Clinical trial NCT05366738
Conditions: Healthy Volunteers
Keywords: Vonoprazan Gastroesophageal Reflux Erosive Esophagitis
Sponsor: Phathom Pharmaceuticals, Inc.
Start date: 2022-05-18; Completion date: 2022-07-26
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary objective of this study is to assess the bioavailability (BA) of a single oral dose of vonoprazan 20 mg sprinkle capsule, either sprinkled on pudding or on applesauce, relative to a vonoprazan 20 mg tablet in healthy participants.

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

Arms: arm 1: Participants assigned to Treatment Sequence 1 will receive vonoprazan 20 mg as a sprinkle capsule on 1 tablespoon of pudding on Day 1 of Treatment Period 1, vonoprazan 20 mg as a sprinkle capsule on 1 tablespoon of applesauce on Day 1 of Treatment Period 2, and vonoprazan 20 mg as a tablet on Day 1 of Treatment Period 3. arm 2: Participants assigned to Treatment Sequence 2 will receive vonoprazan 20 mg as a tablet on Day 1 of Treatment Period 1, vonoprazan 20 mg as a sprinkle capsule on 1 tablespoon of pudding on Day 1 of Treatment Period 2, and vonoprazan 20 mg as a sprinkle capsule on 1 tablespoon of applesauce on Day 1 of Treatment Period 3. arm 3: Participants assigned to Treatment Sequence 3 will receive vonoprazan 20 mg as a sprinkle capsule on 1 tablespoon of applesauce on Day 1 of Treatment Period 1, vonoprazan 20 mg as a tablet on Day 1 of Treatment Period 2, and vonoprazan 20 mg as a sprinkle capsule on 1 tablespoon of pudding on Day 1 of Treatment Period 3.
Interventions: intervention 1: Vonoprazan intervention 2: Vonoprazan
Intervention descriptions: intervention 1: Orally via tablet intervention 2: Orally via sprinkle pellets

Protocol documents:
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CLINICAL STUDY PROTOCOL 
IND 079212 
A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE-DOSE, 
CROSSOVER STUDY TO DETERMINE THE BIOAVAILABILITY OF 
VONOPRAZAN SPRINKLE CAPSULES ON PUDDING OR ON 
APPLESAUCE RELATIVE TO A VONOPRAZAN TABLET IN 
HEALTHY SUBJECTS 
VPED-101 
Sponsor: 
Phathom Pharmaceuticals, Inc. 
2150 E. Lake Cook Road 
Suite 800 
Buffalo Grove, IL 60089 USA 
Sponsor Contact: 
 
Vice President Clinical and Patient Safety 
Telephone: 
 
Medical Monitor: 
 Medical Monitor 
 
SAE Hotline (24 hour): 
 
SAE Fax: 
 
Version of Protocol: 
Amendment 1 (Version 2.0) 
Date of Protocol:  
25 April 2022 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Phathom Pharmaceuticals, Inc. 
The study will be conducted according to the International Council for Harmonisation 
Guideline E6(R2): Good Clinical Practice. 


Phathom Pharmaceuticals, Inc. 
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SIGNATURE PAGE  
 
PROTOCOL TITLE:  
A Phase 1, Open-Label, Randomized, Single-Dose, 
Crossover Study to Determine the Bioavailability of 
Vonoprazan Sprinkle Capsules on Pudding or on Applesauce 
Relative to a Vonoprazan Tablet in Healthy Subjects 
PROTOCOL NUMBER:  
VPED-101 
 
Vice President, Clinical and Patient Safety 
Phathom Pharmaceuticals, Inc. 
 
Chief Operating Officer 
Phathom Pharmaceuticals, Inc. 
  
Chief Medical Officer 
Phathom Pharmaceuticals, Inc. 
 
Vice President, Biostats & Programming 
Phathom Pharmaceuticals, Inc. 
 
Clinical Pharmacology Consultant 
Phathom Pharmaceuticals, Inc. 


Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VPED-101 
Clinical Study Protocol Amendment 1 
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
 
 
I agree to conduct the study as outlined in the protocol titled  A Phase 1, Open-Label, 
Randomized, Single-Dose, Crossover Study to Determine the Bioavailability of Vonoprazan 
Sprinkle Capsules on Pudding or on Applesauce Relative to a Vonoprazan Tablet in Healthy 
Subjects in accordance with the guidelines and all applicable government regulations 
including US Title 21 of the Code of Federal Regulations Part 54. I have read and understand 
all sections of the protocol. 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 


Phathom Pharmaceuticals, Inc. 
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Protocol No. VPED-101 
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TABLE OF CONTENTS  
TITLE PAGE  .......................................................................................................................... 1 
SIGNATURE PAGE  ............................................................................................................... 2 
INVESTIGATOR P ROTOCOL AGREEMENT PAGE
 ..................................................... 3 
TABLE OF CONTENTS  ........................................................................................................ 4 
1. 
INTRODUCTION  ............................................................................................... 7 
1.1 
BACKGROUND ................................................................................................7 
1.2 
RATIONALE FOR STUDY ..............................................................................9 
1.3 
RATIONALE FOR DOSE SELECTION...........................................................9 
2. 
STUDY OBJECTIVES  ...................................................................................... 10 
2.1 
PRIMARY OBJECTIVES ................................................................................10 
2.2 
SECONDARY OBJECTIVES .........................................................................10 
3. 
STUDY DESIGN  ................................................................................................ 10 
3.1 
SCHEDULE OF EVENTS ...............................................................................13 
4. 
STUDY POPULATION ..................................................................................... 16 
4.1 
INCLUSION CRITERIA .................................................................................16 
4.2 
EXCLUSION CRITERIA ................................................................................16 
4.3 
WITHDRAWAL CRITERIA ...........................................................................18 
4.4 
SUBJECT REPLACEMENT ...........................................................................18 
5. 
STUDY TREATMENTS  ................................................................................... 19 
5.1 
TREATMENTS ADMINISTERED .................................................................19 
5.2 
INVESTIGATIONAL PRODUCTS ................................................................19 
5.2.1 
Study Drug Preparation and Storage ............................................................19 
5.2.2 
Study Drug Accountability ...........................................................................20 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS .........20 
5.4 
BLINDING .......................................................................................................20 
6. 
STUDY PROCEDURES  ................................................................................... 20 
6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS ......................20 
6.1.1 
Pharmacokinetic Sample Collection .............................................................21 
6.1.2 
Pharmacokinetic Sample Analysis................................................................21 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS ..............................................21 
6.2.1 
Adverse Events .............................................................................................21 
6.2.2 
Clinical Laboratory Assessments .................................................................22 
6.3 
CYP GENOTYPING ........................................................................................23 
7. 
STATISTICAL ANALYSIS PLANS  ................................................................ 23 
7.1 
SAMPLE SIZE CALCULATIONS..................................................................23 
7.2 
ANALYSIS SETS ............................................................................................23 


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7.3 
STATISTICAL ANALYSES ............................................................................24 
7.3.1 
Pharmacokinetic Analyses ............................................................................24 
7.3.2 
Safety Analyses ............................................................................................25 
7.4 
HANDLING OF MISSING DATA ..................................................................25 
7.5 
INTERIM ANALYSES ....................................................................................26 
8. 
REFERENCE LIST ........................................................................................... 27 
9. 
APPENDICES  .................................................................................................... 29 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS ..................................................29 
9.2 
APPENDIX 2: STANDARD PROCEDURES .................................................31 
9.2.1 
Removal of Subjects From Therapy or Assessment .....................................31 
9.2.1.1 
General Criteria for Withdrawal .............................................................. 31 
9.2.1.2 
Handling of Withdrawals ......................................................................... 32 
9.2.2 
Prior and Concomitant Medications and Therapies .....................................32 
9.2.2.1 
Prior Medications ..................................................................................... 32 
9.2.2.2 
Concomitant Medications ........................................................................ 32 
9.2.3 
Treatment Compliance..................................................................................32 
9.3 
APPENDIX 3: ADVERSE EVENT DEFINITIONS AND REPORTING ......33 
9.3.1 
Adverse Event Definitions ...........................................................................33 
9.3.2 
Eliciting and Documenting Adverse Events .................................................35 
9.3.3 
Reporting Adverse Events ............................................................................36 
9.3.4 
Additional Points to Consider for Pre-Treatment Events and Adverse Events
 ......................................................................................................................37 
9.3.5 
Assessment of Severity .................................................................................40 
9.3.6 
Assessment of Causality ...............................................................................40 
9.3.6.1 
Relationship to Study Procedures ............................................................ 41 
9.3.6.2 
Start Date ................................................................................................. 41 
9.3.6.3 
Stop Date ................................................................................................. 41 
9.3.6.4 
Frequency ................................................................................................ 41 
9.3.6.5 
Action Concerning Study Drug ............................................................... 41 
9.3.6.6 
Outcome ................................................................................................... 42 
9.3.7 
Follow-Up of Adverse Events ......................................................................42 
9.3.8 
Pregnancy .....................................................................................................43 
9.3.9 
Safety Reporting to Investigators, Institutional Review Boards, Independent 
Ethics Committees, and Regulatory Authorities ..........................................43 
9.4 
APPENDIX 4: STUDY GOVERNANCE .......................................................44 
9.4.1 
Data Quality Assurance ................................................................................44 
9.4.2 
Investigator Obligations ...............................................................................44 
9.4.2.1 
Confidentiality ......................................................................................... 44 


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9.4.2.2 
Institutional Review ................................................................................. 45 
9.4.2.3 
Subject Consent ....................................................................................... 45 
9.4.2.4 
Study Reporting Requirements ................................................................ 45 
9.4.2.5 
Financial Disclosure and Obligations ...................................................... 46 
9.4.2.6 
Investigator Documentation ..................................................................... 46 
9.4.2.7 
Study Conduct ......................................................................................... 47 
9.4.2.8 
Case Report Forms and Source Documents ............................................ 47 
9.4.2.9 
Adherence to Protocol ............................................................................. 47 
9.4.2.10 
Reporting Adverse Events ....................................................................... 48 
9.4.2.11 
Investigators Final Report ...................................................................... 48 
9.4.2.12 
Records Retention .................................................................................... 48 
9.4.2.13 
Publications .............................................................................................. 48 
9.4.3 
Study Management .......................................................................................49 
9.4.3.1 
Monitoring ............................................................................................... 49 
9.4.3.2 
Management of Protocol Amendments and Deviations .......................... 49 
9.4.3.3 
Premature Termination or Suspension of the Study or Investigational Site
 ................................................................................................................. 50 
9.4.3.4 
Study Termination .................................................................................... 51 
9.4.3.5 
Final Report ............................................................................................. 51 
 


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1. 
INTRODUCTION  
Vonoprazan belongs to a novel class of acid suppressants known as potassium-competitive 
acid blockers (PCABs) that suppress gastric acid secretion by competitively inhibiting gastric 
hydrogen, potassium-adenosine triphosphatase (H+, K+-ATPase). Vonoprazan is formulated 
and administered orally as its fumarate salt, vonoprazan fumarate (MW 461.46). Following 
oral administration, the fumarate salt is rapidly converted to the free base form (MW 345.39), 
and vonoprazan fumarate is not detectable in human plasma. Vonoprazan fumarate is also 
referred to as TAK-438, and the free base form of vonoprazan is also referred to as 
TAK-438F. Vonoprazan was discovered and developed by Takeda Pharmaceutical Company, 
Japan and is being developed by Phathom Pharmaceuticals (Phathom) in the United States, 
Europe, and Canada 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, maintenance of healing of all grades of EE and relief of heartburn, 
and treatment of Helicobacter pylori infection. Vonoprazan has been studied in a number of 
other gastric acid-related diseases including healing of gastric ulcer/duodenal ulcer and for 
the prevention of recurrence of peptic ulcer during nonsteroidal anti-inflammatory drugs or 
aspirin administration. Vonoprazan is approved in Japan and other countries in Asia, Latin 
America, and Russia for a variety of these indications in adults. 
1.1 
BACKGROUND  
The gastric H+, K+-ATPase, also known as the proton pump, is responsible for acid secretion 
from parietal cells in the stomach. It is inactive in cytoplasmic vesicles but relocates from the 
cytosol to the secretory membrane of parietal cells when food is present in the stomach, 
thereby becoming active and pumping H+ ions out of cells and into the canaliculi in 
exchange for K+ ions. The gastric proton pump represents an attractive pharmacological 
target because 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: proton pump inhibitors (PPIs) and PCABs. As a 
PCAB, vonoprazan has a unique mechanism of action and pharmacokinetics (PK) relative to 
PPIs, as follows: 
x Acid activation and stability: Conventional PPIs are prodrugs that are activated by acid 
and covalently bind H+, K+-ATPase; however, activated PPIs are not stable under acidic 
conditions. In contrast, vonoprazan does not require acid activation, is stable under acidic 
conditions, and does not require enteric-coated formulations; thus, vonoprazan has a 
more durable effect than conventional PPIs. Furthermore, vonoprazan is rapidly 


