Clinical trial NCT06106022
Conditions: Gastroesophageal Reflux Disease
Keywords: Gastrology Vonoprazan Gastroesophageal Reflux Disease Children GERD Pharmacokinetics
Sponsor: Phathom Pharmaceuticals, Inc.
Start date: 2023-11-01; Completion date: 2024-04-29
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study is to evaluate the pharmacokinetic (PK) profile of vonoprazan (10 or 20 mg once daily \[QD\]) in children ≥ 6 to \< 12 years of age who have symptomatic Gastroesophageal Reflux Disease (GERD).

Detailed description:

Arms: arm 1: Participants will receive vonoprazan 10mg QD for 14 days. arm 2: Participants will receive vonoprazan 20mg QD for 14 days.
Interventions: intervention 1: Vonoprazan
Intervention descriptions: intervention 1: Administered orally

Protocol documents:
Prot_000.pdf: 
Protocol Number: VPED-103 
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 
Children Aged ≥ 6 to < 12 Years Who Have Symptomatic Gastroesophageal Reflux Disease 
NCT Number: NCT06106022 
Document Date: 31 Aug 2023






Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 3 
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 Children Aged ≥ 6 
to < 12 Years Who Have Symptomatic Gastroesophageal Reflux 
Disease 
Protocol Number VPED-103 
Protocol Version 
and Date 
Amendment 2 
30 August 2023 
Protocol accepted and approved by: 
Principal/Coordinating Investigator 
 
 
 
 
 
 
Signature 
Date 
31-Aug-2023


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 4 
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 Children Aged ≥ 
6 to < 12 Years Who Have 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 Amendment 2, dated 30 August 2023, 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/Independent Ethic Committee approval except to eliminate an 
immediate risk to subjects. I agree to administer study drug only to subjects under my 
personal supervision or the supervision of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Phathom Pharmaceuticals, Inc. 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 5 
Table of Contents 
Table of Contents .......................................................................................................................5 
List of Tables ..............................................................................................................................8 
List of Figures ............................................................................................................................9 
Protocol Synopsis.....................................................................................................................10 
List of Abbreviations................................................................................................................14 
1 
Introduction ......................................................................................................................16 
1.1 
Study Rationale .......................................................................................................16 
1.2 
Background .............................................................................................................16 
1.2.1 
Epidemiology, Symptoms, and Current Treatments for GERD ...............16 
1.2.2 
Vonoprazan ..............................................................................................17 
1.3 
Justification for Dose ..............................................................................................19 
2 
Study Objectives and Endpoints ......................................................................................21 
3 
Investigational Plan ..........................................................................................................22 
3.1 
Study Design ...........................................................................................................22 
3.1.1 
Rationale of Study Design .......................................................................24 
4 
Subject Selection and Withdrawal Criteria ......................................................................26 
4.1 
Selection of Study Population .................................................................................26 
4.1.1 
Inclusion Criteria .....................................................................................26 
4.1.2 
Exclusion Criteria ....................................................................................27 
4.1.3 
Screen Failures .........................................................................................29 
4.2 
Withdrawal of Subjects From Study Drug and/or the Study ..................................29 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................29 
4.2.2 
Handling of Withdrawals .........................................................................31 
4.2.3 
Lost to Follow-up.....................................................................................31 
4.2.4 
Replacements ...........................................................................................32 
5 
Study Drugs ......................................................................................................................33 
5.1 
Method of Assigning Subjects to Treatment Groups ..............................................33 
5.2 
Treatments Administered ........................................................................................33 
5.3 
Identity of Investigational Product..........................................................................34 


Phathom Pharmaceuticals, Inc. 
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Protocol: VPED-103 Amendment 2 
30 August 2023 
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5.4 
Management of Clinical Supplies ...........................................................................34 
5.4.1 
Study Drug Packaging and Storage .........................................................34 
5.4.2 
Study Drug Accountability ......................................................................34 
5.5 
Overdose Management ...........................................................................................35 
5.5.1 
Treatment of Overdose ............................................................................35 
5.6 
Blinding...................................................................................................................35 
5.7 
Study Compliance ...................................................................................................35 
5.7.1 
Treatment Compliance .............................................................................35 
5.8 
Prior and Concomitant Therapy ..............................................................................36 
5.8.1 
Excluded Medications..............................................................................37 
6 
Study Assessments and Procedures ..................................................................................38 
6.1 
Pharmacokinetic and Pharmacodynamic Assessments ...........................................38 
6.1.1 
Pharmacokinetic Assessments .................................................................38 
6.1.2 
Pharmacodynamic Assessments ..............................................................40 
6.2 
Efficacy Assessments ..............................................................................................41 
6.2.1 
GERD Symptom Assessment-Investigator ..............................................41 
6.3 
Safety Assessments .................................................................................................41 
6.3.1 
Pretreatment Events and Adverse Events ................................................41 
6.3.1.1 
Definitions ...............................................................................................41 
6.3.1.2 
Documenting Adverse Events ..................................................................48 
6.3.1.3 
Time Period and Frequency for Collecting AE and SAE Information ....50 
6.3.1.4 
Regulatory Reporting Requirements for SAEs ........................................53 
6.3.2 
Pregnancy.................................................................................................54 
6.3.3 
Laboratory Analyses ................................................................................55 
6.3.4 
Physical Examinations .............................................................................56 
6.3.5 
Vital Signs ................................................................................................57 
6.3.6 
Electrocardiograms ..................................................................................57 
6.4 
Safety Monitoring Committee ................................................................................57 
7 
Statistical and Analytical Plan ..........................................................................................58 
7.1 
Sample Size Calculations ........................................................................................58 
7.2 
Analysis Sets ...........................................................................................................58 
7.3 
Statistical Analysis Methodology ...........................................................................58 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 7 
7.3.1 
Pharmacokinetic Analyses .......................................................................58 
7.3.2 
Pharmacodynamic Analyses ....................................................................58 
7.3.3 
Efficacy Analyses ....................................................................................59 
7.3.4 
Safety Analyses ........................................................................................59 
7.3.5 
Interim Analyses ......................................................................................59 
8 
Data Quality Assurance ....................................................................................................60 
8.1 
Data Management ...................................................................................................60 
9 
Ethics ................................................................................................................................61 
9.1 
Institutional Review Board or Independent Ethics Committee ..............................61 
9.2 
Ethical Conduct of the Study ..................................................................................61 
9.3 
Subject Information and Consent............................................................................61 
10 Investigator’s Obligations ................................................................................................63 
10.1 Confidentiality ........................................................................................................63 
10.2 Financial Disclosure and Obligations .....................................................................63 
10.3 Investigator Documentation ....................................................................................64 
10.4 Study Conduct .........................................................................................................64 
10.5 Adherence to Protocol.............................................................................................65 
10.6 Adverse Events and Study Report Requirements ...................................................65 
10.7 Investigator’s Final Report .....................................................................................65 
10.8 Records Retention ...................................................................................................65 
10.9 Publications .............................................................................................................65 
11 Study Management ...........................................................................................................67 
11.1 Monitoring ..............................................................................................................67 
11.1.1 
External Data Monitoring Committee .....................................................67 
11.1.2 
Monitoring of the Study ...........................................................................67 
11.1.3 
Inspection of Records ..............................................................................67 
11.2 Management of Protocol Amendments and Deviations..........................................68 
11.2.1 
Modification of the Protocol ....................................................................68 
11.2.2 
Protocol Deviations..................................................................................68 
11.3 Study Termination ...................................................................................................68 
11.4 Final Report ............................................................................................................69 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 8 
12 Reference List...................................................................................................................70 
13 Appendices .......................................................................................................................73 
13.1 Appendix 1: Schedule of Events .............................................................................73 
13.2 Appendix 2: Contraceptive Guidance .....................................................................75 
13.3 Appendix 3: Liver Function Tests ...........................................................................77 
13.3.1 
Liver Function Test Monitoring ...............................................................77 
13.3.2 
Considerations for Temporary Discontinuation of Study Drug ...............77 
13.3.3 
Permanent Discontinuation of Study Drug ..............................................78 
13.3.4 
Re-initiation of Study Drug .....................................................................79 
13.4 Appendix 4: Questionnaires ....................................................................................80 
13.4.1 
GERD Symptom Assessment-Investigator ..............................................80 
13.5 Appendix 5: Tanner Staging ...................................................................................82 
13.6 Appendix 6: National Center for Health Statistics Clinical Body Weight Charts 
with 5th and 95th Percentiles ............................................................................83 
13.6.1 
Girls .........................................................................................................83 
13.6.2 
Boys .........................................................................................................84 
13.7 Appendix 7: Protocol Amendments ........................................................................85 
13.7.1 
Protocol Amendment 1 ............................................................................85 
13.7.2 
Protocol Amendment 2 ..........................................................................121 
 
List of Tables 
Table 2-1 
Study Objectives and Endpoints ..................................................................... 21 
Table 5-1 
Excluded Medications and Treatments ........................................................... 37 
Table 6-1 
Pharmacokinetic Parameters to be Estimated using Vonoprazan Plasma 
Concentration Data ......................................................................................... 40 
Table 6-2 
Medically Significant Adverse Event List ...................................................... 43 
Table 6-3 
Adverse Events of Special Interest List .......................................................... 44 
Table 6-4 
Protocol-Required Safety Laboratory Assessments ........................................ 56 
Table 13-1 
Abnormal Liver Function Criteria for Permanent Discontinuation of Study 
Drug ................................................................................................................ 78 


Phathom Pharmaceuticals, Inc. 
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Protocol: VPED-103 Amendment 2 
30 August 2023 
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Table 6-4 
Protocol-Required Safety Laboratory Assessments ...................................... 125 
 
List of Figures 
Figure 3-1 
Study Scheme.................................................................................................. 23 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 10 
Protocol Synopsis 
Protocol Number: VPED-103 
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 Children Aged ≥ 6 to < 12 
Years Who Have Symptomatic Gastroesophageal Reflux Disease 
Sponsor:  
Phathom Pharmaceuticals, Inc. 
2150 East Lake Cook Road, Suite 800 
Buffalo Grove, IL 60089 USA 
EU Trial Number: 2022-003228-42 
Study Phase: 
1 
Study Sites: 
Approximately 20 to 25 sites in the United States and Europe 
Indication: 
Symptomatic 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 
(sGERD), erosive esophagitis (EE), and Barrett's esophagus. The 
prevalence of GERD increases with age, from 2.5% of children 
between 3 and 9 years of age to 8.5% of those between 10 and 17 years 
of age. Similarly, the overall prevalence of EE increases with age, from 
5.5% in infants to 12.4% in children and adolescents. Younger children 
usually present with extraesophageal manifestations, regurgitation, and 
epigastric pain, while older children and adolescents typically present 
with adult-type GERD symptoms of heartburn and regurgitation. 
Pediatric GERD is a condition that is not always outgrown and can 
manifest itself as a chronic disease.  
Vonoprazan belongs to a new class of acid-inhibitory agents called 
“potassium-competitive acid blockers.” In the United States, 
vonoprazan in combination with amoxicillin and 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 to children ≥ 6 to < 12 years of age. 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-103 Amendment 2 
30 August 2023 
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Objectives: 
Primary: 
• To evaluate the pharmacokinetic profile of vonoprazan (10 or 
20 mg once daily [QD]) in children ≥ 6 to < 12 years of age 
who have symptomatic GERD. 
Safety: 
• To evaluate the safety of vonoprazan (10 or 20 mg QD) in 
children ≥ 6 to < 12 years of age who have symptomatic 
GERD. 
Exploratory: 
• To evaluate symptom relief and pharmacodynamics of 
vonoprazan (10 or 20 mg QD) in children ≥ 6 to < 12 years of 
age who have symptomatic GERD. 
Study Population: Children ≥ 6 to < 12 years of age who have symptomatic GERD, with 
or without EE. 
Study Design and 
Interventions:  
This is a Phase 1, uncontrolled, randomized, open-label, parallel-group, 
multiple-dose study in children ≥ 6 to < 12 years of age who have 
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. Approximately 18 subjects are 
expected to be enrolled in 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 the last dose of study drug 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-103 Amendment 2 
30 August 2023 
Page 12 
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 
(Primary 
Endpoints): 
The primary vonoprazan pharmacokinetic endpoints will include the 
following steady state parameters from data collected on Day 7 and 
Day 14: 
• 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 
(Exploratory 
Endpoints): 
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 
• 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 Endpoints): 
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 preferably prior to eating any breakfast or food 
with approximately 240 mL (8 oz) water between 7 and 10 am each 
day.  
Ethical 
Considerations:  
Clinical studies in adults with GERD have shown a positive benefit-
risk for vonoprazan. This study is anticipated to provide benefits to 
children ≥ 6 to < 12 years of age with symptomatic GERD and risks 
similar to those observed with vonoprazan in adults. This study is 
needed to identify doses to be used in future trials in children ≥ 6 to < 
12 years of age. 
The study was designed to minimize the number of blood samples and 
visits to investigate the pharmacokinetics and safety in this population.  
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-103 Amendment 2 
30 August 2023 
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Sample Size: 
Approximately 18 subjects will be enrolled with 9 subjects in each dose 
group. Attempts will be made to enroll subjects across the ≥ 6 to < 12 
years age range. 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 this 
population. Fewer subjects may be enrolled based on preliminary data, if 
considered sufficient to adequately characterize the pharmacokinetic 
profile. 
Statistical 
Methods: 
Pharmacokinetic Endpoints: 
Individual pharmacokinetic parameter estimates will be summarized 
descriptively by vonoprazan dose.  
Efficacy Endpoint: 
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. 
Pharmacodynamic Endpoints: 
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: 
Amendment 2.0  
30 August 2023 
 
 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 14 
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 
AUC τ 
area under the drug concentration-time curve during the dosing interval 
τ 
CFR 
Code of Federal Regulations 
CL/F 
Oral clearance 
Cmax,ss 
maximum drug concentration at steady state 
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 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LAR 
legally authorized representative 
LFT 
liver function test 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 15 
Abbreviation 
Definition 
LLC 
Limited Liability Company 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCAB 
potassium-competitive acid blocker 
popPK 
population pharmacokinetic 
PPI 
proton pump inhibitor 
PTE 
pretreatment adverse event 
QD 
once daily 
RBC 
Red blood cell  
RNA 
ribonucleic acid 
SAE 
serious adverse event 
sGERD 
Symptomatic non-erosive gastroesophageal reflux disease 
SoE 
schedule of events 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SUSAR 
suspected unexpected serious adverse reaction 
Takeda 
Takeda Pharmaceutical Company Limited 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
Vz/F 
Apparent volume of distribution  
WBC 
White blood cell 
Note: Abbreviations used only in tables and figures are defined with the relevant tables and figures. 


Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 16 
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 
and in combination with amoxicillin and clarithromycin have been approved for the 
treatment of Helicobacter pylori infection in adults. Vonoprazan is being developed for the 
treatment of heartburn in patients with symptomatic non-erosive gastroesophageal reflux 
disease (sGERD), 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 countries other than the United States, vonoprazan has been studied in other gastric acid-
related diseases such as healing of gastric and duodenal ulcers, and for the prevention of 
recurrence of gastric or duodenal ulcer during nonsteroidal anti-inflammatory drug or aspirin 
administration. Vonoprazan has received regulatory approval for adults in Japan, Russia, and 
other countries in Asia and Latin America for a variety of indications, including the healing 
of erosive esophagitis and maintenance of healing of erosive esophagitis. Vonoprazan is not 
currently approved for use in pediatric patients in any country.  
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 children aged ≥ 6 to< 12 
years with symptomatic gastroesophageal reflux disease (GERD) that provides an exposure 
similar to the exposures in adults after administration of vonoprazan 10 or 20 mg once daily 
(QD). Like proton pump inhibitors, vonoprazan is expected to provide benefit in pediatric 
patients with GERD.  
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 


Phathom Pharmaceuticals, Inc. 
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Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 17 
[Vakil 2006]. The term GERD covers a spectrum of conditions, including symptomatic 
non-erosive GERD, EE, and Barrett’s esophagus. 
The prevalence of GERD increases with age, from 2.5% of children between 3 and 9 years of 
age to 8.5% of those between 10 and 17 years of age [Nelson 2000]. Similarly, the overall 
prevalence of EE increases with age, from 5.5% in infants to 12.4% in children and 
adolescents [Gilger 2008]. Younger children usually present with extraesophageal 
manifestations, regurgitation, and epigastric pain, while older children and adolescents 
typically present with adult-type GERD symptoms of heartburn and regurgitation 
[Cezard 2004, Rosen 2018]. Pediatric GERD is a condition that is not always outgrown and 
can manifest itself as a chronic disease [Rosen 2018].  
Management of GERD includes lifestyle changes (eg, diet, weight loss, sleeping position), 
over-the-counter antacids, histamine-2 receptor antagonists (H2RAs), and proton pump 
inhibitors (PPIs). Proton pump inhibitors are considered superior to H2RAs for the healing of 
EE and relief of GERD symptoms and have become the pharmacological mainstay for the 
treatment of adult and pediatric 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.  
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 to 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 


Phathom Pharmaceuticals, Inc. 
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Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 18 
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 
and binds to the 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 (TAK-438_107). 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 with CYP2C19, which is the primary enzyme responsible 
for the metabolism of PPIs [Shin 2013]. 
These unique aspects of the vonoprazan mechanism of action and pharmacokinetics relative 
to PPIs translate into greater magnitude and duration of gastric acid suppression, which are 
reflected in the pharmacodynamic profile [Jenkins 2015; Sakurai 2015]. 
The pharmacokinetic and pharmacodynamic profiles of vonoprazan were assessed in 
multiple studies, including Study TAK-438_107, which showed rapid rise in pH following 
vonoprazan administration 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 were 
43%, 63%, and 86%, respectively, and by Day 7 were 60%, 85%, and 93%, respectively 
[Jenkins 2015].  


Phathom Pharmaceuticals, Inc. 
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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 of 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 no 
evidence of a dose-related increase in adverse effects with vonoprazan from 5 mg to 40 mg 
QD. As of 25 December 2022, the global cumulative post-marketing patient exposure to 
vonoprazan is estimated to be approximately 97 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 
children with symptomatic 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 in pediatric patients ≥ 6 to < 12 
years of age.  
The proposed doses are based on simulations using an updated population pharmacokinetic 
(popPK) model [Facius 2023]. The 2-compartment linear popPK model for vonoprazan was 
developed with adult pharmacokinetic data from healthy subjects aged 18 to 54 years who 
participated in 9 studies specifically selected to enable the extrapolation and characterization 
of the disposition of vonoprazan in pediatric subjects. The final dataset consisted of 354 
subjects (205 Asian and 149 Western) with 8010 plasma concentration observations. 
 
As planned, an analysis of interim PK data from the first adolescent subjects aged 12 to 17 
years randomized in Study VPED-102 was performed using the updated popPK model. 
Interim data from VPED-102 was combined with adult data from the updated popPK model 
to investigate potential differences in the pharmacokinetic properties of vonoprazan between 
adolescents and adults. Individual predicted area under the drug concentration-time curve at 
steady state (AUCss) values for the 8 adolescent subjects with symptomatic GERD included 


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in the preliminary analysis were within the range expected from healthy adults at their 
respective doses and no obvious effect of age or body weight was observed. Model 
assessments indicated the updated popPK model was working well in adolescents and 
substantiated the usefulness of simulations using the model to select doses for younger 
pediatric subjects.   
For predicting the appropriate doses in pediatric subjects aged ≥ 6 to <12 years, simulations 
were performed using the updated popPK model for vonoprazan and were summarized by 
both age and body weight. For reference, all boys and girls aged ≥ 6 to < 12 years who have a 
body weight between the 5th and 95th percentiles would have a body weight between 15 and 
65 kg. Different model assumptions in terms of the allometric weight scaling exponent (as 
estimated (none) in the adult data or fixed at 0.2) were compared. 
The updated model was used to simulate posterior distributions of AUCss in both adults and 
pediatric subjects aged ≥6 to <12 years or with a body weight of 15 to 65 kg for a series of 
pediatric candidate doses. Matching pediatric doses were selected to limit the predicted 
percentage of pediatric subjects with an exposure exceeding the adult reference exposure 
(median AUCss) at 50%. 
For children aged ≥ 6 to < 12 years or with a body weight of 15 to 65 kg each of the 
simulations gave similar exposure predictions, thereby suggesting that the selected doses for 
these pediatric patients (10 and 20 mg) should result in a majority of exposures that are 
within the 95% prediction interval in adults for both the 10 and 20 mg targeted doses. 


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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 children ≥ 6 to 
< 12 years of age who have symptomatic 
GERD. 
• 
Cmax,ss, AUCτ, CL/F, Vz/F from data collected on 
Days 7 and 14. 
Safety 
• To evaluate the safety of vonoprazan (10 or 20 
mg QD) in children ≥ 6 to < 12 years of age 
who have symptomatic GERD. 
• 
Adverse events  
• 
Laboratory test values (hematology, serum 
chemistry, urinalysis*) 
• 
Electrocardiograms (ECGs)  
• 
Vital signs  
Exploratory 
• To evaluate symptom relief and 
pharmacodynamics of vonoprazan (10 or 20 
mg) in children ≥ 6 to < 12 years of age who 
have symptomatic GERD. 
• 
The severity of GERD symptoms at baseline and 
Days 7 and 14, as assessed by the investigator 
• 
Mean pH and % time above pH 4, 5, and 6 at 
baseline 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 drug concentration-time curve during the dosing interval τ; CL/F: oral clearance; Cmax,ss: 
maximum drug concentration at steady-state; ECGs; electrocardiograms; GERD: gastroesophageal reflux 
disease; QD: once daily; Vz/F: apparent volume of distribution 
* Urinalysis is only required if deemed necessary by the investigator. 
 


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3 Investigational Plan 
3.1 
Study Design 
This is a Phase 1, randomized, open-label, parallel-group, multiple-dose study in children 
aged ≥ 6 to < 12 years who have symptomatic GERD. A total of approximately 18 subjects 
will be enrolled.  
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. Gastric pH will be monitored for 24 hours beginning on Day -1 and on Day 7. 
Following completion of study drug dosing on Day 14 or early discontinuation, the subject 
will be transitioned to local standard of care for 14 days during the Follow-up Period. Note, 
standard of care does not include the use of study drug but can include other acid suppressant 
agents.  
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 1 of 
2 vonoprazan doses (10 mg QD or 20 mg QD) for 14 days. 
Follow-up Period (2 weeks): A safety follow-up visit phone call will occur 2 weeks after the 
last dose of study drug to assess adverse events (AEs). Following completion of study drug 
dosing or early discontinuation, the subject will be transitioned to local standard of care for 
14 days. 
End-of-study definition: A subject will be considered to have completed the study (up to 8 
weeks, including 4 weeks of screening, 2 weeks of treatment and 2 weeks of safety follow-
up) if the subject completes the Treatment Period and the safety follow-up visit phone call. 
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 design with 2 dose levels of vonoprazan (10 and 20 mg QD) was selected to 
provide unbiased estimates of the vonoprazan pharmacokinetic and safety profile across 
doses likely to be safe and efficacious in children aged ≥ 6 to < 12 years. Dose justification is 
provided in Section 1.3. A placebo control group is not considered practical or ethical in 
children aged ≥ 6 to < 12 years with symptoms of GERD. 
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 suggest that, if effective, the 
onset of efficacy in pediatric patients would be similar or earlier than with PPIs. 
This study will include children aged ≥ 6 to < 12 years who have symptomatic GERD with or 
without EE. In Study EE-301, which enrolled 1027 adult subjects with endoscopically 
confirmed EE of Los Angeles Classification Grades A to D, 514 subjects were evaluated for 
EE healing after receiving vonoprazan 20 mg QD for 2 weeks. Of the 514 subjects, 74.3% 
had healed EE at Week 2. Based on this data, the proposed 14-day treatment duration will 
provide clinical benefit to subjects with EE, 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 20 to 25 sites in the United States and Europe. 
Approximately 18 subjects will be enrolled. 
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 ≥ 6 to < 12 years of age at the time of informed consent signing. 
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 (Section 13.6). 
3. The subject must have a diagnosis of GERD prior to randomization and medical 
history of signs or 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 and will be recorded in the 
electronic case report form (eCRF). 
4. The subject has at least one moderate GERD symptom based on the GERD Symptom 
Assessment-Investigator scale performed at screening. 
5. The subject must be able to swallow study drug tablet with water. 
6. Parent or legal guardian (ie, legally authorized representative [LAR]) is willing and 
able to complete the informed consent process and subjects are able to comply with 
study procedures and visit schedule. 
7. Female subjects who have experienced menarche must have a negative pregnancy test 
and will be counseled on pregnancy avoidance (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 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 
subject 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. 
9. The subject has any abnormal laboratory test values that are considered clinically 
significant in the opinion of the investigator during 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, ascorbic acid, croscarmellose sodium, magnesium stearate, 
hypromellose, macrogol 8000, and titanium dioxide, or red or yellow ferric oxide). 
11. The subject has used any prescription or over-the-counter medications (including 
herbal or nutritional supplements), other than those already excluded in criteria 1 to 5 
above, within 14 days before the first dose of study drug or throughout the study. That 
is, unless the medication(s) is permitted by the sponsor following a review of 
available data which confirms concomitant administration of the medication is 
unlikely to affect either the safety of the patient or the pharmacokinetics of 
vonoprazan. 
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. The subject has positive results at screening for human immunodeficiency virus, 
hepatitis B virus, or hepatitis C virus (HCV) infection at screening. 
14. The subject has severe renal impairment (estimated glomerular filtration rate < 30 
mL/min). 
15. The subject has moderate to severe hepatic impairment (Child-Pugh Class B and 
Child-Pugh Class C). 
16. The subject has any of the following abnormal laboratory test values at the start of the 
Screening Period: 
a. Creatinine levels: >1 mg/dL (>88 μmol/L). 
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the 
upper limit of normal (ULN) or total bilirubin >2 × ULN (except subjects with 
Gilbert Syndrome). 
17. In the opinion of the investigator, the subject is not suitable for entry into the study. 


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4.1.3 Screen Failures 
Screen failures are defined as subjects whose LAR signed 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 
adverse events (PTEs), AEs, and any serious adverse events (SAEs). 
Subjects may be allowed to be rescreened upon discussion with and approval by the medical 
monitor.  
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 
completing the last dose of study drug in the Treatment Period. 
4.2.1 Reasons for Withdrawal/Discontinuation 
Subjects or LARs 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 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 


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normal/baseline status. See Section 13.2 to monitor LFT abnormalities and for the 
criteria of liver function abnormalities for temporary and permanent discontinuation 
of study drug. 
3. Significant protocol deviation: The discovery post-randomization that the subject 
failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health. 
4. Lost to follow-up: The subject did not return to the clinic and attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented 
(3 documented telephone contact attempts and 1 certified letter, at a minimum) within 
6 weeks of the most recent planned visit. 
5. Voluntary withdrawal: The subject or the LAR 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 Board (IRB)/Independent Ethics 
Committees (IECs), or regulatory agency terminates the study. 
7. Pregnancy: The subject is found to be pregnant. Note: If the subject is found to be 
pregnant, the subject must be withdrawn immediately from the treatment. See 
Section 6.3.2 for further instructions on pregnancy. 
8. Lack of efficacy: The investigator has determined that the subject is not benefiting 
from investigational treatment and continued participation would pose an 
unacceptable risk to the subject. 
9. Other: The subject is discontinued from the study for any reason other than those 
listed above. The specific reason(s) for subject discontinuation will be recorded in the 
eCRF where appropriate. 


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4.2.2 Handling of Withdrawals 
Subjects or LARs 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 signed 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. 


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The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the LAR and reschedule the missed visit as soon as 
possible, counsel the subject and LAR on the importance of maintaining the assigned 
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 source document. 
• 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 
At the discretion of the sponsor, subjects may be replaced to achieve the target of 
approximately 18 subjects with expected usable pharmacokinetic sample collections.  


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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 administered study drug orally at the clinic on Day 1 and on Days 7 and 14, 
after the pre-dose pharmacokinetic sample, with approximately 240 mL (8 oz) of water in the 
morning between 7 and 10 am preferably prior to eating any breakfast or food. If necessary, a 
dosing cup can be used to facilitate administration. Study drug will be dispensed to the 
parent/LAR for study drug to be administered to the subject at home. Clinic staff will provide 
the parent/LAR a Study Drug Reminder Card and instruct the parent/LAR to record the date 
and time of every dose taken at home and to bring this card back to the next clinic visit.  
On Days 2 to 6 and 8 to 13, the parent/LAR will be instructed to give the subject study drug 
orally with approximately 240 mL (8 oz) of water each morning between 7 and 10 am 
preferably prior to eating any breakfast or food. Any missed doses should also be recorded by 
the parent/LAR and communicated to clinic staff immediately. All dosing information 
including missed doses will be recorded on the Study Drug Reminder Card and in the eCRF. 
On Days 7 and 14 subjects may have a meal/snack 30 to 60 minutes after study drug dosing. 


