 
 
 
 
 
 
 
Smoking status and alcohol use 
X 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
Physical examination d 
X 
 
 
X 
 
X 
 
X 
Vital signs e 
X 
 
X 
X 
 
X 
 
X 
Weight and height f 
X 
 
 
X 
 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Concurrent medical conditions 
X 
 
 
 
 
 
 
 
Hepatitis B and C; HIV g 
X 
 
 
 
 
 
 
 
Urine drug screen h 
X 
 
 
 
 
 
 
 
Clinical laboratory tests i 
X 
 
 
X 
 
X 
 
X 
Pregnancy test j 
X 
 
 
X 
 
X 
 
 
Guidance on avoidance of 
pregnancy 
X 
 
 
X 
 
X 
 
 
12-lead electrocardiogram k 
X 
 
 
X 
 
X 
 
 
GERD Symptom Assessment-
Investigator 
X 
 
 
X 
 
X 
 
 
PGSQ-A-SF 
X 
 
 
X 
 
X 
 
 
Randomization l 
 
 
X 
 
 
 
 
 
Dispense study drug m 
 
 
X 
X 
 
 
 
 
Study drug administrationm  
 
 
X 
X 
 
 
 
 


Phathom Pharmaceuticals, Inc.                                                                                                
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In-patient check in/out n 
 
X  
X 
X  
X 
 
 
 
24-hour Gastric pH monitoring o  
X 
 
X 
 
 
 
 
PK blood sample collection p 
 
 
 
X 
 
X 
 
 
Drug return/accountability 
 
 
 
X 
 
X 
 
 
AE/pretreatment event 
assessment q 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 


Phathom Pharmaceuticals, Inc.                                                                                                
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AE: adverse event; ET: early termination; FU: follow-up; GERD: gastroesophageal reflux disease; hCG: 
human chorionic gonadotropin; HIV: human 
immunodeficiency virus, PGSQ-A-SF: Pediatric Gastro-esophageal Symptom and Quality of Life 
Questionnaire-Adolescent-Short Form; PK: pharmacokinetic 
a. 
Visit 2 and Visit 5 only required for subjects undergoing gastric pH monitoring at select sites.  
b. 
At an unscheduled visit, the following procedures are to be completed with additional procedures at the 
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. 
study. 
Subject assent (if applicable) may be obtained as required per site guidelines.  
d. 
A complete physical examination will be performed at screening (at minimum, assessment of skin, cardiovascular, 
respiratory, gastrointestinal, and neurological systems). A brief physical examination will be performed at other 
visits (at minimum, assessment of skin, cardiovascular, respiratory, and gastrointestinal systems). Interim physical 
examinations may be performed at the discretion of the investigator, if necessary, to evaluate AEs or clinical 
laboratory abnormalities. 
e. 
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and temperature.  
f. 
Height collected only at screening. 
g. 
Hepatitis B surface antigen, hepatitis C virus antibody, and HIV type 1 and 2 antibodies.  
h. 
Urine drug/alcohol screen will occur at screening per the site standard procedures.  
i. 
Clinical laboratory testing will include hematology, serum chemistry, and urinalysis. Glucose will be obtained after 
an 8-hour fast at all visits. Blood draws should follow vital signs or electrocardiograms.  
j. 
Only female subjects with childbearing potential will have urine hCG; if positive, confirm with serum hCG.  
k. 
Single 12-lead electrocardiogram recordings will be made after the subject has been in the supine position for at 
least 5 minutes at screening. A single repeat measurement is permitted at screening for eligibility determination. 
Measurements of the following intervals will be reported: PR interval, RR interval, QRS interval, and QT 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. Assessments should include comments on whether the tracings are normal or abnormal 
(if abnormal, whether clinically significant or not clinically significant); rhythm; the presence of arrhythmia or 
conduction defects; any evidence of myocardial infarction; and ST-segment, T-wave, and U-wave abnormalities.  
l. 
Subject will be randomized to study treatment after all eligibility criteria have been met.  
m. Subjects will self-administer study drug, possibly with assistance from the parent/caregiver. Study drug will be 
dispensed and administered in the clinic on Days 1, 7, and 14. Study drug for at-home administration will be 
dispensed on Day 1 (to be taken on Days 2-6) and Day 7 (to be taken on Days 8-13). Study drug should be taken 
every day between 7 and 10 am on an empty stomach. The exact time of dosing on Day 6 and Day 13, if the dose 
was taken on an empty stomach should be noted by the subject or parent/caregiver and recorded by clinic staff upon 
arrival at the clinic. Subjects will be instructed not to eat any food or take study drug on the morning of Days 7 and 
14 prior to their arrival at the clinic. If a subject consumes any food prior to the dose on Days 6 and 13 or prior to 
arrival at the clinic on Days 7 or 14, the time and content of the meal is to be noted and recorded in the eCRF by 
clinic staff. On Days 7 and 14, water is permitted as desired except for the period 1 hour before and 1 hour after 
administration of study drug (other than as permitted for study drug dosing). Subjects will be provided a meal 30-60 
 
n. 
Check in on Day -1 and Check out on Day 1 and Check in on Day 7 and Check out on Day 8 (as determined by PI) 
is only for subjects who will undergo 24-hour gastric pH monitoring.  
o. 
Gastric pH monitoring on Day -1 for 24 hours and on Day 7 for 24 hours; only if clinically indicated. 
p. 
Blood samples for PK analysis of vonoprazan in plasma will be collected on Days 7 and 14. On both days, one pre-
dose sample will be collected prior to the morning administration of vonoprazan and two additional samples will be 
collected after drug administration: one between 0.5 and 2 hours post-dose and one between 2.5 and 4 hours post-
dose. The exact time of each pharmacokinetic sample should be recorded in the source and eCRF. 
q. 
Collection of pretreatment events will start after the informed consent form has been signed. Adverse events will be 
assessed from time of informed consent signing until the follow-up visit and should be followed until they are 
resolved, stable, or judged by the investigator to be not clinically significant. 
 


Phathom Pharmaceuticals, Inc.                                                                                                
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12.3. 
Appendix 3: GERD Symptom Assessment-Investigator 
 
The following 5 symptoms of GERD will be evaluated. 
 
Symptom  
Definition  
 
Heartburn 
 
A burning feeling in the mid-epigastric 
area and/or chest 
Acid regurgitation 
 
Flow of sour or bitter fluid into the 
mouth 
Dysphagia 
 
Difficulty in swallowing 
Belching 
 
The voiding of gas from the stomach 
through the mouth, which may have been 
associated with acid regurgitation 
 
Epigastric pain 
 
Central upper abdominal pain 
. 
The maximum severity of each GERD symptom occurring during the 7 days prior to the 
study visit will be assessed as detailed below. 
 
 
Severity 
Definition  
 
None 
No symptom 
 
Mild 
Symptom did not last long and was easily 
tolerated 
 
Moderate 
Symptom caused discomfort and/or 
interrupted usual activities (including 
sleep) 
 
Severe 
Symptom caused great interference with 
usual activities and may have been 
incapacitating (including sleep) 
 
Very severe 
Symptom caused intense and constant 
discomfort and/or marked interference 
with usual activities (including sleep)