Phathom Pharmaceuticals, Inc. 
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protonated in the parietal cell canaliculi, which concentrates the drug proximal to H+, 
K+-ATPase (Scarpignato and Hunt 2019). 
x Activity against active and inactive proton pumps: Vonoprazan inhibits acid secretion by 
competitively inhibiting the binding of potassium ions to H+, K+-ATPase. Vonoprazan 
selectively concentrates in parietal cells in both resting and stimulated states, binds to 
active pumps, and remains associated with active and inactive pumps. In contrast, PPIs 
covalently bind H+, K+-ATPase only when the pump is active, as an acidic environment 
is required for the activation and accumulation of PPIs in parietal cells (Scott et al 2015). 
x Vonoprazan maintains acid control over 24 hours with once daily dosing (Engevik et al 
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 and Kim 2013). 
x Extended half-life: The plasma half-life of vonoprazan is typically 7 to 8 hours after 
single and multiple once daily administration. This is significantly longer than the 
half-life of conventional PPIs (<2 hours) (Shin and Kim 2013). 
x Metabolism: Vonoprazan is predominantly metabolized by cytochrome P450 
(CYP)3A4/5, which lacks a high degree of genetic polymorphisms compared with 
CYP2C19, the primary enzyme responsible for the metabolism of PPIs (Shin and 
Kim 2013). Therefore, vonoprazan can be administered without regard to CYP2C19 
metabolizer status. 
These unique aspects of vonoprazans mechanism of action and PK relative to those of PPIs 
translate into a greater magnitude and duration of gastric acid suppression, which are 
reflected in the pharmacodynamic profile (Jenkins et al 2015; Sakurai et al 2015). 
Vonoprazan is absorbed rapidly following oral administration, with the median time of peak 
plasma concentrations (Tmax) typically occurring 1.5 to 2 hours after once daily dosing. 
Vonoprazan exhibits time-independent pharmacokinetics, and steady state concentrations are 
achieved by Day 3 to 4. There is little accumulation of vonoprazan in plasma after multiple 
once daily doses, with an accumulation ratio index based on an area under the plasma 
concentration versus time curve (AUC) of <1.2 for doses ranging from 10 to 40 mg. Overall, 
vonoprazan has been well tolerated in healthy subjects in Phase 1 studies, as well as in 


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subjects with gastric acid-related diseases who completed Phase 2 and 3 studies in the United 
States, Europe, Japan, and Asia (outside of Japan). 
Further information on the study drug can be found in the investigators brochure (IB) 
(Takeda Pharmaceutical 2022). 
1.2 
RATIONALE FOR STUDY  
Phathom is developing vonoprazan in pediatrics for the healing of all grades of EE and relief 
of heartburn, maintenance of healing of all grades of EE and relief of heartburn and treatment 
of heartburn associated with sGERD. 
The current adult formulation and size of vonoprazan tablets are appropriate for 
administration in pediatric subjects 12 years of age or older, who are capable of swallowing 
tablets. However, different strengths and formulations will need to be developed to support 
the pediatric clinical program for the pediatric age group <12 years of age and for pediatric 
patients incapable of swallowing tablets. Phathom is investigating a sprinkle capsule 
formulation for these pediatric patients. Therefore, this study will investigate the 
bioavailability (BA) of vonoprazan in healthy adult subjects when administered as 20 mg 
sprinkle capsules on pudding or on applesauce relative to 20 mg tablets, in accordance with 
the Food and Drug Administration (FDA) Guidance for industry: Bioavailability and 
Bioequivalence Studies Submitted in NDAs or INDs  General Considerations 
(DHHS 2014). The use of healthy adult subjects is appropriate for the BA study prior to 
initiation of studies in pediatric patients. 
Relative BA will be based on the maximum observed plasma concentration (Cmax), area 
under the plasma concentration versus time curve from time 0 to the last quantifiable 
concentration (AUC0-t), and area under the plasma concentration versus time curve from 
time 0 extrapolated to infinity (AUC0-inf) to determine the peak and total drug exposure. 
Analysis of plasma concentrations will characterize the single-dose PK of vonoprazan 20 mg 
sprinkle capsule (either sprinkled on pudding or on applesauce). 
1.3 
RATIONALE FOR DOSE SELECTION
 
A single 20 mg dose of vonoprazan, either as a sprinkle capsule or a tablet, was selected 
because this is the highest planned clinical dose strength. Oral dosing will be used for 
vonoprazan sprinkle capsules and tablets as this is the intended route of clinical 
administration for both formulations. Multiple oral doses of vonoprazan 20 mg tablets have 


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been shown to be safe and well tolerated in patients and a single dose of up to 120 mg in 
healthy adult subjects. 
2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE S 
x To assess the BA of a single oral dose of vonoprazan 20 mg sprinkle capsule, either 
sprinkled on pudding or on applesauce, relative to a vonoprazan 20 mg tablet in healthy 
subjects 
2.2 
SECONDARY OBJECTIVE S 
The secondary objectives of the study are as follows: 
x To assess the PK profile of a single oral dose of vonoprazan when administered to 
healthy subjects as 20 mg sprinkle capsule, either sprinkled on pudding or on applesauce, 
relative to a 20 mg tablet 
x To assess the safety and tolerability of a single oral dose of vonoprazan when 
administered to healthy subjects as 20 mg sprinkle capsule, either sprinkled on pudding 
or on applesauce, or as a 20 mg tablet 
3. 
STUDY DESIGN  
This is a Phase 1, single-dose, open-label, randomized, 3-period, 3-sequence crossover study 
designed to assess the BA of vonoprazan 20 mg sprinkle capsule, either sprinkled on pudding 
or on applesauce, relative to a vonoprazan 20 mg tablet under fasted conditions in healthy 
subjects. 
The study will consist of a screening period, a Check-in, 3 treatment periods, and a follow-up 
(telephone call). The treatment periods will include administration of single doses of 
vonoprazan 20 mg (tablet/sprinkle capsule) on Day 1 of each period. There will be a washout 
interval of a minimum of 7 days between study drug dosing in each period. 
Subjects who meet all the inclusion and none of the exclusion criteria will be randomly 
assigned to 1 of 3 treatment sequences in a 1:1:1 ratio. 
On the first day of each dosing period, subjects will receive 1 of the following study 
treatments according to the treatment sequence they are randomly assigned to: 


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x Treatment A: Vonoprazan 20 mg sprinkle capsule on 1 tablespoon of pudding 
administered orally under fasted conditions. 
x Treatment B: Vonoprazan 20 mg sprinkle capsule on 1 tablespoon of applesauce 
administered orally under fasted conditions. 
x Treatment C: Vonoprazan 20 mg tablet administered orally under fasted conditions. 
Table 3-1  
Study Treatment Sequence  
Sequence  
Period 1  
Period 2  
Period 3  
1 
A 
B 
C 
2 
C 
A 
B 
3 
B 
C 
A 
In each period, subjects will fast overnight (nothing to eat or drink except water) for at least 
10 hours before study drug administration. Subjects will remain fasted for 4 hours after 
dosing with study drug, excluding the pudding and applesauce used for dosing. Water (other 
than the water consumed with the administration of vonoprazan tablets or sprinkle capsule) is 
permitted as desired except for 1 hour before and 1 hour after administration of vonoprazan. 
For Treatment A, vonoprazan sprinkle capsule administration on pudding, the following 
should be done: 
x Open sprinkle capsule. 
x Sprinkle pellets on 1 tablespoon of pudding. 
x Administer pudding with pellets and have the subject swallow it immediately. 
x The subject should not chew the pellets. 
x Immediately follow with swish/swallow of 240 mL of room temperature water. 
For Treatment B, vonoprazan sprinkle capsule administration on applesauce, the following 
should be done: 
x Open the sprinkle capsule. 
x Sprinkle pellets on 1 tablespoon of applesauce. 
x Administer applesauce with pellets and have the subject swallow it immediately. 
x The subject should not chew the pellets. 
x Immediately follow with swish/swallow of 240 mL of room temperature water. 


Phathom Pharmaceuticals, Inc. 
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For Treatment C, vonoprazan tablet administration with water, the following should be done: 
x Administer the tablet whole with 240 mL of room temperature water and swallow 
immediately. 
x The subject should not chew the tablet. 
Pharmacokinetic samples will be collected through 48 hours following dosing, and safety 
endpoints will be evaluated throughout the study. 
Subjects will be confined to the clinical unit from Day 1 until discharge on Day 17. A 
follow-up telephone call will occur on Day 31 (–2 days). The duration of the study, 
excluding Screening will be approximately 33 days.


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3.1 
SCHEDULE OF EVENTS 
Phase Screening Check-in 
Treatment Periods 1 to 3(b) 
Follow-up 
(Phone 
Call)/EOS 
 
Day –28 to –2 
–1 
Day 1 
Day 2 
Day 3 
(ET) 
Day 31  
(±2) 
Procedure(a) 
Hours 
— 
— 
Predose 
0 0.25 0.5 1 1.5 2 
4 
6 
8 10 12 16 24 36 
48 
 
Admission to clinic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from clinic(c) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Telephone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology(d) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 screening 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH(e) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug/alcohol/cotinine screen(f) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight, and BMI(g) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical examination(h) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital sign measurements(i) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG(j) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical laboratory testing(k) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test(l) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Guidance on avoidance of pregnancy 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Randomization(m) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration(n) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sample collection(o) 
 
 
X 
 
X 
X 
X 
X 
X X X X X 
X 
X X 
X 
X 
 
CYP genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting period(p) 
 
X 
X 
X 
X 
X 
X 
X 
X X 
 
 
 
 
 
 
 
 
 
Non-fasting period(q) 
 
 
 
 
 
 
 
 
 
 
X X X 
X 
X X 
X 
X 
 
PTEs monitoring(r) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs(s) 
 
 
 