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Following completion of study drug dosing on Day 14 or early discontinuation, the subject 
will be transitioned to local standard of care for 14 days. Note, the local standard of care does 
not include study drug but can include other acid suppressant agents.  
5.3 
Identity of Investigational Product  
Vonoprazan study medication will be supplied as 10 mg and 20 mg tablets. 
 
 manufactures the vonoprazan fumarate drug 
substance. 
 manufactures the 
vonoprazan tablets. 
Vonoprazan tablets contain vonoprazan free base (MW 345.39) and the following inactive 
excipients: D-Mannitol, microcrystalline cellulose, hydroxypropyl cellulose, fumaric acid, 
ascorbic acid, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene 
glycol 8000, titanium dioxide, and red or yellow ferric oxide. 
Study drug will be packaged for shipment to the investigational site. 
5.4 
Management of Clinical Supplies 
5.4.1 Study Drug Packaging and Storage 
Vonoprazan tablets will be packaged 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 are 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 detailed information regarding packaging and 
labeling and 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 


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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. 
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 with study drug dosing will be assessed by clinic staff reviewing the Study Drug 
Reminder Card returned at each visit, direct questioning and counting any returned tablets, 
which will be documented in the source documents and eCRF.  
The date and time of each dose taken (in clinic or at home) must be recorded on the Study 
Drug Reminder Card, source documents and eCRF. If a subject misses any dose for any 


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reason, the sponsor must be notified immediately, and the date of the missed dose(s) and 
reason must be recorded in the eCRF.   
If a subject misses a scheduled visit or exhibits poor compliance, as assessed by tablet 
counts, the sponsor should be notified immediately to determine appropriate mitigation. 
Actions may include subjects provided with specific dosing instructions to continue study 
drug or discontinuation from the study. The LARs and subjects should be counseled at each 
visit on the importance of good compliance regarding the dosing regimen and scheduled 
study visits.    
5.8 
Prior and Concomitant Therapy 
Any medication including H2RAs and PPIs or vaccines (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 
• 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. 
The medical monitor should be contacted if there are any questions regarding prior or 
concomitant therapy. 
 
 


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5.8.1 Excluded Medications 
A list of excluded medications is provided in Table 5-1. 
Table 5-1 
Excluded Medications and Treatments 
Excluded Medications and Treatments 
Beginning of 
Exclusion 
End of Exclusion 
Other investigational drugs or drugs administered due 
to participation in another clinical trial 
30 days prior to start of 
Screening Period 
Follow-up  
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 
Day 14 (end of 
study drug 
dosing) 
CYP3A4 substrates with a narrow therapeutic index 
14 days prior to Day 1 
Day 14 (end of 
study drug 
dosing) 
CYP2C19 substrates clopidogrel, citalopram, 
cilostazol 
14 days prior to Day 1 
Day 14 (end of 
study drug 
dosing) 
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 


Phathom Pharmaceuticals, Inc. 
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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 with the principal investigator and 
medical monitor immediately 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 
Parents/LARs will ensure that the subject arrives at the clinic in the morning on Days 7 and 
14 for pharmacokinetic sampling. Subjects should not eat or take the vonoprazan study drug 
before arriving at the clinic. The Day 7 and 14 dose of study drug will be given in the clinic.   
Blood samples for pharmacokinetic analysis of vonoprazan in plasma will be collected on 
Days 7 and 14. On Day 7, one pre-dose sample will be collected prior to the morning 
administration of vonoprazan along with two additional samples collected after drug 
administration: one between 0.5 to 1.5 hours post-dose and one between 2.5 to 3.5 hours 
post-dose. On Day 14, one pre-dose sample will be collected prior to the morning 
administration of vonoprazan along with two additional samples collected after drug 
administration: one between 1 to 2 hours post-dose and one between 3 to 4 hours post-dose. 
The exact date and time of each pharmacokinetic sample must be recorded in subject source 
document and eCRF. 


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If a subject terminates early, an attempt should be made to collect one blood sample if it can 
be collected within 24 hours following the last dose of study drug. The exact date and time of 
the early termination sample must be recorded. 
Blood samples will be collected into sodium heparin vacutainer collection tubes and 
processed into plasma. Details of 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 0.5 to 100 ng/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. The primary vonoprazan pharmacokinetic endpoints will include the 
following steady state parameters: Cmax,ss, AUCτ, CL/F and Vz/F. 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 
Select sites may participate in a sub-study collecting gastric pH when deemed clinically 
necessary by the principal investigator. In the pharmacodynamic sub-study, gastric pH will be 
measured and recorded continuously for a 24-hour period on Day -1 and Day 7 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 for Day -1 will 
commence 24-hours prior to the first dose of study drug. The 24-hour continuous pH 
recording session for Day 7 will commence 30 to 60 minutes prior to the next dose of study 
drug. The reason for pH assessments, start time, stop time and any interruptions will be 
recorded in the source document and the eCRF. To minimize the discomfort of probe 
insertion, administration of a topical anesthetic (lidocaine) will be permitted per the 
institutional process. Details of collection, processing, storage and shipping will be contained 
in the Gastric pH Monitoring Plan.  


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6.2 
Efficacy Assessments  
6.2.1 GERD Symptom Assessment-Investigator 
The GERD Symptom Assessment-Investigator scale evaluates 4 symptoms of GERD: 
heartburn, vomiting, acid regurgitation, and trouble eating. The maximum severity of each 
GERD symptom occurring during the 7 days prior to the study visit, Day 7 and Day 14 will 
be assessed. The severity for each symptom will be recorded as either none, mild, moderate, 
severe or very severe. At screening, the subject will be eligible for inclusion in the study if 
the subject has at least one moderate GERD symptom. Symptom and severity definitions are 
presented in Section 13.4.1. 
6.3 
Safety Assessments 
6.3.1 Pretreatment Events and Adverse Events 
6.3.1.1 Definitions  
6.3.1.1.1 Definitions of Pretreatment Adverse Events 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject 
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. 
6.3.1.1.2 
Definitions of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to study drug. An AE can therefore be an unfavorable 
sign or symptom, or a disease temporally associated with the use of study drug. 
A treatment-emergent adverse event (TEAE) is defined as any event that occurs after the first 
dose of study drug or any event at baseline that worsens in either intensity or frequency after 
the first dose of study drug. 


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6.3.1.1.3 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence at any dose for which the following 
occurs:  
1. Results in DEATH.  
2. Is LIFE-THREATENING. The term “life-threatening” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe.  
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.  
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.  
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:  
• May require intervention to prevent items 1 through 5 above 
• May include any event or symptoms described in the medically significant AE list 
(Table 6-2) 
• Exposes the subject to danger, even though the event is not immediately 
life-threatening or fatal or does not result in hospitalization 


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Table 6-2 
Medically Significant Adverse Event List 
Term 
Acute respiratory failure / acute respiratory distress syndrome 
Torsade de pointes / ventricular fibrillation / ventricular tachycardia 
Malignant hypertension 
Convulsive seizure  
Agranulocytosis  
Aplastic anemia  
Toxic epidermal necrolysis/Stevens-Johnson syndrome  
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis 
Confirmed or suspected endotoxin shock 
Confirmed or suspected transmission of infectious agent by a medicinal product 
Neuroleptic malignant syndrome / malignant hyperthermia 
Spontaneous abortion / stillbirth and fetal death 
 
The PTEs that fulfill one or more of the serious criteria above are also to be considered SAEs 
and should be reported and followed up in the same manner (see Section 6.3.1.3.2 and 
Section 6.3.1.3.3). 
If a subject is noted to ALT or AST value >3 × the 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 13.2). 


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6.3.1.1.4 
Adverse Events 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 
Hypersensitivity reactions (anaphylaxis)  
Acute interstitial nephritis/tubulointerstitial nephritis   
Bone fracture 
Hematologic abnormalities 
 
For additional details on liver function monitoring, see Section 13.2. 
6.3.1.1.5 
Additional Points to Consider for PTEs and AEs 
An untoward finding generally may involve the following: 
• Indicates a new diagnosis or unexpected worsening of a pre-existing condition. 
(Intermittent events for pre-existing conditions or underlying disease should not be 
considered PTEs or AEs.) 
• Necessitates therapeutic intervention. 
• Requires an invasive diagnostic procedure. 
• Requires discontinuation or a change in dose of study drug or a concomitant 
medication. 
• Is considered unfavorable by the investigator for any reason.  


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• Is caused by a study procedure (eg, a bruise after blood collection); these events 
should be recorded as a PTE/AE. 
Diagnoses versus signs and symptoms: 
• Each event is required to be recorded to represent a single diagnosis or disorder using 
standard medical terminology rather than individual symptoms. Accompanying signs 
(including abnormal laboratory values or 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). 


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Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”). 
• If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any 
occurrence of an episode should only be captured as a PTE/AE if the episodes 
become more frequent, serious, or severe in nature, that is, investigators should 
ensure that the AE term recorded captures the change in the condition from baseline 
(eg “worsening of…”).  
• If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be captured as a PTE/AE if 
occurring to a greater extent than that which would be expected. Again, investigators 
should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”). 
Worsening of PTEs or AEs: 
• If the subject experiences a worsening or complication of a PTE after starting 
administration of the study drug, the worsening or complication should be recorded 
appropriately as an AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).  
• If the subject experiences a worsening or complication of an AE after any change in 
study drug, the worsening or complication should be recorded as a new AE. 
Investigators should ensure that the AE term recorded captures the change in the 
condition (eg, “worsening of…”). 
• At each required study visit, all AEs that have occurred since the previous visit or 
AEs that have changed in severity since the previous visit must be recorded in the AE 
record of the eCRF. 
Changes in severity of AEs/serious PTEs: 
• If the subject experiences a 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 cardiovascular accident but 
with some persisting paresis). 
• Fatal: The AEs/PTEs are considered the cause of death. 
• Unknown: The course of the AE/PTE cannot be followed up due to a hospital change 
or residence change at the end of the subject’s participation in the study. 
6.3.1.3 Time Period and Frequency for Collecting AE and SAE 
Information 
6.3.1.3.1 Collection and Reporting of Adverse Events 
Collection of PTEs will commence from the time the 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 
 Pharmacovigilance. 
 
 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, IRB/IECs, and Regulatory 
Authorities 
The sponsor designee (contract research organization) will be delegated the responsibility for 
reporting all suspected unexpected serious adverse reactions (SUSARs) and any other 
applicable SAEs to regulatory authorities, investigators, and the IRB/IEC, 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 (eg, EudraVigilance 
Database, FDA Adverse Event Reporting System) 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 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/IEC, 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/IEC, if appropriate, according to local requirements. 
If there is an increase in unexpected SAEs or if there is a change in the frequency and 
character of expected SAEs based on the known safety profile of vonoprazan, further 
evaluation will be conducted to characterize these events and any impact on benefit/risk. 
Health authorities will be consulted to agree upon the appropriate action to be taken 
regarding the conduct of the study, including no change to the protocol, revision of the safety 
monitoring plan, suspension of enrollment, or discontinuation of the study. 
6.3.2 Pregnancy 
If any subject is found to be pregnant during the study, she should be withdrawn, and any 
sponsor-supplied drug (vonoprazan active) should be immediately discontinued. If the 
pregnancy occurs during administration of active study drug, eg, after Visit 2 or within 2 
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 subject 
(and LAR, if legally applicable) 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. The laboratory reports must be filed with the source documents. Abnormal 
laboratory findings that are expected with the underlying disease should not be 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the subject’s condition. 
• All laboratory tests with abnormal values considered clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the 
sponsor notified. 
o All protocol-required laboratory assessments, as defined in Table 6-4, must be 
conducted in accordance with the laboratory manual and the SoE. 
 If laboratory values from non–protocol-specified laboratory 
assessments performed at the institution’s local laboratory require a 
change in subject management or are considered clinically significant 
by the investigator (eg, SAE, AE, or dose modification), then the 
results must be recorded in the unscheduled laboratory eCRF. 
All samples will be collected in accordance with acceptable laboratory procedures. Details of 
these procedures and required safety monitoring will be provided in the laboratory manual. 
All study-required laboratory assessments will be performed by a central laboratory. 


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Table 6-4 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
• 
Platelet count 
• 
RBC count 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC indices: MCV, MCH 
• 
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 b  
• 
GGT 
Routine urinalysis c  
• 
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 
• 
Serology (HIV antibody, HBsAg, HCV antibody, HCV viral load RNA 
[qualitative]), hCG pregnancy test d  
ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; 
HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV: human immunodeficiency virus; hCG: 
human chorionic gonadotropin; 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 at Visit 1 and at any unscheduled visit. 
c 
At the discretion of the investigator. 
d    Only female subjects who have experienced menarche will have urine hCG; if the urine hCG test is 
positive confirm with serum hCG. 
 
Investigators must document their review of each laboratory safety report. 
6.3.4 Physical Examinations 
Refer to the SoE (Section 13.1) for the timing and frequency for full and brief physical 
examinations, as well as height and body weight.  


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A complete physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, neurological systems and Tanner staging 
(Section 13.5). Height and body weight will also be measured and recorded. The subject 
should be dressed in light clothing and without shoes when the body weight is being 
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 recording will be made after the subject has been in the 
supine position for at least 5 minutes. ECGs will be read and interpreted centrally by a 
pediatric cardiologist for eligibility during Screening and on Day 14. A single repeat 
measurement is permitted during screening period for eligibility determination. Assessments 
will include whether the tracings are normal or abnormal (if abnormal, whether clinically 
significant or not clinically significant). 
6.4 
Safety Monitoring Committee 
Based on the well-characterized safety profile in adults, a Safety Monitoring Committee is 
not planned for this study. The sponsor and investigators will review safety and tolerability 
data throughout the study. 


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7 Statistical and Analytical Plan 
This section describes the statistical and analytical methods to be used for the study. 
7.1 
Sample Size Calculations 
Approximately 18 subjects are expected to be enrolled with 9 subjects in each dose group. 
Attempts will be made to enroll subjects across the ≥ 6 to < 12 years age range. 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 this 
population. 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 
7.3.1 Pharmacokinetic Analyses 
The individual pharmacokinetic parameter estimates in Table 6-1 will be summarized 
descriptively by vonoprazan dose. 
The following pharmacokinetic parameters will be considered the primary endpoints for the 
study: Cmax,ss, AUCτ, CL/F, Vz/F. 
7.3.2 Pharmacodynamic Analyses 
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. 


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7.3.3 Efficacy 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. 
7.3.4 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 treatment and overall, as well as by severity and relationship to 
study drug. Serious AEs and AEs leading to discontinuation of study drug will also be 
presented in the data listings and summarized by treatment and overall. 
Actual values and changes from baseline for clinical laboratory test results and vital sign 
measurements will be summarized at each time point using descriptive statistics (number of 
subjects, mean, SD, median, minimum, and maximum). Shift tables will be generated for 
clinical laboratory test results.  
7.3.5 Interim Analyses 
No formal interim analyses will be performed in this study. 
However, a popPK analysis of interim data from a subset of subjects may be conducted prior 
to completion of enrollment to assess whether plasma exposure in pediatric subjects aged ≥ 6 
to < 12 years is within the range observed in adults receiving the same dose.  


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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 and 
Regulation 536/2014 of the European Parliament and of the council of 16 April 2014 on 
clinical trials on medicinal products for human use and repealing Directive 2001/20/EC. 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 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 or Independent Ethics Committee 
Federal regulations, national regulations, and the ICH guidelines require that approval be 
obtained from an IRB/IEC before participation of human subjects in research studies. Before 
study onset, the protocol, informed consent, advertisements to be used for the recruitment of 
study subjects, and any other written information regarding this study to be provided to the 
subject and/or LAR must be approved by the IRB/IEC. Documentation of all IRB/IEC 
approvals and of the IRB/IEC compliance with ICH harmonised tripartite guideline, E6: 
Good Clinical Practice (GCP), will be maintained by the site and will be available for review 
by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairperson or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
9.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
All potential serious breaches must be reported to the sponsor or designee immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the 
study or the protocol which is likely to affect to a significant degree the safety or physical or 
mental integrity of the subjects of the study or the scientific value of the study. 
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 


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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/IEC submission. Once reviewed, the consent and 
assent materials will be submitted by the investigator to his or her IRB/IEC for review and 
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/IEC but will not result in protocol amendments. 
The Investigator will also be responsible for providing oversight of the conduct of the study 
or site, including oversight of all personnel involved in the study, and adherence to all 
applicable laws and regulations as set forth in the Clinical Trial Agreement.  
Personnel involved in conducting this study will be qualified by education, training and 
experience prior to performing their respective tasks. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject, except as necessary for monitoring and auditing by the sponsor, its 
designee, the United States Food and Drug Administration (FDA) or any regulatory 
authority(ies), or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 Code of Federal Regulations (CFR) 54. In addition, the investigator must provide to the 
sponsor a commitment to promptly update this information if any relevant changes occur 
during the course of the investigation and for 1 year following the completion of the study. 


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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. 
10.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6 8.2 and 
Title 21 of the CFR by providing the following essential documents, including but not limited 
to the following: 
• IRB/IEC approval 
• Original investigator-signed investigator agreement page of the protocol 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 for United States sites and equivalent form for non-US sites  
• Curriculum vitae for the investigator and each subinvestigator listed on Form 
FDA 1572 equivalent form for non-US sites 
• Financial disclosure information to allow the sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR 54. In addition, 
the investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study. 
• IRB/IEC-approved informed consent 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. The investigator will conduct all aspects of this study in accordance with all 


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national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of subjects begins. 
10.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6 and all applicable guidelines and regulations. 
10.6 Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs to the 
sponsor and/or IRB/IEC according to the timeline and method outlined in the protocol. In 
addition, the investigator agrees to submit annual reports to the study site IRB/IEC as 
appropriate. 
10.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
10.8 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
10.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 


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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. This is a Phase 1 study 
with 14 days dosing and adverse events will be evaluated on an ongoing basis. Additionally, 
vonoprazan has a well characterized safety profile in adults.  
11.1.2 Monitoring of the Study 
The clinical monitor, acting as the main line of communication between the sponsor (or 
designee) and the investigator and as a representative of the sponsor, has the obligation to 
follow the study closely. In doing so, the monitor will visit the investigator and study site at 
periodic intervals, in addition to maintaining necessary telephone and letter contact. The 
monitor will maintain current personal knowledge of the study through observation, review 
of study records and source documentation, and discussion of the conduct of the study with 
the investigator and personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.3 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, representatives 
of the sponsor, or a regulatory agency access to all study records. 
The investigator should promptly notify the sponsor and 
 of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 


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11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB/IEC for approval before subjects can be enrolled into an amended protocol. 
11.2.2 Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review, to the sponsor for agreement, and to the 
regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
subject or investigator that results in a significant additional risk to the subject. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, or nonadherence to 
FDA regulations or ICH GCP guidelines, and may lead to the subject being withdrawn from 
the study (Section 4.2). 
Protocol deviations will be documented by 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/IEC should be notified of all protocol deviations they consider 
reportable in a timely manner. 
11.3 Study Termination 
Although the sponsor has every intention of completing the study, the sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 


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The end of the study is defined as the date on which the last subject completes the last visit 
(includes follow-up visit). 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 
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 sponsor will submit to clinical trial registries a summary of the results of the clinical trial 
and where applicable a summary that is understandable to a layperson, and the clinical study 
report health authorities, within 6 months after the end of the study. The investigator is 
encouraged to share the summary results with the LARs and study subjects, as appropriate.  
 


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12 Reference List 
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Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), 
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Addendum to E6(R1) March 2018. [cited 2021 Jan 12] Available from: 
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Engevik AC, Kaji I, Goldenring JR. The physiology of the gastric parietal cell. Physiol 
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Facius A. Population PK Analysis to Support the Paediatric Development of Vonoprazan 
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Gilger MA, El-Serag HB, Gold BD, et al. Prevalence of endoscopic findings of erosive 
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Gold BD, Freston JW. Gastroesophageal reflux in children: pathogenesis, prevalence, 
diagnosis, and role of proton pump inhibitors in treatment. Paediatr Drugs 
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Gold BD, Gunasekaran T, Tolia V, et al. Safety and symptom improvement with 
esomeprazole in adolescents with gastroesophageal reflux disease. J Pediatr Gastroenterol 
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Gremse D, Winter H, Tolia V, et al. Pharmacokinetics and pharmacodynamics of 
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James L, Walson P, Lomax K, et al. Pharmacokinetics and tolerability of rabeprazole sodium 
in subjects aged 12 to 16 years with gastroesophageal reflux disease: an open-label, single- 
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Kukulka M, Wu J, Perez MC. Pharmacokinetics and safety of dexlansoprazole MR in 
adolescents with symptomatic GERD. J Pediatr Gastroenterol Nutr 2012;54(1):41-7. 
Kukulka M, Nudurupati S, Perez MC. Pharmacokinetics and safety of dexlansoprazole MR 
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Li J, Zhao J, Hammer-Maansson JE, et al. Pharmacokinetic properties of esomeprazole in 
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Nelson SP, Chen EH, Syniar GM, Christoffel KK. Prevalence of symptoms of 
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Sakurai Y, Mori Y, Okamoto H, et al. Acid-inhibitory effects of vonoprazan 20 mg compared 
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Scott DR, Munson KB, Marcus EA, Lambrecht NW, Sachs G. The binding selectivity of 
vonoprazan (TAK-438) to the gastric H+, K+ -ATPase. Aliment Pharmacol Ther 
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Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. 
J Neurogastroenterol Motil 2013;19(1):25-35. 
Tolia V, Bishop PR. Tsou VM, et al. Multicenter, randomized, double-blind study comparing 
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Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus Group. The Montreal 
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Zannikos PN, Doose DR, Leitz GJ, et al. Pharmacokinetics and tolerability of rabeprazole in 
children 1 to 11 years old with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 
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a 
For subjects participating in the pharmacodynamic substudy, Visit 2 (Day -1) and Visit 6 (Day 8) are only required for 
subjects undergoing gastric pH monitoring if clinically indicated at select sites. pH monitoring will be conducted on 
Day -1 for 24 hours and on Day 7 for 24 hours. pH probes would be placed on Days -1 and 7 and removed on Days 1 
and 8. 
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, neurological systems and Tanner staging). 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 
Clinical laboratory testing will include hematology, serum chemistry, and urinalysis (if deemed necessary by the PI). 
Blood draws should follow vital signs or electrocardiograms. 
i 
Only female-born subjects who have reached menarche, will require guidance on avoidance of pregnancy and urine or 
serum hCG; if urine hCG is positive, confirm with serum hCG.  
j 
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 pediatric cardiologist will interpret the ECG for eligibility and any abnormality. A single repeat 
measurement is permitted at screening for eligibility determination after the read by a pediatric cardiologist. 
Assessments should include comments on whether the tracings are normal or abnormal (if abnormal, whether clinically 
significant or not clinically significant). An ECG will be collected at the final visit and interpreted by a pediatric 
cardiologist. 
k 
Subject will be randomized to study treatment after all eligibility criteria have been met. 
l 
Study drug will be administered in the clinic on Days 1, 7, and 14. Study drug should be taken every day between 7 and 
10 am preferably prior to eating any breakfast or food. Study drug for at home administration will be dispensed on Day 
1 (to be taken on Days 2 to 6) and Day 7 (to be taken on Days 8 to 13). At home, parents/caregivers will administer 
study drug to subjects. Clinic staff will review instructions with parents/LARs for administering study drug at home 
and completing the Study Drug Reminder Card. Phone call reminders may be conducted as required.  
m 
Blood samples for PK analysis of vonoprazan in plasma will be collected on Days 7 and 14. On Day 7 days, one pre-
dose sample will be collected prior to the morning administration of vonoprazan along with two additional samples 
collected after drug administration: one between 0.5 to 1.5 hours post-dose and one between 2.5 to 3.5 hours post-dose. 
On Day 14 days, one pre-dose sample will be collected prior to the morning administration of vonoprazan along with 
two additional samples collected after drug administration: one between 1 to 2 hours post-dose and one between 3 to 4 
hours post-dose. The exact time of each pharmacokinetic sample should be recorded in the source and eCRF.  
If a subject terminates early, an attempt should be made to collect one blood sample if it can be collected within 24 
hours following the last dose of study drug. The exact date and time of the early termination sample must be recorded. 
n 
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 International units per liter 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  


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• Copper T PLUS condom or spermicide 
• 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 baseline ALT or AST levels experience ALT or AST >8 × ULN, 
follow-up laboratory tests (at a minimum, serum alkaline phosphatase, ALT, AST, total 
bilirubin, GGT, and INR) should be repeated within a maximum of 48 hours after the 
abnormality was found. 
13.3.2 Considerations for Temporary Discontinuation of Study Drug 
If the ALT or AST levels remain elevated >3 × ULN in subjects with normal baseline ALT or 
AST levels and a 2-fold increase above baseline OR if the ALT or AST levels remain 
elevated >5 × ULN in subjects with elevated baseline ALT or AST levels on 2 consecutive 
occasions, the investigator must contact the medical monitor to discuss additional testing, 
recommended monitoring, possible temporary discontinuation of study drug, and possible 
alternative etiologies. 


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13.3.3 Permanent Discontinuation of Study Drug 
If any of the circumstances occur as mentioned in Table 13-1 at any time during treatment, 
the study drug should be permanently discontinued: 
Table 13-1 
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 Appendix 4: Questionnaires 
13.4.1 GERD Symptom Assessment-Investigator 
The following 4 symptoms of GERD will be evaluated, as defined below when asked of 
children 9 to 12 years of age. 
Symptom 
Definition 
Heartburn 
Hurting or burning in the stomach, chest or throat  
Vomiting  
Something coming out of your mouth (throw-up) 
Acid regurgitation  
Food come up from your stomach to your mouth 
Trouble eating  
Ate less than usual, did not want to eat, did not want to eat certain 
foods because of hurting or burning 
 
The following 4 symptoms of GERD will be evaluated, as defined below when asked of 
parents of children 6 to 8 years of age if the child reported or they observed any of the 
following behaviors. 
Symptom 
Definition 
Heartburn 
Hurting or burning in the stomach, chest or throat such as holding 
his/her stomach/chest/throat, lying in curled up position, crying, 
acting fussy, or other behaviors 
Vomiting  
Something coming out of the mouth  
Acid regurgitation  
Partially digested food or stomach contents coming up in their 
mouth 
Trouble eating  
Refused to eat anything, ate less than usual, refused to eat certain 
foods because of hurting or burning or stomach contents coming up 
in their mouth 
 
 
 


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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: Tanner Staging  
Tanner Staging will be reported based on the following criteria:  
 
 
 
 


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13.6 Appendix 6: National Center for Health Statistics Clinical Body 
Weight Charts with 5th and 95th Percentiles 
13.6.1  Girls 
 


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13.6.2  Boys 
  


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13.7 Appendix 7: 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.  
Globally “with body weight ≥ 30 kg” was removed and is not highlighted below unless other 
information changed within the section.  
13.7.1 Protocol Amendment 1 
Synopsis (EU Trial Number)  
2022-003228-42 
 
Synopsis (Study Sites)  
Approximately 20 to 25 sites in the United States and Europe 
 
Synopsis (Study Design and Interventions)  
This is a Phase 1, uncontrolled, randomized, open-label, parallel-group, multiple-dose study 
in children ≥ 6 to < 12 years of age with a body weight ≥ 30 kg who have 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. Approximately A total of 
18 subjects are expected to be enrolled in 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. 


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Following the last dose of study drug or early discontinuation, the subject will be transitioned 
to local standard of care in accordance with each site’s prespecified process. 
Synopsis (Pharmacokinetic Assessments (Primary Endpoints))  
The primary vonoprazan pharmacokinetic endpoints will include the following steady state 
parameters from data collected on Day 7 and Day 14: 
• 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) 
 
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 
preferably prior to eating any breakfast or food with approximately 240 mL (8 oz) water 
between 7 and 10 am each day. 
Synopsis (Ethical Considerations) 
Clinical studies in adults with GERD have shown a positive benefit-risk for vonoprazan. This 
study is anticipated to provide benefits to children ≥ 6 to < 12 years of age with symptomatic 
GERD and risks similar to those observed with vonoprazan in adults. This study is needed to 
identify doses to be used in future trials in children ≥ 6 to < 12 years of age. 
The study was designed to minimize the number of blood samples and visits to investigate 
the pharmacokinetics and safety in this population. 
 
Synopsis (Sample Size)  
Approximately 18 subjects will be enrolled with 9 subjects in each dose group. Attempts will 
be made to enroll subjects across the ≥ 6 to < 12 years age range. 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 this 
population. Fewer subjects may be enrolled based on preliminary data, if considered 
sufficient to adequately characterize the PK pharmacokinetic profile 
 
Synopsis (Statistical Methods) 
Pharmacokinetic Endpoints: 
Individual pharmacokinetic parameter estimates will be summarized descriptively by 
vonoprazan dose.  


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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. 
Pharmacodynamic Endpoints: 
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. 
 
Introduction (Section 1.0) 
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 
and in combination with amoxicillin and clarithromycin have been approved for the 
treatment of Helicobacter pylori infection in adults. Vonoprazan is being developed for the 
treatment of heartburn in patients with symptomatic non-erosive gastroesophageal reflux 
disease (sGERD), 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 countries other than the United States, vonoprazan has been studied in other gastric acid-
related diseases such as healing of gastric and duodenal ulcers, and for the prevention of 
recurrence of gastric or duodenal ulcer during nonsteroidal anti-inflammatory drug or aspirin 
administration. Vonoprazan has received regulatory approval for adults in Japan, Russia, and 
other countries in Asia and Latin America for a variety of indications, including the healing 
of erosive esophagitis and maintenance of healing of erosive esophagitis. Vonoprazan is not 
currently approved for use in pediatric patients in any country.  
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. 
 


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Study Rationale (Section 1.1) 
The purpose of this study is to determine a dose of vonoprazan in children aged ≥ 6 to < 12 
years with body weight ≥ 30 kg with symptomatic gastroesophageal reflux disease (GERD) 
that provides an exposure similar to the exposures in adults after administration of 
vonoprazan 10 or 20 mg once daily (QD). Like proton pump inhibitors, vonoprazan is 
expected to provide benefit in pediatric patients with GERD.  
 
Vonoprazan (Section 1.2.2) 
The gastric hydrogen, potassium–adenosine triphosphatase (H+, K+-ATPase), also known as 
the proton pump, is responsible for acid secretion from parietal cells in the stomach. It is 
inactive in the cytosol but relocates from the cytosol to the secretory membrane of the 
parietal cells when food is present in the stomach, thereby becoming active and pumping 
H+ ions out of the cells and into the canaliculi in exchange for K+ ions. It represents an 
attractive pharmacological target since it is the final step of the acid secretion process.  
Two classes of pharmaceuticals, with distinct mechanisms of action for inhibiting the gastric 
proton pump, have been developed for clinical application: 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 to 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 
and binds to the 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].  