X 
Prior/concomitant medications 
X 


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Abbreviations: AE, adverse event; BMI, body mass index; COVID-19, coronavirus disease 2019; CYP, cytochrome P450; ECG, electrocardiogram; EOS, end of study; 
ET, end-of-treatment period phase; FSH, follicle stimulating hormone; ICF, informed consent form; PK, pharmacokinetic; PTE, pre-treatment event; QTcF, QT 
interval corrected for heart rate using Fridericias formula. 
Notes: 
(a) When procedures overlap or occur at the same time point, all blood draws should follow vital signs or ECGs, and PK sampling should be timed to occur 
last and as close to the scheduled time window as possible. 
(b) There will be a washout interval of a minimum of 7 days between study drug dosing in each period. 
(c) Discharge will occur following the last study assessment on Day 17 (ET, ie, Day 3 of Period 3). 
(d) Serology testing will include hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus types 1 and 2 antibodies. The 
testing will be conducted at Screening. 
(e) Females with at least 12 months of amenorrhea should have a serum FSH test performed at Screening, if required, to confirm postmenopausal status per 
Inclusion Criterion #4 (FSH level >40 IU/mL). 
(f) A urine drug/alcohol/cotinine screen will occur at Screening and Check-in. 
(g) Height and weight will be measured, and BMI (kg/m2) will be calculated at Screening only. Only weight will be measured at Check-in and ET. 
(h) A full physical examination will be performed at Screening (at minimum, assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, heart, 
cardiovascular, abdomen, lymph nodes, and musculoskeletal system/extremities). A brief physical examination will be performed at Check-in and ET (at 
minimum, assessment of skin, lungs, cardiovascular system, and abdomen [liver and spleen]). Interim physical examinations may be performed at the 
discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. 
(i) Vital signs will be measured at Screening and Check-in, within 15 minutes prior to vonoprazan dosing in each period, and at ET. Vital signs will be 
measured after the subject has been in the seated position for at least 5 minutes and will include systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature. 
(j) Single 12-lead ECG recordings will be made at Screening, Check-in, and ET after the subject has been in the supine position for at least 5 minutes. A 
single repeat measurement is permitted at Screening for eligibility determination. Measurements of the following intervals will be reported: RR interval, 
PR interval, QRS width, QT interval, and QTcF. Assessments should include comments on whether the tracings are normal or abnormal; rhythm; 
presence of arrhythmia or conduction defects; morphology; any evidence of myocardial infarction; or ST-segment, T-wave, and U-wave abnormalities. 
(k) Clinical laboratory testing will occur at Screening, Check-in, and ET. A complete list of assessments is provided in Section 6.2.2. Blood and urine 
samples will be collected and prepared per the clinics standard procedures; blood sample will be collected under fasted conditions. 
(l) All women will have a serum pregnancy test performed at Screening. At Check-in and ET, a urine pregnancy test will be performed, and if the test result 
is positive, a serum pregnancy test will be performed for confirmation. 
(m) Subjects will be randomized only on Day 1 of Period 1. 
(n) The time of vonoprazan dosing will be called 0 hour in each period and is denoted with gray shading. Vonoprazan sprinkle capsule sprinkled on 
1 tablespoon of pudding will be swallowed and will be followed with swish/swallow of 240 mL of room temperature water; vonoprazan sprinkled on 
1 tablespoon of applesauce will be swallowed and will be followed with swish/swallow of 240 mL of room temperature water. Vonoprazan tablet will be 
administered and swallowed whole with 240 mL of room temperature water. Subjects will maintain an upright (ie, seated or standing) position for at least 
4 hours after dosing. 
(o) Blood samples for PK analysis of vonoprazan in plasma will be collected within 15 minutes prior to vonoprazan dosing in each period and at 0.25, 0.5, 1, 
1.5, 2, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours following vonoprazan dosing in each period. The window for PK sample collection up to 4 hours following 
vonoprazan dosing will be –5 minutes; from 6 hours up to 12 hours post dose will be –10 minutes; and from 16 hours up to 48 hours will be –30 minutes. 


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(p) During fasting periods, subjects should have nothing to eat or drink except water for 10 hours prior to vonoprazan dosing until 4 hours after dosing. Water 
(other than the water consumed with the administration of vonoprazan tablet or sprinkle capsule) is permitted as desired except for 1 hour before and 
1 hour after administration of vonoprazan. 
(q) During non-fasting periods, subjects should receive standardized meals per the clinics standard procedures that will be scheduled at the same time in 
each period of the study. 
(r) Collection of PTEs will start after the subject has signed the ICF. 
(s) Adverse events will be assessed from the time of the first vonoprazan dosing until the follow-up telephone call or withdrawal from the study and should 
be followed until they are resolved, stable, or judged by the investigator to be not clinically significant.


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4. 
STUDY POPULATION  
Approximately 27 healthy male and female subjects will be enrolled at a single center in the 
United States to achieve at least 24 evaluable subjects. 
4.1 
INCLUSION CRITERIA  
Each subject must meet all of the following criteria to be enrolled in this study: 
1. The subject is male or female 18 to 55 years of age, inclusive, at Screening. 
2. The subject has a body mass index 18 to 32 kg/m2, inclusive, at Screening. 
3. The subject is considered by the investigator to be in good general health as determined 
by medical history, clinical laboratory test results, vital sign measurements, 12-lead 
electrocardiogram (ECG) results, and physical examination findings at Screening. 
4. Male and female subjects of reproductive potential must use an acceptable method of 
birth control (ie, diaphragm with spermicide, intrauterine device, condom with foam or 
vaginal spermicide, oral contraceptives, or abstinence) from the signing of informed 
consent until 4 weeks after the last dose of study drug or be surgically sterile (ie, 
vasectomy, hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or 
postmenopausal (defined as amenorrhea for 12 consecutive months and documented 
plasma follicle stimulating hormone [FSH] level >40 IU/mL during Screening). 
5. Female subjects must have a negative pregnancy test at Screening and upon Check-in. 
6. The subject agrees to comply with all protocol requirements. 
7. The subject is able to provide written informed consent. 
4.2 
EXCL USION CRITERIA  
Subjects meeting any of the following criteria will be excluded from the study: 
1. The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus 
antibody, or human immunodeficiency virus types 1 or 2 antibodies at Screening. 
2. The subject has a positive test result for the presence of severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) at Screening or Check-in. 


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3. The subject has a history of a clinically significant neurological, cardiovascular, 
pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other 
abnormality that may impact the ability of the subject to participate. 
4. The subject has current or recent (within 6 months) gastrointestinal conditions that would 
be expected to influence the absorption of drugs (eg, history of malabsorption, 
esophageal reflux, peptic ulcer disease, EE), frequent (more than once per week) 
occurrence of heartburn, or any surgical intervention. 
5. The subject has any other clinically significant findings on physical examination, clinical 
laboratory abnormalities, and/or ECG results that preclude his/her participation in the 
study, as deemed by the investigator. 
6. The subject has used any prescription (excluding hormonal birth control) and/or 
over-the-counter medications (including CYP3A4 inducers) except acetaminophen (up to 
2 g per day), including herbal or nutritional supplements, within 14 days before the first 
dose of study drug, and/or is expected to require any such medication during the course 
of the study until end of treatment period phase (ET) or end of study (EOS). 
7. The subject has consumed grapefruit and/or grapefruit juice, Seville orange or Seville 
orange-containing products (eg, marmalade), or other food products that may be 
CYP3A4 inhibitors (eg, vegetables from the mustard green family [kale, broccoli, 
watercress, collard greens, kohlrabi, Brussels sprouts, mustard] and charbroiled meats) 
within 7 days (or 5 half-lives) before the first dose of study drug and/or is expected to be 
unable to abstain through the study. 
8. The subject has consumed caffeine- or xanthine-containing products within 48 hours (or 
5 half-lives) before the first dose of study drug and/or is unable to abstain through the 
study. 
9. The subject is a smoker and/or has used nicotine or nicotine-containing products (eg, 
snuff, nicotine patch, nicotine chewing gum, mock cigarettes, or inhalers) within 
6 months before the first dose of study drug. 
10. The subject has a history of alcohol abuse and/or drug addiction within the last year or 
excessive alcohol consumption (regular alcohol intake >21 units per week for male 
subjects and >14 units of alcohol per week for female subjects; 1 unit is equal to 
approximately ‰ pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure 
[25 mL] of spirits) or use of alcohol 48 hours before the first dose of study drug. 


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11. The subject has a positive test result for drugs of abuse, alcohol, or cotinine (indicating 
active current smoking) at Screening or Check-in. 
12. The subject is involved in strenuous activity or contact sports within 24 hours before the 
first dose of study drug and during the study. 
13. The subject has donated blood or blood products >450 mL within 30 days before the first 
dose of study drug. 
14. The subject has a history of relevant drug and/or food allergies (ie, allergy to vonoprazan 
or excipients or any significant food allergy that could preclude a standard diet in the 
clinical unit). 
15. The subject has received a study drug in another investigational study within 30 days of 
dosing. 
16. Female subjects who are pregnant or lactating; intend to become pregnant before, during, 
or within 4 weeks after participating in this study; or intend to donate ova during this time 
period. 
17. The subject is not suitable for entry into the study in the opinion of the investigator. 
4.3 
WITHDRAWAL CRITERIA  
General criteria for subject withdrawal and the handling of withdrawals can be found in 
Appendix 2. 
4.4 
SUBJECT REPLACEMENT  
Subjects may be rescreened at the discretion of the investigator and the sponsor, after 
consultation with the medical monitor. 
At the discretion of the investigator, and after consultation with the medical monitor, any 
subject who withdraws before completing the study may be replaced to retain the target of 
24 evaluable subjects (8 in each treatment sequence). Any replacement subject will be 
assigned to receive the same treatment as the subject he or she is replacing. 


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5. 
STUDY TREATMENTS  
5.1 
TREATMENTS ADMINISTERED  
All subjects will receive the study treatments as described in Section 3 and according to the 
schedule of events (SOE; Section 3.1). Additional instructions for dosing, fasting periods, 
and non-fasting periods can be found in the SOE. 
5.2 
INVESTIGATIONAL PRODUCT S 
The study drugs that will be used are as follows: 
Product  
Supplied Formulation  
Vonoprazan 
20 mg tablet (reference) 
 
20 mg sprinkle capsule (test) 
 
Vonoprazan tablets contain 20 mg vonoprazan free base (MW 345.39) and the following 
inactive excipients: D-Mannitol, microcrystalline cellulose, hydroxypropyl cellulose, fumaric 
acid, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene glycol 8000, 
titanium dioxide, red ferric oxide, and printing ink gray F1. 
Vonoprazan sprinkle capsules contain 20 mg vonoprazan free base (MW 345.39) and the 
following inactive excipients: microcrystalline cellulose pellets, hypromellose, AquaPolishﬁ, 
amino methacrylate copolymer (Eudragitﬁ), sodium lauryl sulfate, stearic acid, talc, and 
colloidal silicon dioxide in a gelatin capsule. 
Further information on the study drug can be found in the IB (Takeda Pharmaceutical 2022). 
5.2.1 
Study Drug Preparation  and Storage  
Phathom will provide the investigator and clinical unit with adequate quantities of 
vonoprazan 20 mg tablets and 20 mg sprinkle capsules (pellets) for the conduct of the study 
plus required retention samples (DHHS 2020).  The study drugs will be provided in 21-count 
high-density polyethylene bottles. The clinical unit pharmacy will prepare the study 
treatments for each subject according to the SOE (Section 3.1). 
All study drugs must be stored according to the labeled instructions in a secure cabinet or 
room with access restricted to necessary clinic personnel. The site will be required to keep a 
temperature log to establish a record of compliance with storage conditions. 


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5.2.2 
Study Drug Accountability  
The investigator will maintain accurate records of receipt of all study drugs, including dates 
of receipt. Accurate records will be kept regarding when and how much study drug is 
dispensed and used by each subject in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, and to satisfy 
regulatory requirements regarding drug accountability, all study drugs will be reconciled and 
retained (DHHS 2020) or destroyed according to applicable regulations. 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT 
GROUPS  
 will generate the randomization schedule. Subjects who meet all the inclusion and none 
of the exclusion criteria will be randomly assigned to a treatment sequence in a 1:1:1 ratio 
(Section 3). Randomization numbers (in sequential order) will be assigned before the first 
dose of study drug is administered on Day 1 of Period 1 (Section 3). There will be no 
stratification. 
5.4 
BLINDING  
This is an open-label study. 
6. 
STUDY PROCEDURES  
Before performing any study procedures, all potential subjects will sign an informed consent 
form (ICF) as outlined in Section 9.4.2.3. 
x Details of additional standard study procedures can be found in Appendix 2. 
x The total amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed 500 mL. 
6.1 
PHARMACOKINETIC ASSESSMENTS
 AND ENDPOINTS  
The following PK parameters for vonoprazan will be calculated as endpoints using standard 
noncompartmental methods: AUC0-t, AUC0-inf, Cmax, Tmax, terminal elimination rate constant 
(z), terminal phase half-life (t1/2), apparent total body clearance (CL/F), and apparent volume 
of distribution (Vz/F). Additional PK parameters may be calculated as appropriate.  
The primary endpoints will be AUC0-t, AUC0-inf, and Cmax of vonoprazan.  


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x The timing and frequency of PK sample collection is listed in the SOE (Section 3.1). 
x Definitions of the PK parameters can be found in the list of abbreviations, Appendix 1. 
6.1.1 
Pharmacokinetic Sample  Collection  
Details for the collection, processing, storage, and shipping of PK samples will be provided 
to the clinical unit separately. 
6.1.2 
Pharmacokinetic Sample  Analysis 
Pharmacokinetic samples will be analyzed using a validated liquid chromatography coupled 
with tandem mass spectrometry assay for vonoprazan in human plasma. Assay results and 
validation details will be provided in a separate bioanalytical report. Plasma remaining after 
the assays are completed may be stored and used for further exploratory investigation of 
vonoprazan metabolites. 
6.2 
SAFETY ASSESSMENTS  AND ENDPOINTS  
The timing and frequency of all safety assessments is listed in the SOE (Section 3.1). 
Safety and tolerability endpoints will include monitoring and recording of adverse events 
(AEs), clinical laboratory test results (hematology, serum chemistry, and urinalysis), vital 
sign measurements, 12-lead ECG results, and physical examination findings (Section 3.1). 
For all safety assessments, the investigator will determine whether results are clinically 
significant, which is defined as any variation in a result that has medical relevance and may 
result in an alteration in medical care (eg, active observation, diagnostic measures, or 
therapeutic measures). If clinical significance is noted, the result and reason for significance 
will be documented and an AE reported on the AE page of the subjects electronic case report 
form (eCRF). The investigator will monitor the subject until the result has reached the 
reference range or the result at Screening, or until the investigator determines that follow-up 
is no longer medically necessary. 
6.2.1 
Adverse Events  
Definitions and procedures for reporting of AEs can be found in Appendix 3. For this study, 
the following contact information is to be used for serious adverse event (SAE) reporting: 


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Safety Reporting: 
 
 
SAE Hotline (24 hour): 
 
SAE Fax: 
 
6.2.2 
Clinical Laboratory Assessments
 
The following clinical laboratory assessments will be performed: 
Hematology 
Hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, absolute and differential 
leukocyte count (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), mean corpuscular volume, platelet count, red blood 
cell count, and red blood cell distribution width 
Serum Chemistry 
Alanine aminotransferase (ALT), albumin, alkaline phosphatase, 
aspartate aminotransferase (AST), bilirubin (total), blood urea 
nitrogen, calcium, carbon dioxide, chloride, cholesterol (total, 
high-density lipoprotein, and calculated low-density lipoprotein), 
creatinine, gamma-glutamyl transferase, globulin, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total protein, 
triglycerides, and uric acid 
Urinalysis 
Appearance, bilirubin, color, glucose, ketones, leukocyte esterase, 
reflex microscopy (performed if dipstick is positive for protein or 
the blood value is 1+ or greater; and includes bacteria, casts, 
crystals, epithelial cells, red blood cells, and white blood cells), 
nitrites, occult blood, pH, protein, specific gravity, turbidity, and 
urobilinogen 
Serology 
Hepatitis B surface antigen, hepatitis C virus antibody, and human 
immunodeficiency virus antibody types 1 and 2 (Screening only) 
Other analyses 
All subjects: Urine drug screen (alcohol, amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine metabolites, 
cotinine, methamphetamines, methylenedioxymethamphetamine, 
and opiates [including heroin, codeine, and oxycodone]); 
international normalized ratio (INR) (to be done when follow-up 
laboratory tests are required for elevated ALT or AST levels per 
Section 9.3.1) 
All subjects: coronavirus disease 2019 (COVID-19) screening 
Female subjects: FSH, serum and urine pregnancy test (human 
chorionic gonadotropin) 
 
 
x The clinical laboratory that performs the tests will provide the reference ranges for all 
clinical laboratory parameters. 


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x Clinical laboratory tests may be repeated at the discretion of the investigator, if 
necessary, for assessment of inclusion and exclusion criteria or evaluation of clinical 
laboratory abnormalities. 
6.3 
CYP GENOTYPING  
Cytochrome P450 enzymes are involved in the metabolism of vonoprazan. A blood sample 
will be collected on Day -1 as delineated in the SOE (Section 3.1) to determine metabolizer 
status (i.e., poor, normal, intermediate, or ultra-rapid metabolizer) for certain CYP enzymes. 
Instructions for blood sampling, collection, processing, and sample shipment will be 
provided separately. 
These blood samples may be stored and used for future exploratory investigation of CYP 
enzymes involved in the metabolism of vonoprazan. 
7. 
STATISTICAL ANALYSIS  PLANS 
7.1 
SAMPLE SI ZE CALCULATIONS  
The sample size for this study is based on a statistical power calculation.  
This crossover study will enroll 27 subjects to ensure 24 subjects complete the study, 
assuming an approximate dropout rate of 15%. With 24 completed subjects, the study will 
provide at least 97% power to conclude bioequivalence between the test treatments and the 
reference treatment, assuming that the vonoprazan PK parameters Cmax, AUC0-t, and AUC0-inf 
are log-normally distributed, the true GMR is 1, and the intrasubject coefficient of variation 
is no greater than 20%. Subjects will be randomly assigned to 1 of 3 treatment sequences in a 
1:1:1 ratio. 
7.2 
ANALYSIS SETS  
The analysis populations are as follows: 
x The PK population will include subjects who receive at least 1 dose of vonoprazan and 
have sufficient concentration data to support accurate estimation of at least 1 PK 
parameter. Subjects who experience vomiting within 2 times the median Tmax after study 
drug dosing will be excluded from the PK analysis. 
x The safety population will include all subjects who receive at least 1 dose of study drug. 


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7.3 
STATISTICAL ANALYS ES 
Details of all statistical analyses will be described in a separate statistical analysis plan. All 
data collected will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings but not included in the calculation of 
summary statistics. 
For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of subjects, mean, median, 
standard deviation [SD], minimum, and maximum). 
Baseline demographic and background variables will be summarized overall for all subjects. 
The number of subjects who enroll in the study and the number and percentage of subjects 
who complete the study will be presented. Frequency and percentage of subjects who 
withdraw or discontinue from the study, and the reason for withdrawal or discontinuation, 
will also be summarized. 
7.3.1 
Pharmacokinetic Analyses  
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be summarized by time point for each treatment using the 
following descriptive statistics: number of subjects, arithmetic mean, SD, coefficient of 
variation (CV), median, minimum, and maximum. Individual and mean plasma concentration 
versus scheduled time profiles will be presented in figures on both linear and 
semilogarithmic scales. 
Vonoprazan PK parameters will be calculated using actual sampling times. All parameters 
will be calculated using the latest version of Phoenixﬁ WinNonlinﬁ (Certara USA Inc., 
Princeton, New Jersey) or SASﬁ (SAS Institute Inc., Cary, North Carolina). The individual 
PK parameters will be presented in data listings and summarized by treatment using the 
following descriptive statistics: number of subjects, mean, SD, CV, median, minimum, and 
maximum. Geometric means and geometric CV will be included for AUC0-t, AUC0-inf, and 
Cmax. 
A linear mixed model with fixed effects for treatment, sequence, and period and subject 
within sequence as a random effect will be performed on the natural log-transformed values 
of AUC0-t, AUC0-inf, and Cmax to assess the relative BA of the test dose form (vonoprazan 
sprinkle capsule [either sprinkled on pudding, Treatment A, or on applesauce, Treatment B]) 
to the reference dose form (vonoprazan tablet, Treatment C). The geometric least square 


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means and corresponding 90% confidence intervals (CIs) will be computed for AUC0-t, 
AUC0-inf, and Cmax by taking the antilog of the least square means from the linear 
mixed-effect model on the natural logarithms of the corresponding PK parameters. No 
adjustment will be made for multiplicity. 
Relative BA will be reported as the test to reference ratios (A/C or B/C) of the geometric 
means and its corresponding CIs for AUC0-t, AUC0-inf, and Cmax PK parameters. 
Bioequivalence will be concluded if the 90% CI for the geometric mean ratio (GMR) 
between the test treatments (20 mg sprinkle capsule, either sprinkled on pudding or on 
applesauce) and the reference treatment (20 mg tablet) are wholly contained within 0.80 and 
1.25 for the vonoprazan PK parameters Cmax, AUC0-t, and AUC0-inf. 
Nonparametric methods will be used to examine median differences in Tmax for vonoprazan. 
7.3.2 
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). All AE data will be 
presented in a data listing. 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, vital sign 
measurements, and 12-lead ECG results 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. Physical examination 
findings will be presented in a data listing. 
7.4 
HANDLING OF MISSING DATA  
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero 
for descriptive statistics. Mean BLQ concentrations will be presented, and the SD and CV 
will be reported as not applicable. Missing concentrations will be excluded from the 
calculations. 
For the PK analysis, BLQ values will be treated as zero with the exception that a BLQ value 
between 2 quantifiable concentrations will be set as missing. Missing concentrations will be 
treated as missing from the PK parameter calculations. If consecutive BLQ concentrations 


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are followed by quantifiable concentrations in the terminal phase, those concentrations after 
BLQ concentrations will be treated as missing. 
7.5 
INTERIM ANALYSES  
No formal interim analyses will be performed in this study. 


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8. 
REFERENCE LIST  
Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), 
Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER). Guidance for industry. Bioavailability and Bioequivalence Studies 
Submitted in NDAs or INDs  General Considerations. March 2014 [cited 26 July 2021]. 
Available from: https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm389370.pdf. 
Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), 
Health and Human Services (HHS), Compliance Policy for the Quantity of Bioavailability 
and Bioequivalence Samples Retained Under 21 CFR 320.38(c); Guidance for Industry; 
Availability. August 2020 [Docket No. FDA2020D0276]. Available from: 
https://www.govinfo.gov/content/pkg/FR-2020-08-19/pdf/2020-17798.pdf. 
Engevik AC, Kaji I, Goldenring JR. The Physiology of the Gastric Parietal Cell. Physiol Rev. 
2020;100(2):573-602. doi: 10.1152/physrev.00016.2019. Epub 2019 Oct 31. 
Jenkins H, Sakurai Y, Nishimura A, et al. Randomised clinical trial: safety, tolerability, 
pharmacokinetics and pharmacodynamics of repeated doses of TAK-438 (vonoprazan), a 
novel potassium-competitive acid blocker, in healthy male subjects. Aliment Pharmacol Ther 
2015;41(7):636-48. 
Sakurai Y, Mori Y, Okamoto H, et al. Acid-inhibitory effects of vonoprazan 20 mg compared 
with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects--a randomised 
open-label cross-over study. Aliment Pharmacol Ther. 2015;42(6):719-30. doi: 
10.1111/apt.13325. Epub 2015 Jul 21. 
Scarpignato C, Hunt RH. The potential role of potassium-competitive acid blockers in the 
treatment of gastroesophageal reflux disease. Curr Opin Gastroenterol. 2019;35(4):344-55. 
doi: 10.1097/MOG.0000000000000543. 
Scott DR, Munson KB, Marcus EA, et al. The binding selectivity of vonoprazan (TAK-438) 
to the gastric H+, K+ -ATPase. Aliment Pharmacol Ther. 2015;42(11-12):1315-26. 
doi:10.1111/apt.13414. 
Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. 
J Neurogastroenterol Motil. 2013;19(1):25-35. doi: 10.5056/jnm.2013.19.1.25. Epub 2013 
Jan 8. 