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• 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 (TAK-438_107). 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 with CYP2C19, which is the primary enzyme responsible 
for the metabolism of PPIs [Shin 2013]. 
These unique aspects of the vonoprazan mechanism of action and pharmacokinetics relative 
to PPIs translate into greater magnitude and duration of gastric acid suppression, which are 
reflected in the pharmacodynamic profile [Jenkins 2015; Sakurai 2015]. 
The pharmacokinetic and pharmacodynamic profiles of vonoprazan were assessed in 
multiple studies, including Study TAK-438_107, which showed rapid rise in pH following 
vonoprazan administration 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 were 
43%, 63%, and 86%, respectively, and by Day 7 were 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 of 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 no 
evidence of a dose-related increase in adverse effects with vonoprazan from 5 mg to 40 mg 


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QD. As of 25 December 20212022, the global cumulative post-marketing patient exposure to 
vonoprazan is estimated to be approximately 7097 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 
children with symptomatic GERD. 
 
Justification for Dose (Section 1.3) 
The proposed pediatric doses are selected to approximate equivalent adult exposures 
following administration of vonoprazan 10 or 20 mg QD in children aged pediatric patients ≥ 
6 to < 12 years of age with body weight of ≥ 30 kg.  
The proposed doses are based on simulations using aan updated population pharmacokinetic 
(popPK) model [Facius 2023]. The 2-compartment linear popPK model for vonoprazan was 
developed with adult pharmacokinetic data from 13 healthy subjects aged 18 to 54 years who 
participated in 9 studies in healthy volunteers, 1 study in EE patientsspecifically selected to 
enable the extrapolation and 1 study in GERD patients.characterization of the disposition of 
vonoprazan in pediatric subjects. The final dataset consisted of 1,179354 subjects (769205 
Asian and 410149 Western) with 8010 plasma concentration observations. 
 
As planned, an analysis of interim PK data from the first adolescent subjects aged 12 to 17 
years randomized in Study VPED-102 was performed using the updated popPK model. 
Interim data from VPED-102 was combined with adult data from the updated popPK model 
to investigate potential differences in the pharmacokinetic properties of vonoprazan between 
adolescents and adults. Individual predicted AUCss values for the 8 adolescent subjects with 
symptomatic GERD included in the preliminary analysis were within the range expected 
from healthy adults at their respective doses and no obvious effect of age was observed. 
Model assessments indicated the updated popPK model was working well in adolescents and 
substantiated the usefulness of For the pediatric dose simulations using the popPK model to 
select doses for vonoprazan was updated to incorporate body size and maturation correction 
factors,younger pediatric subjects.   
For predicting the appropriate to predictdoses in pediatric subjects aged ≥ 6 to <12 years, 
simulations were performed using the updated popPK model for vonoprazan exposure in 


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infants, children, and adolescents (PopPK Simulation Memo).and were summarized by both 
age and body weight. For reference, all boys and girls aged ≥ 6 to < 12 years who have a 
body weight between the 5th and 95th percentiles would have a body weight between 15 and 
65 kg. Different model assumptions in terms of (i) the allometric weight scaling exponent (as 
estimated (none) in the adult data or fixed at 0.75) and (ii) if or if not to correct for enzyme 
maturation in infants2) were compared. 
The resulting models wereupdated model was used to simulate posterior distributions of area 
under the drug concentration-time curve at steady state (AUCss) in both adults and pediatrics 
pediatric subjects aged ≥6 to <12 years or with a body weight of 15 to 65 kg for a series of 
pediatric candidate doses. Matching pediatric doses were selected to limit the predicted 
percentage of pediatricspediatric subjects with an exposure exceeding the adult reference 
exposure (median AUCss) at 50 to 60%. 
For children aged ≥ 6 to < 12 years or with a body weight ≥ 30of 15 to 65 kg, each of the 
four modelssimulations gave similar exposure predictions, thereby suggesting that the 
selected doses for these pediatric patients (10 and 20 mg) should result in a majority of 
exposures that are within the 95% prediction interval in adults for both the 10 and 20 mg 
targeted doses. 
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 children ≥ 6 to 
< 12 years of age with body weight of ≥ 30 kg 
who have symptomatic GERD. 
• 
Cmax,ss, AUCτ, CL/F, Vz/F from data collected on 
Days 7 and 14. 
Safety 
• To evaluate the safety of vonoprazan (10 or 20 
mg QD) in children ≥ 6 to < 12 years of age 
with body weight of ≥ 30 kg who have 
symptomatic GERD. 
• 
Adverse events  
• 
Laboratory test values (hematology, serum 
chemistry, urinalysis*) 
• 
Electrocardiograms (ECGs)  
• 
Vital signs  
Exploratory 


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Table 2-1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
• To evaluate symptom relief and 
pharmacodynamics of vonoprazan (10 or 20 
mg) in children ≥ 6 to < 12 years of age with 
body weight of ≥ 30 kg who have symptomatic 
GERD. 
• 
The severity of GERD symptoms at baseline and 
Days 7 and 14, as assessed by the investigator 
• 
Mean pH and % time above pH 4, 5, and 6 at 
baseline 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 drug concentration-time curve during the dosing interval τ; CL/F: oral clearance; Cmax,ss: 
maximum drug concentration at steady-state; ECGs; electrocardiograms; GERD: gastroesophageal reflux 
disease; QD: once daily; Vz/F: apparent volume of distribution 
* Urinalysis is only required if deemed necessary by the investigator. 
 
Study Design (Section 3.1) 
This is a Phase 1, uncontrolled, randomized, open-label, parallel-group, multiple-dose study 
in children aged ≥ 6 to < 12 years with body weight of ≥ 30 kg who have symptomatic 
GERD. A total of approximately 18 subjects will be enrolled.  
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. Gastric pH will be monitored for 24 hours beginning on Day -1 and on Day 7. 
Following completion of study drug dosing on Day 14 or early discontinuation, the subject 
will be transitioned to local standard of care for 14 days during the Follow-up Period. Note, 
standard of care does not include the use of study drug but can include other acid suppressant 
agents.  
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 1 of 
2 vonoprazan doses (10 mg QD or 20 mg QD) for 14 days. 
Follow-up Period (2 weeks): A safety follow-up visit phone call will occur 2 weeks after the 
last dose of study drug to assess adverse events (AEs). Following completion of study drug 
dosing or early discontinuation, the subject will be transitioned to local standard of care for 
14 days. 
End-of-study definition: A subject will be considered to have completed the study (up to 8 
weeks, including 4 weeks of screening, 2 weeks of treatment and 2 weeks of safety follow-
up) if the subject completes the Treatment Period and the safety follow-up visit phone call. 
 
Selection of Study Population (Section 4.1) 
This study will be conducted at approximately 20 to 25 sites in the United States and Europe. 
Approximately 18 subjects will be enrolled. 
 
Inclusion Criteria (Section 4.1.1) 
Subjects are eligible for enrollment in the study if they meet all of the following inclusion 
criteria: 
1. The subject is ≥ 6 to < 12 years of age with body weight of ≥ 30 kg at the time of 
informed consent signing. 
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 (Section 13.6). 


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3. The subject must have a diagnosis of GERD prior to randomization and medical 
history of signs or 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 and will be recorded in the 
electronic case report form (eCRF). 
4. The subject has at least one moderate GERD symptom based on the GERD Symptom 
Assessment-Investigator scale performed at screening. 
5. The subject must be able to swallow study drug tablet with water. 
6. Parent or legal guardian (ie, legally authorized representative [LAR]) is willing and 
able to complete the informed consent process and subjects are able to comply with 
study procedures and visit schedule. 
7. Female subjects who have experienced menarche must have a negative pregnancy test 
and will be counseled on pregnancy avoidance (Section 13.2).   
 
Exclusion Criteria (Section 4.1.2) 
Subjects are not eligible for study participation if they meet any of the following exclusion 
criteria: 


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1. The subject has used prescription or non-prescription PPIs or H2RAs within 7 days 
prior to randomization or requires 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 rilpivarine 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 
subject 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. 
9. The subject has any abnormal laboratory test values that are considered clinically 
significant atin the startopinion of the investigator during the Screening Period. 
10. The subject has a history of hypersensitivity or allergies to vonoprazan (including the 
formulation excipients: D-mannitol, microcrystalline cellulose, hydroxypropyl 
cellulose, fumaric acid, ascorbic acid, croscarmellose sodium, magnesium stearate, 
hypermellose hypromellose, macrogol 8000, and titanium dioxide, or red or yellow 
ferric oxide). 


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11. The subject has used any prescription or over-the-counter medications (including 
CYP3A4 inducers), including herbal or nutritional supplements), other than those 
already excluded in criteria 1 to 5 above, 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.That is, unless the 
medication(s) is permitted by the sponsor following a review of available data which 
confirms concomitant administration of the medication is unlikely to affect either the 
safety of the patient or the pharmacokinetics of vonoprazan. 
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. The subject has positive results at screening for human immunodeficiency virus, 
hepatitis B virus, or hepatitis C virus (HCV) infection at screening. 
14. The subject has severe renal impairment (estimated glomerular filtration rate < 30 
mL/min). 
15. The subject has moderate to severe hepatic impairment (Child-Pugh Class B and 
Child-Pugh Class C). 
16. The subject has any of the following abnormal laboratory test values at the start of the 
Screening Period: 
a. Creatinine levels: >2 mg/dL (>177 μmol/L). 
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the 
upper limit of normal (ULN) or total bilirubin >2 × ULN (except subjects with 
Gilbert Syndrome). 
17. In the opinion of the investigator, the subject is not suitable for entry into the study. 
 


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Replacements (Section 4.2.4) 
Discontinued or withdrawn subjects will not be replaced. 
At the discretion of the sponsor, subjects may be replaced to achieve the target of 
approximately 18 subjects with expected usable pharmacokinetic sample collections.  
 
Treatments Administered (Section 5.2) 
Subjects will be administered study drug orally at the clinic on Day 1 and on Days 7 and 14, 
after the pre-dose pharmacokinetic sample, with approximately 240 mL (8 oz) of water in the 
morning between 7 and 10 am preferably prior to eating any breakfast or food. If necessary, a 
dosing cup can be used to facilitate administration. Study drug will be dispensed to the 
parent/LAR for study drug to be administered to the subject at home. Clinic staff will provide 
the parent/LAR a Study Drug Reminder Card and instruct the parent/LAR to record the date 
and time of every dose taken at home and to bring this card back to the next clinic visit.  
On Days 2 to 6 and 8 to 13, the parent/LAR Parents/caregivers will be instructed to havegive 
the subject take randomized study drug orally with approximately 240 mL (8 oz) of water 
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.preferably prior to eating any breakfast or food. Any 
missed doses should also be notedrecorded by the parents/caregiversparent/LAR and 
communicated to clinic staff to recordimmediately. All dosing information including missed 
doses will be recorded on the Study Drug Reminder Card and in the eCRF. 
For the Days 6 and 13 dose, parents/caregivers will note the time it was taken by the subject. 
Clinic staff will record this information in the eCRF. 
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 On Days 7 and 14 
subjects may have a meal/snack 30 to 60 minutes after study drug dosing per the clinic’s. 


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Following completion of study drug dosing on Day 14 or early discontinuation, the subject 
will be transitioned to local standard procedures of care for 14 days. Note, the local standard 
of care does not include study drug but can include other acid suppressant agents.  
Identity of Investigational Product (Section 5.3)  
Vonoprazan study medication will be supplied as 10 mg and 20 mg tablets. 
 
 manufactures 
the vonoprazan fumarate drug substance. 
 
 manufactures the vonoprazan tablets. 
Vonoprazan tablets contain vonoprazan free base (MW 345.39) and the following inactive 
excipients: D-Mannitol, microcrystalline cellulose, hydroxypropyl cellulose, fumaric acid, 
ascorbic acid, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene 
glycol 8000, titanium dioxide, and red or yellow ferric oxide. 
Study drug will be packaged in bottles for shipment to the investigational site. 
 
Study Drug Packaging and Storage (Section 5.4.1)  
Vonoprazan tablets will be packaged 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 are 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 detailed information regarding packaging and 
labeling and for reporting temperature excursions. 
 
Treatment Compliance (Section 5.7.1) 


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Compliance with study drug is to be assessed as specified in the SoE (Section 13.1). 
Compliance with study drug dosing will be assessed by clinic staff reviewing the Study Drug 
Reminder Card returned at each visit, direct questioning and counting any returned 
capsulestablets, 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. Study drug start and stop 
dates will also be recorded in the eCRF. 
If the subjects exhibitThe date and time of each dose taken (in clinic or at home) must be 
recorded on the Study Drug Reminder Card, source documents and eCRF. If a subject misses 
any dose for any reason, the sponsor must be notified immediately, and the date of the missed 
dose(s) and reason must be recorded in the eCRF.   
If a subject misses a scheduled visit or exhibits poor compliance, as assessed by capsuletablet 
counts, the sponsor should be notified immediately to determine appropriate mitigation. 
Actions may include subjects provided with specific dosing instructions to continue study 
drug or discontinuation from the study. The LARs and subjects should be counseled at each 
visit on the importance of good compliance withregarding the study dosing regimen and 
scheduled study visits. 
 
Prior and Concomitant Therapy (Section 5.8) 
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 
• Dosage information, including dose and frequency 


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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. 
 
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 
Day 14 (end of 
study drug 
dosing) 
CYP3A4 substrates with a narrow therapeutic index 
14 days prior to Day 1 
End of treatment 
Day 14 (end of 
study drug 
dosing) 
CYP2C19 substrates clopidogrel, citalopram, 
cilostazol 
14 days prior to Day 1 
End of treatment 
Day 14 (end of 
study drug 
dosing) 
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 
 
Pharmacokinetic Assessments (Section 6.1.1) 
Parents/caregivers will be asked to note the exact time the subject took their study drug dose 
on Days 6 and 13. Clinic staff will record this information in the eCRF. 


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Parents/caregiversParents/LARs will ensure that the subject arrives at the clinic in the 
morning on Days 7 and 14 for pharmacokinetic sampling. Subjects should not eat or take the 
vonoprazan study medicationdrug before arriving toat the clinic. SubjectsThe Day 7 and 14 
dose of study drug will be released from given in 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 this daysOn Day 7, one pre-dose sample will be collected prior to 
the morning administration of vonoprazan along with two additional samples collected after 
drug administration: one between 0.5 to 1.5 hours post-dose and one between 2.5 to 3.5 hours 
post-dose. On Day 14, one pre-dose sample will be collected prior to the morning 
administration of vonoprazan. Two along with two additional samples will be collected after 
drug administration: one between 0.5 and1 to 2 hours post-dose and one between 2.5 and 3 to 
4 hours post-dose. The exact date and time of each pharmacokinetic sample must be recorded 
in subject source document and eCRF. 
If a subject terminates early, an attempt should be recorded.made to collect one blood sample 
if it can be collected within 24 hours following the last dose of study drug. The exact date 
and time of the early termination sample must be recorded. 
SamplesBlood samples will be collected into appropriate bloodsodium heparin vacutainer 
collection tubes, as specified by the bioanalytical laboratory and processed into plasma. 
Details of 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 10.5 to 100 µgng/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. 


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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. The primary vonoprazan pharmacokinetic endpoints will include the 
following steady state parameters: Cmax,ss, AUCτ, CL/F and Vz/F. 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. 
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 
 
Pharmacodynamic Assessments (Section 6.1.2) 
IfSelect sites may participate in a sub-study collecting gastric pH when deemed clinically 
indicatednecessary by the principal investigator. In the pharmacodynamic sub-study, gastric 
pH will be measured and recorded continuously for a 24-hour period on scheduled daysDay -
1 and Day 7 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 for Day -1 will commence 24-hours prior to the first dose of study drug. The 24-hour 
continuous pH recording session for Day 7 will commence 30 to 60 minutes prior to 
treatment administration the next dose of study drug. The reason for pH assessments, start 


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time, stop time and any interruptions will be recorded in the source document and the case 
report form (CRF) eCRF. To minimize the discomfort of probe insertion, administration of a 
topical anesthetic (lidocaine) will be permitted. After each 24-hour period, per the 
flashcardinstitutional process. Details of collection, processing, storage and shipping will be 
removed fromcontained in the recorder and the Gastric pH data will be transferred to the 
computer.Monitoring Plan.  
 
Gerd Symptom Assessment-Investigator (Section 6.2.1) 
The GERD Symptom Assessment-Investigator scale evaluates 4 symptoms of GERD: 
heartburn, vomiting, acid regurgitation, and trouble eating. The maximum severity of each 
GERD symptom occurring during the 7 days prior to the study visit, Day 7 and Day 14 will 
be assessed. The severity for each symptom will be recorded as either none, mild, moderate, 
severe or very severe. At screening, the subject will be eligible for inclusion in the study if 
the subject has at least one moderate GERD symptom. Symptom and severity definitions are 
presented in Section 13.4.1. 
Adverse Events 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. 


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Adverse events of special interest include any event listed in Table 6-23. 
Table 6-23 
Adverse Events of Special Interest List 
Term 
Hepatotoxicity  
Severe cutaneous adverse reactions, including hypersensitivity 
Clostridium difficile infections and pseudomembranous colitis 
Hypersensitivity reactions (anaphylaxis)  
Acute interstitial nephritis/tubulointerstitial nephritis   
Bone fracture 
Hematologic abnormalities 
 
For additional details on liver function monitoring, see Section 13.2. 
Safety Reporting to Investigators, IRB/IECs, and Regulatory Authorities (Section 6.3.1.3.4) 
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, investigators, and the IRB/IEC, 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 (eg, EudraVigilance 
Database, FDA Adverse Event Reporting System) 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. 
Laboratory Analyses (Section 6.3.3) 
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 


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eCRF. The laboratory reports must be filed with the source documents. Abnormal 
laboratory findings that are expected with the underlying disease should not be 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the subject’s condition. 
• All laboratory tests with abnormal values considered clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the 
sponsor notified. 
o All protocol-required laboratory assessments, as defined in Table 6-34 , must 
be conducted in accordance with the laboratory manual and the SoE. 
 If laboratory values from non–protocol-specified laboratory 
assessments performed at the institution’s local laboratory require a 
change in subject management or are considered clinically significant 
by the investigator (eg, SAE, AE, or dose modification), then the 
results must be recorded in the unscheduled laboratory eCRF. 
All samples will be collected in accordance with acceptable laboratory procedures. Details of 
these procedures and required safety monitoring will be provided in the laboratory manual. 
All study-required laboratory assessments will be performed by a central laboratory. 
 
 
 


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Table 6-4 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
• 
Platelet count 
• 
RBC count 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC indices: MCV, MCH 
• 
Percent reticulocytes 
• 
WBC count with differential: neutrophils, lymphocytes, monocytes, eosinophils, 
basophils 
Clinical chemistry a 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Total and direct bilirubin 
• 
ALT/SGPT 
• 
AST/SGOT 
• 
Alkaline phosphatase 
• 
Total protein 
• 
Potassium 
• 
Sodium 
• 
Calcium 
• 
Glucose b  
• 
GGT 
Routine urinalysis c  
• 
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 
• 
Serology (HIV antibody, HBsAg, and HCV antibody, hepatitis C, HCV viral 
load RNA [qualitative]), hCG pregnancy test d  
ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; 
HBsAg: hepatitis B surface antigen; 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 13.2 13.3 for the appropriate guidance on reporting of abnormal liver function tests. For 
liver function test monitoring, see Section 13.2.113.3.1 For temporary and permanent discontinuation of 
study drugs due to abnormal liver function tests, see Section 13.2.2 and Section 12.2.3 13.3.2 and 
Section 13.3.3, respectively. 
b 
Glucose will be obtained after an 8-hour fast at Visit 1 and at any unscheduled visit. 
c 
At the discretion of the investigator. 
d 
Only female subjects who have experienced menarche will have urine hCG; if the urine hCG test is 
positive confirm with serum hCG. 
 
Investigators must document their review of each laboratory safety report. 
 
 


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Physical Examinations (Section 6.3.4) 
Refer to the SoE (Section 13.1) for the timing and frequency for full and brief physical 
examinations, as well as height and body weight.  
A complete physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, and neurological systems and Tanner staging 
(Section 13.5). Height and body weight will also be measured and recorded. 
A brief physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, and gastrointestinal systems. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 
Electrocardiograms (Section 6.3.6) 
Refer to the SoE (Section 13.1) for the timing and frequency of ECG assessments.  
A single, standard 12-lead ECG recording will be made after the subject has been in the 
supine position for at least 5 minutes. ECGs will be read and interpreted centrally by a 
pediatric cardiologist for eligibility during Screening and on Day 14. A single repeat 
measurement is permitted at during screening period 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 will 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. 
 
 
 


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Statistical and Analytical Plan (Section 7) 
This section describes the statistical and analytical methods to be used for the study. A 
statistical analysis plan will provide further details of the statistical methods for the analysis. 
 
Sample Size Calculations (Section 7.1) 
Approximately 18 subjects are expected to be enrolled with 9 subjects in each dose group. 
Attempts will be made to enroll subjects across the ≥ 6 to < 12 years age range. 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 this 
population. Fewer subjects may be enrolled based on preliminary data, if considered 
sufficient to adequately characterize the PK profile. 
 
Analysis Sets (Section 7.2) 
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.  
 
Pharmacokinetic Analyses (Section 7.3.1)  
The individual pharmacokinetic parameter estimates in Table 6-1 will be summarized 
descriptively by vonoprazan dose. 


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The following pharmacokinetic parameters will be considered the primary endpoints for the 
study: Cmax,ss, AUCτ, CL/F, Vz/F. 
 
Pharmacodynamic Analyses (Section 7.3.2) 
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. 
 
Efficacy Analyses (Section 7.3.3) 
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. 
 
Interim Analyses (Section 7.3.5) 
No formal interim analyses will be performed in this study. 
However, a popPK analysis of interim data from a subset of subjects may be conducted prior 
to completion of enrollment to assess whether plasma exposure in pediatric subjects aged ≥ 6 
to < 12 years is within the range observed in adults receiving the same dose.  
 
Data Quality Assurance (Section 8) 
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 and 
Regulation 536/2014 of the European Parliament and of the council of 16 April 2014 on 
clinical trials on medicinal products for human use and repealing Directive 2001/20/EC. 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 


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sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). 
 
Ethical Conduct of the Study (Section 9.2)  
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. 
All potential serious breaches must be reported to the sponsor or designee immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the 
study or the protocol which is likely to affect to a significant degree the safety or physical or 
mental integrity of the subjects of the study or the scientific value of the study. 
 
Investigator’s Obligations (Section 10) 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
The Investigator will also be responsible for providing oversight of the conduct of the study 
or site, including oversight of all personnel involved in the study, and adherence to all 
applicable laws and regulations as set forth in the Clinical Trial Agreement.  
Personnel involved in conducting this study will be qualified by education, training and 
experience prior to performing their respective tasks. 
 
External Data Monitoring Committee (Section 11.1.1) 
An external data monitoring committee will not be used for this study. This is a Phase 1 study 
with 14 days dosing and adverse events will be evaluated on an ongoing basis. Additionally, 
vonoprazan has a well characterized safety profile in adults.  


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Final Report (Section 11.4) 
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 sponsor will 
submit to clinical trial registries a summary of the results of the clinical trial and where 
applicable a summary that is understandable to a layperson, and the clinical study report 
health authorities, within 6 months after the end of the study. The investigator is encouraged 
to share the summary results with the LARs and study subjects, as appropriate.  
 
 
 




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a 
For subjects participating in the pharmacodynamic substudy, Visit 2 (Day -1) and Visit 56 (Day 8) are only required for 
subjects undergoing gastric pH monitoring if clinically indicated at select sites. pH monitoring will be conducted on 
Day -1 for 24 hours and on Day 7 for 24 hours. pH probes would be placed on Days -1 and 7 and removed on Days 1 
and 8. 
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 and Tanner staging). 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 
Clinical laboratory testing will include hematology, serum chemistry, and urinalysis (if deemed necessary by the PI). 
Blood draws should follow vital signs or electrocardiograms. 
i 
Only female-born subjects, Tanner stage 2 development who have reached menarche, will require guidance on 
avoidance of pregnancy and urine or serum hCG; if urine hCG is positive, confirm with serum hCG.  
j 
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 pediatric cardiologist will interpret the ECG for eligibility and any abnormality. 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.after the read by a 
pediatric cardiologist. 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. An ECG will be 
collected at the final visit and interpreted by a pediatric cardiologist. 
k 
Subject will be randomized to study treatment after all eligibility criteria have been met. 
l 
Study drug will be administered in the clinic on Days 1, 7, and 14. On Days 7 and 14, subjects will be provided a meal 
30 60 minutes after study drug dosing per the clinic’s standard procedures. Study drug should be taken every day 
between 7 and 10 am preferably prior to eating any breakfast or food. Study drug for at home administration will be 
dispensed on Day 1 (to be taken on Days 2 to 6) and Day 7 (to be taken on Days 8 to 13). At home, parents/caregivers 
will administer study drug to subjects. Study drug should be taken every day between 7 and 10 am. Clinic staff will 
review instructions with parents/LARs for administering study drug at home and completing the Study Drug Reminder 
Card. Phone call reminders may be conducted as required.  
m 
Gastric pH monitoring on Day 1 for 24 hours and on Day 7 for 24 hours; only if clinically indicated. pH probes would 
be placed on Days 1 and 7 and removed on Days 1 and 8. Blood samples for PK analysis of vonoprazan in plasma will 
be collected on Days 7 and 14. On bothOn Day 7 days, one pre-dose sample will be collected prior to the morning 
administration of vonoprazan along with two additional samples collected after drug administration: one between 0.5 to 
1.5 hours post-dose and one between 2.5 to 3.5 hours post-dose. On Day 14 days, one pre-dose sample will be collected 
prior to the morning administration of vonoprazan and along with two additional samples will be collected after drug 
administration: one between 0.51 to 2 hours post-dose and one between 2.5 and 3 to 4 hours post-dose. The exact time 
of each pharmacokinetic sample should be recorded in the source and eCRF.  
If a subject terminates early, an attempt should be made to collect one blood sample if it can be collected within 24 
hours following the last dose of study drug. The exact date and time of the early termination sample must be recorded. 
n 
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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Appendix 2: Contraceptive Guidance (Section 13.2) 
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 International units per liter 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  


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• Copper T PLUS condom or spermicide 
• 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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Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 118 
Appendix 5: Tanner Staging (Section 13.5) 
Tanner Staging will be reported based on the following criteria:  
 
 
 
 


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Appendix 6: National Center for Health Statistics Clinical Body Weight Charts with 5th and 
95th Percentiles (Section 13.6) 
13.6.1 Girls 
 


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13.6.2 Boys  
 


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13.7.2 Protocol Amendment 2 
Exclusion Criteria (Section 4.1.2) 
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 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 
subject 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. 
9. The subject has any abnormal laboratory test values that are considered clinically 
significant in the opinion of the investigator during the Screening Period. 


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10. The subject has a history of hypersensitivity or allergies to vonoprazan (including the 
formulation excipients: D-mannitol, microcrystalline cellulose, hydroxypropyl 
cellulose, fumaric acid, ascorbic acid, croscarmellose sodium, magnesium stearate, 
hypromellose, macrogol 8000, and titanium dioxide, or red or yellow ferric oxide). 
11. The subject has used any prescription or over-the-counter medications (including 
herbal or nutritional supplements), other than those already excluded in criteria 1 to 5 
above, within 14 days before the first dose of study drug or throughout the study. That 
is, unless the medication(s) is permitted by the sponsor following a review of 
available data which confirms concomitant administration of the medication is 
unlikely to affect either the safety of the patient or the pharmacokinetics of 
vonoprazan. 
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. The subject has positive results at screening for human immunodeficiency virus, 
hepatitis B virus, or hepatitis C virus (HCV) infection at screening. 
14. The subject has severe renal impairment (estimated glomerular filtration rate < 30 
mL/min). 
15. The subject has moderate to severe hepatic impairment (Child-Pugh Class B and 
Child-Pugh Class C). 
16. The subject has any of the following abnormal laboratory test values at the start of the 
Screening Period: 
a. Creatinine levels: >21 mg/dL (>17788 μmol/L). 
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the 
upper limit of normal (ULN) or total bilirubin >2 × ULN (except subjects with 
Gilbert Syndrome). 


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17. In the opinion of the investigator, the subject is not suitable for entry into the study. 
Pregnancy (Section 3.3.2) 
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 42 
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 subject 
(and LAR, if legally applicable) 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. 
Prior and Concomitant Therapy (Section 5.8) 
Any medication including H2RAs and PPIs or vaccines (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 
• 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. 


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Protocol: VPED-103 Amendment 2 
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The medical monitor should be contacted if there are any questions regarding prior or 
concomitant therapy. 
Laboratory Analyses (Section 6.3.3) 
Investigators must document their review of each laboratory safety report. 
See Table 6-4 for the list of clinical laboratory tests to be performed and the SoE 
(Section 13.1) for the timing and frequency. 
• The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Abnormal 
laboratory findings that are expected with the underlying disease should not be 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the subject’s condition. 
• All laboratory tests with abnormal values considered clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the 
sponsor notified. 
o All protocol-required laboratory assessments, as defined in Table 6-4 must be 
conducted in accordance with the laboratory manual and the SoE. 
 If laboratory values from non–protocol-specified laboratory 
assessments performed at the institution’s local laboratory require a 
change in subject management or are considered clinically significant 
by the investigator (eg, SAE, AE, or dose modification), then the 
results must be recorded in the unscheduled laboratory eCRF. 
All samples will be collected in accordance with acceptable laboratory procedures. Details of 
these procedures and required safety monitoring will be provided in the laboratory manual. 