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Takeda Pharmaceutical Company, Ltd. Vonoprazan fumarate (TAK-438). Global 
Investigators Brochure, 12th ed. 2022. 241 p. 


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9. 
APPENDICES  
9.1 
APPENDIX  1: LIST OF ABBREVIATIONS  
Abbreviation  
Term  
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC0-inf 
area under the plasma concentration versus time curve from time 0 
extrapolated to infinity 
AUC0-t 
area under the plasma concentration versus time curve from time 0 
to the last quantifiable concentration 
BA 
bioavailability 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
apparent total body clearance 
Cmax 
maximum observed plasma concentration 
COVID-19 
coronavirus disease 2019 
CV 
coefficient of variation 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EE 
erosive esophagitis 
EOS 
end of study 
ET 
end-of-treatment period phase 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GMR 
geometric mean ratio 
IB 
investigators brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
H+, K+-ATPase 
hydrogen, potassium-adenosine triphosphatase 
z 
terminal elimination rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCAB 
potassium-competitive acid blocker 
PK 
pharmacokinetic(s) 
PPI 
proton pump inhibitor 


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Abbreviation  
Term  
PTE 
pre-treatment event 
QTcF 
QT interval corrected for heart rate using Fridericias formula 
SAE 
serious adverse event 
SD 
standard deviation 
sGERD 
symptomatic non erosive gastroesophageal reflux disease 
SOE 
schedule of events 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal phase half-life 
Tmax 
time to maximum observed plasma concentration 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution 


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9.2 
APPENDIX 2: STANDARD PROCEDURES  
9.2.1 
Removal of Subjects From Therapy or Assessment
 
9.2.1.1 
General Criteria  for Withdrawal  
Subjects can withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment. 
The investigator may withdraw a subject from the study if the subject meets any of the 
following criteria: 
1. Is noncompliant with the protocol 
2. Experiences an SAE or intolerable AE(s) that, in the investigators opinion, requires 
withdrawal from the study 
3. Has laboratory safety assessments that reveal clinically significant hematological or 
biochemical changes from baseline values (if a subjects ALT or AST or total bilirubin is 
>3 × ULN at any time during study medication treatment, the study medication should be 
discontinued immediately with appropriate clinical follow-up, including repeat laboratory 
tests, until the subjects laboratory profile has returned to normal/baseline status) 
4. Develops symptoms or conditions that are listed in the exclusion criteria during the 
course of the study 
5. Requires a medication prohibited by the protocol 
6. Requests early discontinuation for any reason 
7. Becomes pregnant 
The investigator can also withdraw a subject upon the request of the sponsor or if the sponsor 
terminates the study. If withdrawal is considered because of an SAE or intolerable 
pre-treatment event (PTE)/AE, the investigator will confer with the sponsor. If a subject is 
discontinued because of a PTE/AE, the event will be followed until it is resolved, stable, or 
judged by the investigator to be not clinically significant. 


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9.2.1.2 
Handling of Withdrawals  
When a subject withdraws from the study, the reason(s) for withdrawal shall be recorded by 
the investigator on the relevant page of the eCRF. Whenever possible, any subject who 
prematurely withdraws from the study will undergo all ET assessments. Any subject who 
fails to return for final assessments will be contacted by the site in a reasonable attempt to 
have them comply with the protocol. The status of subjects who fail to complete final 
assessments will be documented in the eCRF. 
9.2.2 
Prior and Concomitant Medications and Therapies
 
Restrictions for prior and concomitant medications and therapies are provided in Section 4.2. 
Prior and concomitant medications and therapies will be coded using the latest version of the 
World Health Organization Drug Dictionary. 
9.2.2.1 
Prior Medications  
Information regarding prior medications taken by the subject within the 30 days before 
signing the ICF will be recorded in the subjects eCRF. 
9.2.2.2 
Concomitant Medications  
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. If a concomitant medication is taken, 
except for those specified in the protocol, a joint decision will be made by the investigator 
and the sponsor to continue or discontinue the subject based on the time the medication was 
administered, its pharmacology and PK, and whether the use of the medication will 
compromise the safety of the subject or the interpretation of the data. The investigator is 
responsible for ensuring that details regarding the medication are adequately recorded in the 
eCRF. 
9.2.3 
Treatment Compliance  
All doses of study drug will be administered in the clinical unit under direct observation of 
clinic personnel and will be recorded in the eCRF. Clinic personnel will confirm that the 
subject has received the entire dose of study drug. 
The date and time of study drug dosing will be recorded on the appropriate page of the eCRF. 
If a subject is not administered study drug, the reason for the missed dose will be recorded. 


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9.3 
APPENDIX 3: ADVERSE  EVENT  DEFINITIONS AND 
REPORTING  
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF 
and reported to the sponsor, regardless of their relationship to study drug or clinical 
significance. If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported. 
9.3.1 
Adverse Event Definitions  
A PTE is defined as any untoward medical occurrence that has occurred prior to 
administration of any study drug in a clinical investigation subject who has signed informed 
consent to participate in a study; it does not necessarily have to have a causal relationship 
with study participation. 
An AE is defined as any untoward medical occurrence in a subject enrolled in this study 
regardless of its causal relationship to study drug. An AE can therefore be an unfavorable 
sign or symptom, or a disease temporally associated with the use of study drug. 
A treatment-emergent AE 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. 
An SAE is defined as any untoward medical occurrence at any dose that meets one of the 
following criteria: 
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: 
x May require intervention to prevent items 1 through 5 above 


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x May include any event or symptoms described in the medically significant AE list 
(Table 9-1) 
x Exposes the subject to danger, even though the event is not immediately 
life-threatening or fatal or does not result in hospitalization 
Table 9-1 
Medically Significant Adverse Event List
 
Term  
Acute respiratory failure/acute respiratory distress syndrome 
Torsade de pointes/ventricular fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizures 
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 
COVID-19 pneumonia 
COVID-19 related disease 
Abbreviation: COVID-19, coronavirus disease 2019. 
The PTEs that fulfill one or more of the serious criteria above are also considered SAEs and 
should be reported and followed up in the same manner. 
A special interest AE (serious or nonserious) is one of scientific and medical concern specific 
to the study drug or program for which ongoing monitoring and rapid communication by the 


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investigator to Phathom may be appropriate. Such events may require further investigation in 
order to characterize and understand them and would be described in protocols and 
instructions provided for investigators as to how and when they should be reported to 
Phathom. There are no special interest AEs for this study. 
Reporting of Abnormal Liver Function Tests: 
If a subject is noted to have an ALT or AST value >3 × ULN and a total bilirubin value 
>2 × ULN during the treatment or follow-up period for which an alternative etiology has not 
been identified, the event should be reported as an SAE. 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, other acute liver disease, medical history, or 
concurrent medical conditions. Study drug should be discontinued immediately as per 
Section 9.2.1.1. Laboratory tests should be followed-up as described in Section 6.2.2. In 
addition, a Liver Function Test Increase eCRF must be completed and transmitted with the 
SAE form. 
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, and INR) should be 
repeated within a maximum of 7 days and preferably within 48 to 72 hours after the 
abnormality is found. 
If subjects with elevated baseline ALT or AST levels experience ALT or AST >5 × ULN, 
follow-up laboratory tests (at a minimum, serum alkaline phosphatase, ALT, AST, total 
bilirubin, gamma-glutamyl transferase, and INR) should be repeated within a maximum of 
7 days and preferably within 48 to 72 hours after the abnormality is found. 
If subjects with either normal or elevated baseline ALT or AST levels experience ALT or AST 
>8 × ULN, follow-up laboratory tests (at a minimum, serum alkaline phosphatase, ALT, AST, 
total bilirubin, -glutamyl transferase, and INR) should be repeated within a maximum of 
48 hours after the abnormality is found. 
9.3.2 
Eliciting and Documenting Adverse Events
 
Collection of PTEs will commence at the time the subject signs the informed consent to 
participate in the study and will continue until the subject is first administered study drug or 
until screen failure. For subjects who discontinue prior to study drug administration, PTEs 
will be collected until the subject discontinues study participation. Collection of AEs will 


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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. 
On each study day, 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, do not need to 
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. 
In addition to subject observations, AEs will be documented from any data collected on the 
AE page of the eCRF (eg, laboratory values, physical examination findings, and ECG 
changes) or other documents that are relevant to subject safety. 
9.3.3 
Reporting Adverse Events  
All PTEs and AEs will be documented on the PTE/AE page of the eCRF, regardless of 
whether the investigator concludes that the event is related to drug treatment. Information to 
be collected includes event term, start and stop date, seriousness, severity, investigators 
opinion of the causal relationship between the event and administration of study drug(s) 
(related or not related; not applicable for PTEs), action concerning study drug (not applicable 
for PTEs), any required treatment or evaluations, and the outcome of the event. 
Any AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported. All AEs will 
be followed until they are resolved, stable, or judged by the investigator to be not clinically 
significant. Any medical condition that is present at the time that the subject is screened but 
does not deteriorate should not be reported as an AE. However, if the medical condition 
deteriorates at any time during the study, it should be recorded as an AE. Section 9.3.4 
provides additional details. The MedDRA will be used to code all AEs. 
Any AE that is considered serious by the investigator or that meets SAE criteria 
(Section 9.3.1) must be reported to the sponsor within 24 hours (after the investigator has 
confirmed the occurrence of the SAE). The investigator will assess whether there is a 
reasonable possibility that the study drug(s) caused the SAE. The sponsor will be responsible 


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for notifying the relevant regulatory authorities of any SAE as outlined in US Title 21 Code 
of Federal Regulations (CFR) Parts 312 and 320. The investigator is responsible for notifying 
the institutional review board (IRB) directly. Contact information to be used for SAE 
reporting can be found in Section 6.2.1. 
Any SAE spontaneously reported to the investigator following the AE collection period 
should be reported to the sponsor if it is considered related to study participation. 
Investigators are not obligated to actively seek information regarding new AEs or SAEs after 
the conclusion of 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 or 
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 
same procedure as SAE reporting. 
9.3.4 
Additional Points to Consider for Pre
-Treatment  Events and 
Adverse Events  
An untoward finding generally may involve the following: 
x Indicates a new diagnosis or unexpected worsening of a pre-existing condition 
(pre-existing conditions or underlying disease should not be considered PTEs or AEs) 
x Necessitates therapeutic intervention 
x Requires an invasive diagnostic procedure 
x Requires discontinuation or a change in dose of study drug or a concomitant medication 
x Is considered unfavorable by the investigator for any reason 
Pre-treatment events/AEs caused by a study procedure (eg, a bruise after blood draw) should 
be recorded as a PTE/AE. 
Diagnoses versus signs and symptoms: 
x Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, signs or symptoms should be 
recorded appropriately as PTEs or as AEs. 


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Laboratory values and ECG findings: 
x Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if 
they are judged to be clinically significant (ie, if some action or intervention is required 
or if the investigator judges the change to be beyond the range of normal physiologic 
fluctuation). A laboratory or ECG retest or continued monitoring of an abnormal value or 
finding is not considered an intervention. In addition, repeated or additional noninvasive 
testing for verification, evaluation, or monitoring of an abnormality is not considered an 
intervention. 
x If abnormal laboratory values or ECG findings are the result of pathology for which there 
is an overall diagnosis (eg, increased creatinine in renal failure), only the diagnosis 
should be reported as a PTE or an AE. 
Pre-existing conditions: 
x Pre-existing conditions (present at the time of signing of informed consent) are 
considered concurrent medical conditions and should NOT be recorded as PTEs or AEs. 
Baseline evaluations (eg, laboratory tests, ECGs, etc) should NOT be recorded as PTEs 
unless related to study procedures. However, if the subject experiences a worsening or 
complication of such a concurrent medical condition, the worsening or complication 
should be recorded appropriately as a PTE (if the worsening or complication occurs 
before administration of study drug) or an AE (if the worsening or complication occurs 
after administration of study drug). Investigators should ensure that the recorded event 
term captures the change in the condition (eg, worsening of). 
x If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, 
epilepsy), any occurrence of an episode should be captured as a PTE/AE only if the 
condition becomes more frequent, serious, or severe in nature. Investigators should 
ensure that the recorded AE term captures the change in the condition from baseline (eg, 
worsening of). 
x If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE/AE if it occurs to 
a greater extent than would be expected. Investigators should ensure that the recorded AE 
term captures the change in the condition (eg, worsening of). 