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Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 125 
All study-required laboratory assessments will be performed by a central laboratory. 
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 b
•
GGT
Routine urinalysis c  
•
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 
• 
Serology (HIV antibody, HBsAg, HCV antibody, HCV viral load RNA 
[qualitative]), hCG pregnancy test d  
ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; 
HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV: human immunodeficiency virus; hCG: 
human chorionic gonadotropin; MCH: mean corpuscular hemoglobin; MCV: mean corpuscular volume; 
RBC: red blood cell; RNA: ribonucleic acid; SGOT: serum glutamic-oxaloacetic transaminase; SGPT: serum 
glutamic-pyruvic transaminase; WBC: white blood cell 
a 
See Section 13.3 for the appropriate guidance on reporting of abnormal liver function tests. For liver 
function test monitoring, see Section 13.3.1. For temporary and permanent discontinuation of study 
drugs due to abnormal liver function tests, see Section 13.3.2 and Section 13.3.3, respectively. 
b 
Glucose will be obtained after an 8-hour fast at Visit 1 and at any unscheduled visit. 
c 
At the discretion of the investigator. 
d    Only female subjects who have experienced menarche will have urine hCG; if the urine hCG test is 
positive confirm with serum hCG. 
Investigators must document their review of each laboratory safety report. 


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Protocol: VPED-103 Amendment 2 
30 August 2023 
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Physical Examinations (Section 6.3.4) 
Refer to the SoE (Section 13.1) for the timing and frequency for full and brief physical 
examinations, as well as height and body weight.  
A complete physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, neurological systems and Tanner staging 
(Section 13.5). Height and body weight will also be measured and recorded. The subject 
should be dressed in light clothing and without shoes when the body weight is being 
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. 
 
 




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Protocol: VPED-103 Amendment 2 
30 August 2023 
Page 128 
a 
For subjects participating in the pharmacodynamic substudy, Visit 2 (Day -1) and Visit 6 (Day 8) are only required for 
subjects undergoing gastric pH monitoring if clinically indicated at select sites. pH monitoring will be conducted on 
Day -1 for 24 hours and on Day 7 for 24 hours. pH probes would be placed on Days -1 and 7 and removed on Days 1 
and 8. 
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, neurological systems and Tanner staging). 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 
Clinical laboratory testing will include hematology, serum chemistry, and urinalysis (if deemed necessary by the PI). 
Blood draws should follow vital signs or electrocardiograms. 
i 
Only female-born subjects who have reached menarche, will require guidance on avoidance of pregnancy and urine or 
serum hCG; if urine hCG is positive, confirm with serum hCG.  
j 
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 pediatric cardiologist will interpret the ECG for eligibility and any abnormality. A single repeat 
measurement is permitted at screening for eligibility determination after the read by a pediatric cardiologist. 
Assessments should include comments on whether the tracings are normal or abnormal (if abnormal, whether clinically 
significant or not clinically significant). An ECG will be collected at the final visit and interpreted by a pediatric 
cardiologist. 
k 
Subject will be randomized to study treatment after all eligibility criteria have been met. 
l 
Study drug will be administered in the clinic on Days 1, 7, and 14. Study drug should be taken every day between 7 and 
10 am preferably prior to eating any breakfast or food. Study drug for at home administration will be dispensed on Day 
1 (to be taken on Days 2 to 6) and Day 7 (to be taken on Days 8 to 13). At home, parents/caregivers will administer 
study drug to subjects. Clinic staff will review instructions with parents/LARs for administering study drug at home 
and completing the Study Drug Reminder Card. Phone call reminders may be conducted as required.  
m 
Blood samples for PK analysis of vonoprazan in plasma will be collected on Days 7 and 14. On Day 7 days, one pre-
dose sample will be collected prior to the morning administration of vonoprazan along with two additional samples 
collected after drug administration: one between 0.5 to 1.5 hours post-dose and one between 2.5 to 3.5 hours post-dose. 
On Day 14 days, one pre-dose sample will be collected prior to the morning administration of vonoprazan along with 
two additional samples collected after drug administration: one between 1 to 2 hours post-dose and one between 3 to 4 
hours post-dose. The exact time of each pharmacokinetic sample should be recorded in the source and eCRF.  
If a subject terminates early, an attempt should be made to collect one blood sample if it can be collected within 24 
hours following the last dose of study drug. The exact date and time of the early termination sample must be recorded. 
n 
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-103 
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 
Children Aged ≥ 6 to < 12 Years Who Have Symptomatic Gastroesophageal Reflux Disease 
NCT Number: NCT06106022 
Document Date: 11 Jun 2024 


Phathom Pharmaceuticals, Inc. 
  Statistical Analysis Plan, Version 1.0 
VPED-103     
     Date Issued:11JUN2024
Phathom Pharmaceuticals, Inc 
VPED-103 
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 Children Aged ≥6 to <12 Years 
Who Have Symptomatic Gastroesophageal Reflux Disease 
11th Jun 2024 
Statistical Analysis Plan 
Version 1.0 
Prepared by: 
 
 
  




Phathom Pharmaceuticals, Inc.                                                                                                              Statistical Analysis Plan, Version 1.0 
VPED-103                                                                                                                                                                  Date Issued:11JUN2024 
 
3 
 
 
Summary of Changes  
 
Amendment History and Reasons for Amendment  
 
Version  
Date  
Reasons for Amendment  
 
 
 


Phathom Pharmaceuticals, Inc.                                                                                                              Statistical Analysis Plan, Version 1.0 
VPED-103                                                                                                                                                                  Date Issued:11JUN2024 
 
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TABLE OF CONTENTS 
AUTHOR(S): ....................................................................................................................2 
APPROVED BY: ..............................................................................................................2 
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 
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. ANALYSIS SETS ....................................................................................................... 10 
4.4.1. 
Screened Set .................................................................................................... 10 
4.4.2. 
Enrolled Set ..................................................................................................... 10 
4.4.3. 
Pharmacokinetic Set ........................................................................................ 10 
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 .......................................................................................... 11 
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 ..............................................................12 
7.1. PRIOR AND CONCOMITANT MEDICATIONS .............................................................. 12 


Phathom Pharmaceuticals, Inc.                                                                                                              Statistical Analysis Plan, Version 1.0 
VPED-103                                                                                                                                                                  Date Issued:11JUN2024 
 
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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 .................................................................................... 13 
8. 
EFFICACY ANALYSIS ........................................................................................14 
8.1. PHARMACOKINETIC ANALYSES ............................................................................... 14 
8.2. EXPLORATORY ANALYSES....................................................................................... 14 
8.2.1. 
GERD Symptom Assessment ........................................................................... 14 
8.2.2. 
Pharmacodynamic Assessment ....................................................................... 14 
9. 
SAFETY ANALYSIS .............................................................................................15 
9.1. ADVERSE EVENTS ................................................................................................... 15 
9.1.1. 
Adverse Events of Special Interest (AESI) ...................................................... 16 
9.2. CLINICAL LABORATORY EVALUATIONS .................................................................. 18 
9.2.1. 
Clinical Chemistry ........................................................................................... 18 
9.2.2. 
Urinalysis ........................................................................................................ 19 
9.3. VITAL SIGN MEASUREMENTS ................................................................................. 19 
9.4. PHYSICAL EXAMINATION ........................................................................................ 20 
9.5. ELECTROCARDIOGRAM RESULTS ............................................................................. 20 
9.6. PREGNANCY TEST ................................................................................................... 21 
10. 
INTERIM ANALYSIS/OTHER ANALYSIS ......................................................21 
10.1. INTERIM ANALYSIS ................................................................................................. 21 
11. 
CHANGES IN THE PLANNED ANALYSIS ......................................................21 
12. 
APPENDICES ........................................................................................................22 
12.1. APPENDIX 1:  IMPUTATION ALGORITHM FOR PARTIAL AND MISSING DATES .......... 22 
12.1.1. Rules for Concomitant Medication Start Date Imputation ............................. 22 
12.1.2. Rules for Concomitant Medication End Date Imputation ............................... 23 
12.1.3. Rules for Prior Medication Start Date Imputation ......................................... 24 
12.1.4. Rules for AE Start Date Imputation ................................................................ 24 
12.2. APPENDIX 2: SCHEDULE OF EVENTS ....................................................................... 25 
12.3. APPENDIX 3: GERD SYMPTOM ASSESSMENT-INVESTIGATOR ................................ 28 
 
 
 
 
 
 
 


Phathom Pharmaceuticals, Inc.                                                                                                              Statistical Analysis Plan, Version 1.0 
VPED-103                                                                                                                                                                  Date Issued:11JUN2024 
 
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List of Abbreviations 
AE 
AESI 
ALT 
AST 
ATC 
AUC 
BLQ 
BMI 
CRF 
CTMS 
adverse event 
adverse event of special interest 
alanine aminotransferase 
aspartate aminotransferase 
Anatomical Therapeutic Chemical 
area under the curve 
below the limit of quantification 
body mass index 
Case Report Form 
Clinical Trial Management System 
ECG 
eCRF 
EE 
GERD 
hCG 
electrocardiogram 
electronic case report form 
erosive esophagitis 
gastroesophageal reflux disease 
human chorionic gonadotropin 
ICF 
IRT 
LAR 
LFT 
MedDRA 
informed consent form 
interactive response technology 
legally authorized representative 
liver function test 
Medical Dictionary for Regulatory Activities 
PD 
PK 
PPI 
PT 
PTE 
QD 
QTcB 
 
QTcF 
 
SAE 
SAP 
SD 
SE 
SOC 
SoE 
Pharmacodynamic 
pharmacokinetic 
proton pump inhibitor 
preferred Term 
pretreatment event 
once daily 
QT interval from an ECG corrected for heart rate via Bazett’s 
methodology 
QT interval from an ECG corrected for heart rate via Fredericia’s 
methodology 
serious adverse event 
statistical analysis plan 
standard deviation 
standard error 
system organ class 
schedule of events 
TEAE 
treatment-emergent adverse event 
ULN 
WHO 
upper limit of normal 
World Health Organization 
 
 
 


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1. Introduction 
  
Vonoprazan belongs to a new class of acid-inhibitory agents called “potassium-
competitive acid blockers”. Vonoprazan is being developed in adults for the treatment of 
heartburn in subjects with symptomatic non-erosive gastroesophageal reflux disease 
(sGERD), healing of all grades of erosive esophagitis (EE) and relief of heartburn, 
maintenance of healing of all grades of EE and relief of heartburn, and treatment of 
Helicobacter pylori infection. 
 
The purpose of this study is to determine a dose of vonoprazan in children aged ≥6 to <12 
years with symptomatic GERD that provides an exposure similar to the exposure in adults 
after administration of vonoprazan 10 mg or 20 mg once daily (QD). Like proton pump 
inhibitors (PPIs), vonoprazan is expected to provide benefit in pediatric patients with 
GERD. 
 
The pediatric doses for this study were selected to approximate equivalent adult exposures 
following administration of vonoprazan 10 or 20 mg QD. 
 
This document outlines the statistical methods to be implemented in the analysis of data 
collected within the scope of Phathom Pharmaceuticals, Inc., Protocol VPED-103 (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 Children Aged ≥6 to <12 Years Who h7ave 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 (30 August 2023) and the case report forms (CRFs) version 
1.0 (Date: 26 Sep 2023). 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 children ≥6 to 
<12 years of age who have symptomatic GERD. 
2.2. Safety Objective  
To evaluate the safety of vonoprazan (10 or 20 mg QD) in children ≥6 to <12 years of age 
who have symptomatic GERD. 
2.3. Exploratory Objective  
To evaluate symptom relief and pharmacodynamics of vonoprazan (10 or 20 mg QD) in 
children ≥6 to <12 years of age who have symptomatic GERD. 


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3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is a Phase 1, randomized, open-label, parallel-group, multiple-dose study in children 
aged ≥6 to <12 years who have 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. Approximately 18 subjects are expected to 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 for 14 days. 
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. 
 
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 
τ (AUCτ) 
 Apparent oral clearance (CL) 
 Apparent volume of distribution (Vc) 
3.2.2. Efficacy and Pharmacodynamic Assessments 
Efficacy and pharmacodynamic characteristics will be assessed by the following: 
 The severity of GERD symptoms at baseline and Days 7 and 14 as assessed 
by the investigator. 


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 Mean pH and percentage of time above pH 4, 5, and 6 at baseline (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 in pediatric subjects ≥6 to < 12 
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 
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 
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-zero counts. A row denoted “Missing” will be included in count tabulations where 
specified on the shells to account for missing values. The denominator for all percentages 
will be the number of subjects in that treatment group 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. 


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4.1. Sample Size 
Approximately 18 subjects are expected to be enrolled with 9 subjects in each dose group. 
Attempts will be made to enroll subjects across the ≥6 to < 12 years age range. 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 this population. 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. The 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, Day 1 is defined as the day of 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.  
4.4. Analysis Sets 
4.4.1. Screened Set  
The Screened Set will include all subjects whose legally authorized representative (LAR) 
signed the study informed consent form (ICF). 
4.4.2. Enrolled Set 
The Enrolled Set will include all subjects whose LAR signed the study ICF and have been 
randomized. 
4.4.3. Pharmacokinetic Set 
The Pharmacokinetic (PK) Set will include subjects who receive at least 1 dose of study 


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drug and have sufficient concentration data to support accurate estimation of at least 1 
pharmacokinetic parameter.  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 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 LAR signs the ICF 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 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.  
 


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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 and Pharmacokinetic Set. Baseline demographic data to be evaluated will 
include age, sex, race, ethnicity, fertility status, height (cm), weight (kg) and body mass 
index (BMI) (kg/m2) . Descriptive statistics will be presented for age, height, weight and 
body mass index. Sex, race, ethnicity, body mass index category, fertility status and 
Tanner staging 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 Set. 
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. 
7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
All medications will be coded according to the World Health Organization Drug 
Dictionary (WHODrug Global), Version March 2021 or later.  
A prior medication is defined as any medication that is taken prior to the first dose of study 
drug. A concomitant medication is defined as any medication taken on or after the first dose 
of study drug. 
The total number of both prior/concomitant medications and the number and percentages of 
subjects with at least one prior/concomitant medication will be summarized. The number 


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and percentages of all prior/concomitant medications will be summarized and listed by 
Anatomical Therapeutic Chemical (ATC) level 4 and preferred term. Algorithms for 
imputing partially missing start or end dates are included 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 
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.  
All summaries will be performed using the Safety Set. All prior and concomitant 
medications will be presented in a listing for subjects in the Safety Set . 
7.2. Study Drug 
The study drug details related to study drug administration and accountability 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 
minus the date and time of first dose + 1) as recorded on the End of Study page on the 
eCRF. If the last dose date and time on the End of Study page is missing, then the last dose 
date and time recorded on the Study Drug Administration page on the eCRF will be used. 
The number of days of missed doses will be summarized in the same table as well. 
Duration of exposure and number of days of missed doses 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 Set. A listing on Extent of Exposure will also be presented. 
7.3.2. Treatment Compliance 
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.  
 


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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. 
Blood samples will be collected at the following time points for PK assessment using a 
population PK approach:  
 
Day 7: Pre-dose (prior to morning administration of Vonoprazan) and at 0.5 to 1.5, 
and 2.5 to 3.5, hours after drug administration. 
Day 14: Pre-dose (prior to morning administration of Vonoprazan) and at 1 to 2 
and 3 to 4 hours after drug administration  
 
Individual plasma concentrations will be presented in data listings with their scheduled 
collection times. 
8.2. Exploratory analyses 
   
8.2.1. GERD Symptom Assessment 
The GERD Symptom Assessment-Investigator scale evaluates 4 symptoms of GERD: 
heartburn, vomiting, acid regurgitation, and trouble eating. The maximum severity of each 
GERD symptom occurring during the 7 days prior to the study visit, Day 7 and Day 14 
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, Day 7 and 
Day 14 as assessed by the investigator will be summarized overall and by treatment group. 
GERD Symptom Assessment and GERD diagnostic testing will be listed for the Safety 
Set. 
8.2.2. Pharmacodynamic Assessment 
Mean pH and 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 
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. 
 
The pharmacodynamic assessments will be analyzed for the Pharmacodynamic Set. 


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9. Safety Analysis 
Safety will be assessed based on AEs, vital sign measurements, electrocardiogram (ECG) 
results, and clinical laboratory evaluations (clinical chemistry, hematology, and urinalysis). 
All safety analyses will be conducted for the Safety Set.  
9.1. Adverse Events 
Adverse events will be coded using 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 pretreatment adverse event (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 TEAEs 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 Events of Special Interest  
 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 
SOC level. For table summaries if severity is missing then ‘severe’ is assumed. If 
relationship is missing, relationship to study drug is assumed to be ‘related’.  
 
The number and percentage of subjects with TEAEs will be summarized 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 


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The number and percentage of subjects with TEAEs related to study drug  will be 
summarized by treatment in the following ways: 
 by primary SOC, preferred term and maximum severity 
 
The number and percentage 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 
 
All adverse events will be included in a listing using the Safety Set. Pre-treatment AEs will 
be listed using the Screened Set. TEAEs and serious AEs will be listed using the Safety 
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 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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1: Adverse Events Special Interest – Search Criteria 
Adverse Event of Special Interest 
Search Criteria 
Clostroides difficile enteric infection 
Pseudomembranous colitis SMQ (Narrow) 
Bone Fracture 
Bone Fracture Custom Query (PTs defined below) 
Acetabulum fracture  
Fractured skull depressed  
Ankle fracture  
                  Lumbar vertebral fracture  
Atypical femur fracture  
Metaphyseal corner fracture  
Atypical fracture                    Multiple fractures  
Avulsion fracture                    Open fracture  
Bone fissure  
                  Osteoporotic fracture  
Bone fragmentation                 Patella fracture  
Chance fracture  
                  Pathological fracture  
Clavicle fracture  
                  Pelvic fracture  
Comminuted fracture  
Pubis fracture  
Complicated fracture  
Radius fracture  
Compression fracture  
Rib fracture 
Craniofacial fracture  
Sacroiliac fracture  
Epiphyseal fracture  
Scapula fracture  
Facial bones fracture  
Skull fracture  
Femoral neck fracture  
Skull fractured base  
Femur fracture  
                  Spinal compression fracture  
Fibula fracture  
                  Spinal fracture  
Foot fracture  
                  Spinal fusion fracture  
Forearm fracture                    Sternal fracture  
Fracture                                      Stress fracture  
Fracture blisters  
                  Subchondral insufficiency fracture  
Fracture displacement  
Thoracic vertebral fracture  
Fracture malunion                    Tibia fracture  
Fracture nonunion                    Torus fracture  
Fracture of clavicle         
Traumatic fracture  
    due to birth trauma 
Fractured coccyx                    Ulna fracture  
Fractured ischium                    Upper limb fracture  
Fractured sacrum                   Wrist fracture 
Greenstick fracture  
Hand fracture  
Hip fracture  
Humerus fracture  
Ilium fracture  
Impacted fracture  
Jaw fracture  
Limb fracture  
Lower limb fracture 
 
Severe cutaneous adverse reactions, 
including hypersensitivity 
Severe cutaneous adverse reactions SMQ (Narrow) 
Hepatotoxicity 
 
 Drug related hepatic disorders - comprehensive search (SMQ) (Narrow) 
 Cholestasis and jaundice of hepatic origin (SMQ) (Broad) 
 Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions 
SMQ (Broad) 
 Hepatitis, non-infectious (SMQ) (Broad) 
 Liver related investigations, signs and symptoms (SMQ) (Narrow) 
Acute interstitial 
nephritis/tubulointerstitial nephritis 
Tubulointerstitial nephritis (PT) 


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Hematologic abnormalities 
Haematopoietic cytopenias SMQ 
Haematopoietic cytopenias affecting more than one type of blood cell SMQ 
(Broad) 
Haematopoietic erythropenia SMQ (Broad) 
Haematopoietic leukopenia SMQ (Broad) 
Haematopoietic thrombocytopenia SMQ (Broad) 
 
In addition, 10 PTs not encompassed by these SMQs but associated with possible 
thrombocytopenia, leukopenia, cytopenia, and agranulocytosis will be included. 
 
Disseminated intravascular 
coagulation 
Neutropenic sepsis 
Henoch-Schonlein purpura 
Platelet function test abnormal 
Immune thrombocytopenic purpura 
Thrombocytopenic purpura 
Neutropenic colitis 
Thrombophlebitis septic 
Neutropenic infection 
Thrombotic thrombocytopenic purpura 
Hypersensitivity reactions (anaphylaxis) 
Hypersensitivity SMQ (narrow) 
MedDRA: Medical Dictionary for Regulatory Activities; PT: preferred term; SMQ: Standardized MedDRA Queries. 
 
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  


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 AST > 10xULN  
 AST > 3xULN and Total Bilirubin > 2xULN  
 
 Total Bilirubin > 2xULN  
 
 AST > 3xULN or ALT > 3xULN  
 
 AST > 5xULN or ALT > 5xULN  
 
 AST > 10xULN or ALT > 10xULN  
 
 (AST > 3xULN or ALT > 3xULN) and Total Bilirubin > 2xULN  
 
 AST > 3xULN and ALT > 3xULN  
 
 AST > 5xULN and ALT > 5xULN  
 AST > 10xULN and ALT > 10xULN  
 
 AST > 3xULN and ALT > 3xULN and Total Bilirubin > 2xULN  
 
 Alkaline phosphatase > 1.5xULN  
 ALT > 3xULN and Alkaline phosphatase > 1.5xULN  
 AST > 3xULN and Alkaline phosphatase > 1.5xULN  
 
 Alkaline phosphatase > 3xULN  
 ALT > 3xULN and Alkaline phosphatase > 3xULN  
 AST > 3xULN and Alkaline phosphatase > 3xULN  
 
 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) 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-


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missing baseline and post-baseline measurements. 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 <85 
o >130 
 Diastolic blood pressure (mmHg):  
o <55 
o >85 
 Heart rate (bpm): 
o <60 
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. Documentation of the 
completion of physical examinations will be presented in a listing. 
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 


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o QTc interval increases from baseline >60 msec 
o QTc interval > 450 msec with increase from baseline >30 msec 
 
Results for ECG parameters heart rate, R-R interval, P-R interval, QRS interval, QT 
interval, QTcB interval, QTcF interval and interpretation will be listed using the Safety 
Set. 
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. 
11. Changes in the Planned Analysis 
Not Applicable 
 


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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 
The following rules will be applied to impute the missing numerical fields. If the stop date 
is complete and the imputed start date is after the stop date, then the start date will be 
imputed using the stop date.  
Missing day and month 
 If the year of the incomplete start date is the same as the year of the date of the first 
dose of study drug, then the day and month of the date of the first dose of study 
drug will be assigned to the missing fields. 
 If the year of the incomplete start date is before the year of the date of the first dose 
of study drug, then 31 December will be assigned to the missing fields. 
 If the year of the incomplete start date is after the year of the date of the first dose 
of study drug, then 01 January will be assigned to the missing fields. 
 
Missing month only 
 The day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
 
Missing day only 
 If the month and year of the incomplete start date are the same as the month and 
year of the date of the first dose of study drug, then the day of the date of the first 
dose of study drug will be assigned to the missing day. 
 If either the year is before the year of the date of the first dose of study drug or if 
both years are the same but the month is before the month of the date of the first 
dose of study drug, then the last day of the month will be assigned to the missing 
day. 
 If either the year is after the year of the date of the first dose of study drug or if both 
years are the same but the month is after the month of the date of the first dose of 
study drug, then the first day of the month will be assigned to the missing day. 


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


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12.1.3. Rules for Prior Medication Start Date Imputation 
For prior medications, incomplete (i.e., partially missing) start dates will be imputed and 
will follow the same rules as in Section 12.1.1.  
12.1.4. Rules for AE Start Date Imputation 
For AEs, incomplete (i.e., partially missing) start dates will be imputed and will follow the 
same rules as in Section 12.1.1. Incomplete stop dates will not be imputed.  
 
 
 
 
 


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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 
Phone 
Call 
Day 6 
Day 7 
Day 8 a 
Phone 
Call 
Day 13 
ET 
Day 14 
Phone 
Call 
Day 28 
Unscheduled 
Visit b 
Visit Number: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
Informed consent c 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
Demographic and medical 
history 
X 
 
 
 
 
 
 
 
 
 
Physical examination d 
X 
 
 
 
X 
 
 
X 
 
X 
Vital signs e 
X 
 
X 
 
X 
 
 
X 
 
X 
Weight and height f 
X 
 
 
 
X 
 
 
X 
 
 
Prior/Concomitant medications 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
Concurrent medical conditions 
X 
 
 
 
 
 
 
 
 
 
Hepatitis B and C; HIV g 
X 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests h 
X 
 
 
 
X 
 
 
X 
 
X 
Pregnancy test i 
X 
 
X 
 
X 
 
 
X 
 
 
Guidance on avoidance of 
pregnancy i 
X 
 
X 
 
X 
 
 
X 
 
 
12-lead electrocardiogram j 
X 
 
 
 
 
 
 
X 
 
 
GERD Symptom Assessment-
Investigator 
X 
 
 
 
X 
 
 
X 
 
 
Randomization k 
 
 
X 
 
 
 
 
 
 
 
Dispense study drug l 
 
 
X 
 
X 
 
 
 
 
 
Study drug administration l  
 
 
X 
 
X 
 
 
X 
 
 
Gastric pH monitoring a 
 
X 
X 
 
X 
X 
 
 
 
 
PK blood sample collection 
 
 
 
 
 
X 
 
 
X 
 
 


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Day 7: pre-dose, 0.5 to 1.5 hour 
and 2.5 to 3.5 hours post dose. 
Day 14: pre-dose, 1 to 2 hours, 
and 3 to 4 hours post dose. m 
 
Drug return/accountability 
 
 
 
 
X 
 
 
X 
 
 
Telephone call to subject 
 
 
 
X 
 
 
X 
 
X 
 
AE/pretreatment event 
assessment n 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
 
 


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AE: adverse event; ET: early termination; FU: follow-up; GERD: gastroesophageal reflux disease; HIV: 
human immunodeficiency virus; PK: pharmacokinetic; PTE: pretreatment event 
a. 
For subjects participating in the pharmacodynamic substudy, Visit 2 (Day -1) and Visit 6 (Day 8) are 
only required for subjects undergoing gastric pH monitoring if clinically indicated at select sites. pH 
monitoring will be conducted on Day -1 for 24 hours and on Day 7 for 24 hours. pH probes would be placed on 
Days -1 and 7 and removed on Days 1 and 8. 
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, neurological systems and Tanner staging). 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. 
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.  
i. 
Only female subjects who have reached menarche, will require guidance on avoidance of pregnancy and urine or 
serum hCG; if urine hCG is positive, confirm with serum hCG.  
j. 
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 pediatric cardiologist will interpret the ECG for eligibility and any abnormality. A 
single repeat measurement is permitted at screening for eligibility determination after the read by a pediatric 
cardiologist. Assessments should include comments on whether the tracings are normal or abnormal (if abnormal, 
whether clinically significant or not clinically significant. An ECG will be collected at the final visit and interpreted 
by a pediatric cardiologist. 
k. 
Subject will be randomized to study treatment after all eligibility criteria have been met.  
l. 
Study drug will be dispensed and administered in the clinic on Days 1, 7, and 14. Study drug should be taken every 
day between 7 and 10 am preferably prior to eating any breakfast or food. Study drug for at home administration 
will be dispensed on Day 1 (to be taken on Days 2 to 6) and Day 7 (to be taken on Days 8 to 13). At home, 
parents/caregivers will administer study drug to subjects. Clinic staff will review instructions with parents/LARs for 
administering study drug at home and completing the Study Drug Reminder Card. Phone call reminders may be 
conducted as required. 
m. Blood samples for PK analysis of vonoprazan in plasma will be collected on Days 7 and 14. On Day 7 days, one 
pre-dose sample will be collected prior to the morning administration of vonoprazan along with two additional 
samples collected after drug administration: one between 0.5 to 1.5 hours post-dose and one between 2.5 to 3.5 
hours post-dose. On Day 14 days, one pre-dose sample will be collected prior to the morning administration of 
vonoprazan along with two additional samples collected after drug administration: one between 1 to 2 hours post-
dose and one 3 to 4 hours post-dose. The exact time of each pharmacokinetic sample should be recorded in the 
source and eCRF. If a subject terminates early, an attempt should be made to collect one blood sample if it can be 
collected within 24 hours following the last dose of study drug. The exact date and time of the early termination 
sample must be recorded.  
n. 
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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12.3. 
Appendix 3: GERD Symptom Assessment-Investigator 
 
The following 4 symptoms of GERD will be evaluated. 
 
Symptom  
Definition  
 
Heartburn 
Hurting or burning in the stomach, chest or throat  
Vomiting 
Something coming out of your mouth (throw-up) 
Acid regurgitation  
Food come up from your stomach to your mouth 
Trouble eating  
Ate less than usual, did not want to eat, did not want to eat certain 
foods because of hurting or burning 
 
The following 4 symptoms of GERD will be evaluated, as defined below when asked of 
parents of children 6 to 8 years of age if the child reported or they observed any of the 
following behaviors. 
 
Symptom  
Definition  
 
Heartburn 
Hurting or burning in the stomach, chest or throat such as holding 
his/her stomach/chest/throat, lying in curled up position, crying, 
acting fussy, or other behaviors 
Vomiting 
Something coming out of the mouth  
Acid regurgitation  
Partially digested food or stomach contents coming up in their 
mouth  
Trouble eating 
Refused to eat anything, ate less than usual, refused to eat certain 
foods because of hurting or burning or stomach contents coming 
up in their mouth 
 
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)