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Worsening of PTEs or AEs: 
x If the subject experiences a worsening or complication of a PTE after the start of study 
drug, the worsening or complication should be recorded as an AE. Investigators should 
ensure that the recorded AE term captures the change in the PTE (eg, worsening of). 
x 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 recorded AE term captures the change in the condition 
(eg, worsening of). 
Changes in intensity of AEs/serious PTEs: 
x If the subject experiences changes in the intensity of an AE/serious PTE, the event should 
be captured once with the maximum intensity recorded. 
Preplanned procedures (surgeries or interventions): 
x Preplanned procedures (surgeries or therapies) 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 recorded as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
x Elective procedures performed when 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): 
x 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: 
Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs but instead will be documented on the overdose page of the eCRF. Any 


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manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the eCRF. 
9.3.5 
Assessment of Severity  
The severity (or intensity) of an AE refers to the extent to which it affects the subjects daily 
activities and will be classified as mild, moderate, or severe using the following criteria: 
x Mild: The event is transient and easily tolerated by the subject. 
x Moderate: The event causes the subject discomfort and interrupts the subjects usual 
activities. 
x Severe: The event causes considerable interference with the subjects usual activities. 
Changes in the severity of an AE should be documented to allow the duration of the event at 
each level of intensity to be assessed. An AE characterized as intermittent does not require 
documentation of the onset and duration of each episode. 
9.3.6 
Assessment of Causality  
The investigators assessment of an AEs relationship to study drug is part of the 
documentation process but 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 investigator will assess causality (ie, whether there is a reasonable possibility that the 
study drug caused the event) for all AEs and SAEs. The relationship will be classified as 
follows: 
x Not related: An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant drugs, and concurrent treatments. 
x 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. 


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9.3.6.1 
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. 
9.3.6.2 
Start Date  
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the 
subject or investigator. 
9.3.6.3 
Stop Date  
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved 
with sequelae, or the subject died. 
9.3.6.4 
Frequency  
Episodic AEs/PTEs (eg, vomiting) or those that occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous. 
9.3.6.5 
Action Concerning Study Drug  
x Drug withdrawn: The study drug is stopped due to the particular AE. 
x Dose not changed: The particular AE does not require stopping study drug. 
x Unknown: Only to be used if it cannot be determined what action was taken. 
x Not applicable: Study drug is stopped for a reason other than the particular AE; eg, the 
study was terminated, the subject died, or dosing with study drug was already stopped 
before the onset of the AE. 
x Dose reduced: The dose is reduced due to the particular AE. 
x Dose increased: The dose is increased due to the particular AE. 
x Drug interrupted: The dose is interrupted due to the particular AE. 


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9.3.6.6 
Outcome 
x Recovered/resolved: The subject returns to first assessment status with respect to the 
AE/PTE. 
x Recovering/resolving: The intensity is decreased by 1 or more stages, the diagnosis or 
signs/symptoms have almost disappeared, the abnormal laboratory value has improved 
but has not returned to the normal range or to baseline, or the subject dies from a cause 
other than the particular AE/PTE with the condition remaining recovering/resolving. 
x 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 is worse than when it started; the condition is an irreversible 
congenital anomaly; or the subject died from another cause while the particular AE/PTE 
state was not recovered/not resolved.  
x Resolved with sequelae: The subject recovers from an acute AE/PTE but is left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis). 
x Fatal: AEs/PTEs that are considered the cause of death. 
x Unknown: The course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subjects participation in the study. 
9.3.7 
Follow-Up of Adverse Events  
All AEs must be reported in detail on the appropriate page of the eCRF and followed until 
they are resolved, stable, or judged by the investigator to be not clinically significant. 
For SAEs, if information not available at the time of the first report becomes available at a 
later date, the investigator should update the SAE eCRF form and transmit it immediately 
within 24 hours of receipt. Copies of any relevant data from the hospital notes (eg, ECG 
results, laboratory test results, discharge summary, postmortem results) should be provided, if 
requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 


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9.3.8 
Pregnancy  
During the course of the study, human chorionic gonadotropin pregnancy tests will be 
performed for women, and subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures (Section 3.1). 
If any subject is found to be pregnant during the study, she should be withdrawn and any 
study drug should be immediately discontinued. If the pregnancy occurs during 
administration of active study drug or within 4 weeks of the last dose of active study drug, 
the pregnancy should be reported immediately, using a pregnancy notification form, to the 
contact listed in Section 6.2.1. If the female subject agrees that the primary care physician 
can be 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 in subjects receiving study drug will be 
followed up to final outcome using the pregnancy form. The outcome, including any 
premature termination, must be reported to the sponsor. An evaluation after the birth of the 
child will also be conducted. 
9.3.9 
Safety Reporting to Investigators, Institutional Review 
Boards, Independent Ethics Committees, and Regulatory 
Authorities  
The sponsor is responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
independent ethics committees (IECs), as applicable, in accordance with national regulations 
in the countries where the study is conducted. The SUSARs will be submitted to the 
regulatory authorities as an expedited report within 7 days for fatal and life-threatening 
events and 15 days for other serious events relative to the first awareness of the event by/or 
further provision to the sponsor or sponsors designee, unless otherwise required by national 
regulations. The sponsor also will prepare an expedited report for other safety issues that 
might materially alter the current benefit-risk assessment of a study drug/sponsor-supplied 
drug or that would be sufficient to consider changes in the study drug/sponsor-supplied drug 
administration or in the overall conduct of the trial. The study site also will forward a copy of 
all expedited reports to their IRB or IEC in accordance with local regulations. 


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9.4 
APPENDIX 4: STUDY GOVERNANCE  
9.4.1 
Data Quality Assurance  
This study will be conducted using the quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and 
will comply with current International Council for Harmonisation (ICH) guidance on quality 
and risk management. All aspects of the study will be monitored for compliance with 
applicable government regulatory requirements, current Good Clinical Practice (GCP), the 
protocol, and standard operating procedures. 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 staff. 
Electronic case report forms and electronic data capture will be utilized. The electronic data 
capture system is validated and compliant with US Title 21 CFR Part 11. Each person 
involved with the study will have an individual identification code and password that allows 
for record traceability. 
Important protocol deviations, should they occur during the study, will be presented in 
Section 10.2 of the clinical study report. 
9.4.2 
Investigator Obligations  
The following administrative items are meant to guide the investigator in the conduct of the 
study and may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB 
but will not result in protocol amendments. 
9.4.2.1 
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 FDA, or the IRB. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 


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study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
9.4.2.2 
Institutional Review  
Federal regulations and ICH guidelines require that approval be obtained from an IRB before 
participation of human subjects in research studies. Before study onset, the protocol, ICF, 
advertisements to be used for the recruitment of study subjects, and any other written 
information regarding this study that is to be provided to the subject must be approved by the 
IRB. Documentation of all IRB approvals and of the IRB compliance with the ICH 
harmonised tripartite guideline E6(R2): GCP will be maintained by the site and will be 
available for review by the sponsor or its designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favorable opinion was granted. 
9.4.2.3 
Subject Consent  
Written informed consent in compliance with US Title 21 CFR Part 50 shall be obtained from 
each subject before he or she enters the study or before performing any unusual or nonroutine 
procedure that involves risk to the subject. If any institution-specific modifications to 
study-related procedures are proposed or made by the site, the consent should be reviewed by 
the sponsor or its designee or both before IRB submission. Once reviewed, the investigator 
will submit the ICF to the IRB for review and approval before the start of the study. If the 
ICF is revised during the course of the study, all active participating subjects must sign the 
revised form. 
Before recruitment and enrollment, each prospective subject will be given a full explanation 
of the study and will be allowed to read the approved ICF. Once the investigator is assured 
that the subject understands the implications of participating in the study, the subject will be 
asked to give his or her consent to participate in the study by signing the ICF. A copy of the 
ICF will be provided to the subject. 
9.4.2.4 
Study Reporting Requirements
 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB as appropriate. 


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9.4.2.5 
Financial Disclosure and Obligations
 
The investigator is required to provide financial disclosure information to allow the sponsor 
to submit the complete and accurate certification or disclosure statements required under US 
Title 21 CFR Part 54. In addition, the investigator must provide to the sponsor a commitment 
to promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor 
 is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor 
 is financially responsible for 
further treatment of the disease under study. 
9.4.2.6 
Investigator Documentation  
Prior to beginning the study, the investigator will be asked to comply with ICH 
E6(R2) Section 8.2 and US Title 21 of the CFR by providing essential documents, including 
but not limited to, the following: 
x IRB approval. 
x An original investigator-signed investigator agreement page of the protocol. 
x Form FDA 1572, fully executed, and all updates on a new fully executed 
Form FDA 1572. 
x Curriculum vitae for the principal investigator and each subinvestigator listed on Form 
FDA 1572. Current licensure must be noted on the curriculum vitae. Curriculum vitae 
will be signed and dated by the principal investigators and subinvestigators at study 
start-up, indicating that they are accurate and current. 
x Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under US Title 21 CFR Part 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. 
x An IRB-approved ICF, samples of site advertisements for recruitment for this study, and 
any other written information about this study that is to be provided to the subject. 


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x Laboratory certifications and reference ranges for any local laboratories used by the site, 
in accordance with US Title 42 CFR Part 493. 
9.4.2.7 
Study Conduct  
The investigator agrees to perform all aspects of this study in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, ICH E6(R2): GCP; the 
protocol; and all national, state, and local laws or regulations. 
9.4.2.8 
Case Report Forms and Source Documents
 
Site personnel will maintain source documentation, enter subject data into the eCRF as 
accurately as possible, and will rapidly respond to any reported discrepancies. 
Electronic CRFs and electronic data capture will be utilized. The electronic data capture 
system is validated and compliant with US Title 21 CFR Part 11. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and any subsequent investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records, as well as 
the time and date of any modifications. There may be an internal quality review audit of the 
data and additional reviews by the clinical monitor. 
Each eCRF is presented as an electronic copy, allowing data entry by site personnel, who can 
add and edit data, add new subjects, identify and resolve discrepancies, and view records. 
This system provides immediate direct data transfer to the database, as well as immediate 
detection of discrepancies, enabling site coordinators to resolve and manage discrepancies in 
a timely manner. 
Paper copies of the eCRFs and other database reports may be printed and signed by the 
investigator. This system provides site personnel, monitors, and reviewers with access to 
hardcopy audits, discrepancy reviews, and investigator comment information. 
9.4.2.9 
Adherence to Protocol  
The investigator agrees to conduct the study as outlined in this protocol, in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 


Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VPED-101 
Clinical Study Protocol Amendment 1 
 
Page 48 
9.4.2.10 
Reporting Adverse Events  
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB as appropriate. The investigator also agrees to 
provide the sponsor with an adequate report, if applicable, shortly after completion of the 
investigators participation in the study. 
9.4.2.11 
Investigators Final Report
 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the studys 
outcome and the sponsor and regulatory authorities with any reports required. 
9.4.2.12 
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 until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study drug. These documents should be 
retained for a longer period, however, if required by applicable regulatory requirements or by 
an agreement with the sponsor. The sponsor is responsible for informing the 
investigator/institution when these documents no longer need to be retained. 
9.4.2.13 
Publications  
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and any 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 their prior 
authorization, but data and any publication thereof will not be unduly withheld. 


Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VPED-101 
Clinical Study Protocol Amendment 1 
 
Page 49 
9.4.3 
Study Management  
9.4.3.1 
Monitoring  
9.4.3.1.1 
Monitoring of the Study  
The clinical monitor, as a representative of the sponsor, is obligated 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 email 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 
staff. 
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 ICH E6(R2) 
guidelines and standard operating procedures. 
9.4.3.1.2 
Inspection of Records  
The investigator and institution involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the investigator agrees to allow the sponsor, their representatives, the 
FDA, or other regulatory agencies access to all study records. 
The investigator should promptly notify the sponsor and study site(s) of any audits scheduled 
by any regulatory authorities and promptly forward copies of any audit reports received to 
the sponsor. 
9.4.3.2 
Management of Protocol Amendments and Deviations
 
9.4.3.2.1 
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 designee. 
Amendments to the protocol must be submitted in writing to the investigators IRB for 
approval before subjects are enrolled into an amended protocol. 


Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VPED-101 
Clinical Study Protocol Amendment 1 
 
Page 50 
9.4.3.2.2 
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 to, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB for review and approval, to the sponsor for agreement, and to 
the regulatory authorities, if required. 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important deviation (sometimes referred to as a major 
or significant deviation) is a subset of protocol deviations that leads to a subject being 
discontinued from the study, or significantly affects the subjects rights, safety, or well-being 
and/or the completeness, accuracy, and reliability of the study data. An important deviation 
can include nonadherence to inclusion or exclusion criteria or nonadherence to FDA 
regulations or ICH E6(R2) guidelines. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The investigator will be notified in writing by the monitor of deviations. 
The IRB should be notified of all protocol deviations, if appropriate, in a timely manner. 
9.4.3.3 
Premature Termination
 or Suspension of the Study or 
Investigational Site  
9.4.3.3.1 
Criteria for Premature Termination or Suspension of the 
Study  
The study will be completed as planned unless one or more of the following criteria that 
require temporary suspension or premature termination of the study are met: 
x New information or other evaluation regarding the safety or efficacy of the study 
medication that indicates a change in the known risk/benefit profile for the compound 
such that the risk/benefit is no longer acceptable for subjects participating in the study. 
x Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety. 


Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VPED-101 
Clinical Study Protocol Amendment 1 
 
Page 51 
9.4.3.3.2 
Criteria for Premature Termination or Suspension of 
Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the 
investigator) is found in significant violation of GCP, the protocol, or contractual agreement 
or is unable to ensure adequate performance of the study or as otherwise permitted by the 
contractual agreement. 
9.4.3.3.3 
Procedures for Premature Termination or Suspension of 
the Study or the Participation of Investigational Sites 
In the event that the sponsor, an IRB, or regulatory authority elects to terminate or suspend 
the study or the participation of an investigational site, a study-specific procedure for 
premature termination or suspension will be provided by the sponsor; the procedure will be 
followed by applicable investigational sites during the course of termination or study 
suspension. 
9.4.3.4 
Study Termination 
Although the sponsor has every intention of completing the study, they reserve the right to 
discontinue it at any time for clinical or administrative reasons. 
The EOS is defined as the date on which the last subject completes the last visit (including 
the EOS visit and any additional long-term follow-up). Any additional long-term follow-up 
that is required for monitoring of the resolution of an AE or finding may be appended to the 
clinical study report. 
9.4.3.5 
Final Report 
Regardless of whether the study is completed or prematurely terminated, the sponsor will 
ensure that clinical study reports are prepared and provided to regulatory agency(ies) as 
required by the applicable regulatory requirement(s). The sponsor will also ensure that 
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 complete study results. 


Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VPED-101 
Clinical Study Protocol Amendment 1 
 
Page 52 
Upon completion of the clinical study report, the investigator(s) will be provided with the 
final approved clinical study report, as appropriate. 

SAP_001.pdf: 
Protocol Number: VPED-101
Official Title: A Phase 1, Open-Label, Randomized, Single-Dose, Crossover Study to Determine the 
Bioavailability of Vonoprazan Sprinkle Capsules on Pudding or on Applesauce Relative to A 
Vonoprazan Tablet in Healthy Subjects
NCT Number: NCT05366738
Document Date: 14 June 2022


Phathom Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0
VPED-101
Date Issued: 14/06/2022
Client:
Phathom Pharmaceuticals, Inc.
Protocol Number:
VPED-101
Document Description:
Final Statistical Analysis Plan
SAP Title:
A Phase 1, Open-Label, Randomized, Single-Dose, 
Crossover Study to Determine the Bioavailability of
Vonoprazan Sprinkle Capsules on Pudding or on
Applesauce Relative to A Vonoprazan Tablet in Healthy
Subjects
SAP Version Number:
Final Version 1.0
Effective Date:
14 June 2022
Author(s):
For 
: 
, Associate Biostatistician
Approved by:
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Phathom Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0 
VPED-101 
Date Issued: 14/06/2022 
Page 1 of 23 
Phathom Pharmaceuticals, Inc. 
VPED-101
A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE-DOSE, 
CROSSOVER STUDY TO DETERMINE THE BIOAVAILABILITY OF 
VONOPRAZAN SPRINKLE CAPSULES ON PUDDING OR ON 
APPLESAUCE RELATIVE TO A VONOPRAZAN TABLET IN HEALTHY 
SUBJECTS 
14/06/2022 
Final Statistical Analysis Plan 
Version 1.0 
Prepared by: 
 
Page 3


Phathom Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0 
Protocol: VPED-101 
Date Issued: 14/06/2022 
Page 2 of 23 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 4 
1.
INTRODUCTION ............................................................................................................ 6 
2.
OBJECTIVES AND ENDPOINTS ................................................................................. 6 
2.1 OBJECTIVES ......................................................................................................................... 6 
2.1.1 
Primary Objective ....................................................................................................... 6 
2.1.2 
Secondary Objectives .................................................................................................. 7 
2.2 ENDPOINTS .......................................................................................................................... 7 
2.2.1 
Pharmacokinetic Endpoints ........................................................................................ 7 
2.2.2 
Safety Endpoints.......................................................................................................... 7 
3.
STUDY DESIGN ............................................................................................................... 7 
4.
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 8 
4.1. 
SAMPLE SIZE ...................................................................................................................... 9 
4.2. 
RANDOMIZATION AND BLINDING ....................................................................................... 9 
4.3. 
ANALYSIS POPULATION ..................................................................................................... 9 
5.
SUBJECT DISPOSITION ............................................................................................. 10 
5.1 DISPOSITION ...................................................................................................................... 10 
5.2 PROTOCOL DEVIATIONS ..................................................................................................... 10 
5.3 INCLUSION AND EXCLUSION CRITERIA .............................................................................. 10 
6.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 10 
6.1 DEMOGRAPHICS ................................................................................................................. 10 
6.2 MEDICAL HISTORY ............................................................................................................ 11 
7.
TREATMENTS AND MEDICATIONS ....................................................................... 11 
7.1 PRIOR AND CONCOMITANT MEDICATIONS ......................................................................... 11 
7.2 MEDICAL OR SURGICAL TREATMENT PROCEDURES ........................................................... 11 
7.3 STUDY TREATMENT ........................................................................................................... 11 
7.4 MEAL STATUS .................................................................................................................... 11 
8.
PHARMACOKINETICS ............................................................................................... 12 
8.1 DATA HANDLING ............................................................................................................... 12 
8.2 PLASMA CONCENTRATIONS ............................................................................................... 12 
8.3 PLASMA PHARMACOKINETIC PARAMETERS ....................................................................... 13 
8.4 PHARMACOKINETIC STATISTICAL ANALYSES .................................................................... 14 
8.4.1 
Bioequivalence Assessment ....................................................................................... 14 
9.
SAFETY ANALYSIS ..................................................................................................... 15 
9.1 ADVERSE EVENTS .............................................................................................................. 15 
9.2 CLINICAL LABORATORY EVALUATIONS ............................................................................. 16 
9.3 VITAL SIGN MEASUREMENTS ............................................................................................ 16 
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Phathom Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0 
VPED-101 
Date Issued: 14/06/2022 
Pa-ge 3 of 23 
9.4 PHYSICAL EXAMINATION ................................................................................................... 17 
9.5 ELECTROCARDIOGRAMS .................................................................................................... 17 
9.6 OTHER TESTS ..................................................................................................................... 17 
9.7 COVID-19 VACCINE, INFECTION HISTORY AND IMPACT .................................................. 17 
10.
INTERIM ANALYSIS. .................................................................................................. 18 
11.
CHANGES IN THE PLANNED ANALYSIS .............................................................. 18 
12.
REFERENCES ................................................................................................................ 19 
13.
SCHEDULE OF ASSESSMENTS ................................................................................ 20 
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Phathom Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0 
VPED-101 
Date Issued: 14/06/2022 
Page 4 of 23 
List of Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
%AUCext 
percentage extrapolation of area between AUC0-t to AUC0-inf 
AUC0-inf 
area under the plasma concentration versus time curve from time 0 extrapolated 
to infinity 
AUC0-t 
area under the plasma concentration versus time curve from time 0 to the last 
quantifiable concentration 
BA 
bioavailability 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
CL/F 
apparent total body clearance 
Cmax 
maximum observed plasma concentration 
COVID-19 
coronavirus disease 2019 
CSR 
clinical study report 
CV 
coefficient of variation 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EE 
erosive esophagitis 
EOS 
end of study 
ET 
end-of-treatment period phase 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GMR 
geometric mean ratio 
IB 
investigator’s brochure 
ICF 
informed consent form 
INR 
international normalized ratio 
H+, K+-
ATPase 
hydrogen, potassium-adenosine triphosphatase 
λz 
terminal elimination rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCABs 
potassium-competitive acid blockers 
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Phathom Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0 
VPED-101 
Date Issued: 14/06/2022 
Page 5 of 23 
PK 
pharmacokinetic(s) 
PPIs 
proton pump inhibitors 
PT 
preferred term 
PTE 
pre-treatment event 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SD 
standard deviation 
sGERD 
symptomatic non-erosive gastroesophageal reflux disease 
SOC 
system organ class 
t1/2 
terminal elimination phase half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum observed plasma concentration 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution 
WHODrug 
World Health Organization Drug Dictionary 
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Phathom Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0 
VPED-101 
Date Issued: 14/06/2022 
Page 6 of 23 
1. Introduction
Vonoprazan belongs to a novel class of acid suppressants known as potassium-competitive 
acid blockers (PCABs) that suppress gastric acid secretion by competitively inhibiting 
gastric hydrogen, potassium-adenosine triphosphatase (H+, K+-ATPase). Vonoprazan was 
discovered and developed by Takeda Pharmaceutical Company, Japan and is being 
developed by Phathom Pharmaceuticals (Phathom) 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, maintenance of healing of 
all grades of EE and relief of heartburn, and treatment of Helicobacter pylori infection. 
The current adult formulation and size of vonoprazan tablets are appropriate for 
administration in pediatric subjects 12 years of age and older, and who are capable of 
swallowing tablets. However, different strengths and formulations will need to be 
developed to support the pediatric clinical program for the pediatric age group less than 12 
years of age and for pediatric patients incapable of swallowing tablets. Phathom is 
investigating a sprinkle capsule formulation for these pediatric patients. Therefore, this 
study will investigate the bioavailability (BA) of vonoprazan in healthy adult subjects 
when administered as 20 mg sprinkle capsules on pudding or on applesauce relative to 20 
mg tablets, in accordance with the Food and Drug Administration (FDA) Guidance for 
industry: Bioavailability Studies Submitted in NDAs or INDs – General Considerations 
(DHHS 2022). The use of healthy adult subjects is appropriate for the BA study prior to 
initiation of studies in pediatric patients. 
Relative BA will be based on the maximum observed plasma concentration (Cmax), area 
under the plasma concentration versus time curve from time 0 to the last quantifiable 
concentration (AUC0-t), and area under the plasma concentration versus time curve from 
time 0 extrapolated to infinity (AUC0-inf) to determine the peak and total drug exposure. 
Analysis of plasma concentrations will characterize the single-dose PK of vonoprazan 20 
mg sprinkle capsule (either sprinkled on pudding or on applesauce). 
The purpose of this statistical analysis plan (SAP) is to define the planned statistical 
analysis of the study data consistent with the study objectives. This SAP is written based 
on protocol VPED-101 amendment 1, version 2.0, dated 25 April 2022. 
2. Objectives and Endpoints
2.1 
Objectives
2.1.1 Primary Objective 
To assess the BA of a single oral dose of vonoprazan 20 mg sprinkle capsule, either 
sprinkled on pudding or on applesauce, relative to a vonoprazan 20 mg tablet in healthy 
subjects 
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Phathom Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0 
VPED-101 
Date Issued: 14/06/2022 
Page 7 of 23 
2.1.2 Secondary Objectives 
•
To assess the PK profile of a single oral dose of vonoprazan when administered to
healthy subjects as 20 mg sprinkle capsule, either sprinkled on pudding or on
applesauce, relative to a 20 mg tablet
•
To assess the safety and tolerability of a single oral dose of vonoprazan when
administered to healthy subjects as 20 mg sprinkle capsule, either sprinkled on
pudding or on applesauce, or as a 20 mg tablet
2.2 
Endpoints 
2.2.1 Pharmacokinetic Endpoints 
The primary endpoints will be AUC0-t, AUC0-inf, and Cmax of vonoprazan. 
The secondary endpoints will be Tmax, terminal elimination rate constant (λz), terminal 
phase half-life (t1/2), apparent total body clearance (CL/F), and apparent volume of 
distribution (Vz/F). Additional PK parameters may be calculated as appropriate. 
2.2.2 Safety Endpoints 
Safety and tolerability endpoints will include monitoring and recording of adverse events 
(AEs), clinical laboratory test results (hematology, serum chemistry, and urinalysis), vital 
sign measurements, 12-lead electrocardiogram (ECG) results, and physical examination 
findings. 
3. Study Design
This is a Phase 1, single-dose, open-label, randomized, 3-period, 3-sequence crossover 
study designed to assess the BA of vonoprazan 20 mg sprinkle capsule, either sprinkled on 
pudding or on applesauce, relative to a vonoprazan 20 mg tablet under fasted conditions in 
healthy subjects. 
The study will consist of a screening period, a Check-in, 3 treatment periods, and a follow-
up (telephone call). The treatment periods will include administration of single doses of 
vonoprazan 20 mg (tablet/sprinkle capsule) on Day 1 of each period. There will be a 
washout interval of a minimum of 7 days between study drug dosing in each period. 
Subjects who meet all the inclusion and none of the exclusion criteria will be randomly 
assigned to 1 of 3 treatment sequences in a 1:1:1 ratio. 
On the first day of each dosing period, subjects will receive 1 of the following study 
treatments according to the treatment sequence they are randomly assigned to: 
•
Treatment A: Vonoprazan 20 mg sprinkle capsule on 1 tablespoon of pudding
administered orally under fasted conditions.
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Phathom Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0 
VPED-101 
Date Issued: 14/06/2022 
Page 8 of 23 
•
Treatment B: Vonoprazan 20 mg sprinkle capsule on 1 tablespoon of applesauce
administered orally under fasted conditions.
•
Treatment C: Vonoprazan 20 mg tablet administered orally under fasted conditions.
•
Table 3-1  Study Treatment Sequence
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
C 
A 
B 
3 
B 
C 
A 
Subjects will be confined to the clinical unit from Day –1 until discharge on Day 17. A 
follow-up telephone call will occur on Day 31 (±2 days). The duration of the study, 
excluding Screening will be approximately 33 days. 
Schedules of assessments can be found in Section 13. 
4. General Statistical Considerations
All statistical analyses will be conducted using statistical analysis system SAS® Version 
9.4 or higher (SAS Institute, Cary, NC).  
Descriptive statistics for continuous variables will include number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum, unless otherwise noted. For 
categorical variables, frequencies and percentages will be presented.  
Unless otherwise indicated, all tables, listings, and figures will be presented by treatment 
sequence.  
All data listings will be sorted by treatment sequence and subject number. 
Study days will be calculated with respect to the first dose date as below: 
x If the assessment/observation date is on or after the first dose date, then Study Day 
= Assessment/Observation Date – First Dose Date + 1; 
x Otherwise, Study Day = Assessment/Observation Date – First Dose Date 
Baseline will be defined as the last non-missing assessment (including repeated and 
unscheduled assessments) before the first dose of study drug administration, unless 
otherwise specified. 
For summary of safety assessments, if there are repeated measurements at a time point, the 
first non-missing assessment at that time point will be used in the summary tables.  
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Phathom Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0 
VPED-101 
Date Issued: 14/06/2022 
Page 9 of 23 
Unscheduled results will not be included in the summary tables, except for determining 
Baseline, but will be presented in data listings. 
The methodology and data handling specifications for PK data are detailed in Section 8. 
4.1. 
Sample Size 
The sample size for this study is based on a statistical power calculation. 
This crossover study will enroll 27 subjects to ensure 24 subjects complete the study, 
assuming an approximate dropout rate of 15%. With 24 completed subjects, the study will 
provide at least 97% power to conclude bioequivalence between the test treatments and the 
reference treatment, assuming that the vonoprazan PK parameters Cmax, AUC0-t, and AUC0-
inf are log-normally distributed, the true geometric mean ratio (GMR) is 1, and the 
intrasubject coefficient of variation is no greater than 20%. Subjects will be randomly 
assigned to 1 of 3 treatment sequences in a 1:1:1 ratio. Any replacement subject will be 
assigned to receive the same treatment as the subject he or she is replacing. 
4.2. 
Randomization and Blinding 
 will generate the randomization schedule. Subjects who meet all the inclusion and 
none of the exclusion criteria will be randomly assigned to a treatment sequence in a 1:1:1 
ratio (Section 3). Randomization numbers (in sequential order) will be assigned before the 
first dose of study drug is administered on Day 1 of Period 1 (Section 3). There will be no 
stratification and treatment sequence will not be blinded. 
4.3. 
Analysis Population 
The enrolled population will include all subjects who signed informed consent form (ICF). 
The safety population will include all subjects who received at least 1 dose of vonoprazan. 
The pharmacokinetic (PK) population will include all subjects who received at least 1 dose 
of vonoprazan and have sufficient concentration data to support accurate estimation of at 
least 1 PK parameter. Subjects who experience vomiting within 2 times the median Tmax 
after study drug dosing will be excluded from the summary statistics and statistical 
analysis from the impacted period(s). 
In addition, where subjects experience any other issues which may affect exposure to study 
drug (eg, dosing errors, etc), data will be reviewed by the study pharmacokineticist and 
evaluated for exclusion from the summary statistics and statistical analysis from the 
impacted period(s) on a case-by-case basis. All subjects excluded from the PK analysis 
will be documented in the data listings. 
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Final Statistical Analysis Plan, Version 1.0 
VPED-101 
Date Issued: 14/06/2022 
Page 10 of 23 
5. Subject Disposition
5.1 
Disposition
The following will be summarized for the enrolled population, by treatment sequence (if 
applicable) and overall: 
x 
The number of subjects screened 
x 
The number of subjects who screen failed (both overall and according to reason 
for screen failure) 
x The number of subjects who were randomized 
x The number of subjects who completed the treatment 
x The number of subjects who did not complete the treatment (both overall and 
according to reasons for discontinuation from the treatment) 
x The number of subjects who completed the study 
x The number of subjects who did not complete the study (both overall and according 
to reasons for discontinuation from the study) 
x The number of subjects in each analysis population 
Subject disposition data will be presented in a data listing. 
5.2 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important deviation (sometimes referred to as a 
major or significant deviation) is a subset of protocol deviations that leads to a subject 
being discontinued from the study, or significantly affects the subject’s rights, safety, or 
well-being and/or the completeness, accuracy, and reliability of the study data. 
Important protocol deviations will be summarized by treatment sequence in the table and 
all deviations will be presented in a data listing.  
5.3 
Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria deviations will be presented in a data listing. 
6. Demographics and Baseline Characteristics
6.1 
Demographics
Demographic information will be presented in a data listing.
Descriptive statistics will be calculated for the following continuous demographic 
characteristics:  
x Age (years) 
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Phathom Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0 
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Date Issued: 14/06/2022 
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x Weight (kg) 
x Height (cm) 
x Body mass index (BMI) (kg/m2) 
Frequency counts and percentages will be tabulated for the categorical variables: 
x Sex 
x Race 
x Ethnicity 
The summaries will be presented by treatment sequence and overall for the safety 
population. 
6.2 
Medical History 
The medical history data will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA, version 25.0) and presented in a data listing. 
7. Treatments and Medications
7.1 
Prior and Concomitant Medications
Medications that stop prior to the first dose of study drug will be classified as prior 
medication. Medications that start on or after the first dose of study drug will be classified 
as concomitant. If a medication starts before the first dose of study drug and stops on or 
after the first dose of study drug, then the medication will be classified as both prior and 
concomitant. 
All prior and concomitant medications will be coded according to the World Health 
Organization Drug Dictionary (WHODrug, version 2022-March 1st (Global B3)) and 
presented in a data listing. 
7.2 
Medical or Surgical Treatment Procedures 
Medical or surgical treatment procedures will be presented in a data listing. 
7.3 
Study Treatment 
The study drug administration and fasting condition data as collected on electronic case 
report form (eCRF) will be presented in the data listings. 
7.4 
Meal Status 
The meal status information will be presented in the data listing. 
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Final Statistical Analysis Plan, Version 1.0 
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Date Issued: 14/06/2022 
Page 12 of 23 
8. Pharmacokinetics
All PK listings and individual concentration-time profiles will be presented using the 
safety population. PK tables, mean figures, and all statistical analyses will be presented 
using the PK population. 
8.1 
Data Handling 
Data rounding specifications for PK data will be documented in the PK TLF shells. 
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as 
zero for summary statistics and PK profiles representation. Mean BLQ concentrations will 
be presented as BLQ, and the SD and coefficient of variation (CV) will be reported as not 
applicable. Missing concentrations will be excluded from the calculations.  
For the PK analysis, BLQ values will be treated as zero with the exception that a BLQ 
value between 2 quantifiable concentrations will be set as missing. Missing concentrations 
will be treated as missing from the PK parameter calculations. If consecutive BLQ 
concentrations are followed by quantifiable concentrations in the terminal phase, those 
concentrations after BLQ concentrations will be treated as missing. 
If carry-over occurs between study periods (ie, if predose concentrations after Period 1 are 
above the lower limit of quantification), the subject’s data (without any adjustments) will 
be included in all PK tables and statistical evaluations where the pre-dose concentration is 
d 5% of Cmax for the affected subject profile. If the pre-dose value is > 5% of Cmax, the 
subject will be flagged in all associated data listings and the affected profile will be 
excluded from all PK summaries and statistical evaluations. 
8.2 
Plasma Concentrations 
Serial blood samples for PK analysis of vonoprazan in plasma will be collected within 15 
minutes prior to vonoprazan dosing in each period and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 
16, 24, 36, and 48 hours following vonoprazan dosing in each period.  
The permitted windows for PK sample collection are as follows: 
Pharmacokinetic time points Window  
Pre-dose  
within 15 minutes prior to dosing 
0.25 to 4 hours 
± 5 minutes  
6 to 12 hours 
± 10 minutes  
16 to 48 hours 
± 30 minutes 
PK collections that have an actual sampling time that deviates from the predefined 
collection time windows will be flagged in the data listings and excluded from the 
calculation of concentration summary statistics. 
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Individual plasma concentrations and time deviation data will be presented in data listings. 
Plasma concentrations will be summarized separately by time point for each treatment 
using the following descriptive statistics: number of observations, arithmetic mean, 
standard deviation (SD), CV, median, minimum, and maximum.  
Individual plasma concentrations will be plotted by actual time on both linear and semi-
logarithmic scales with all treatments overlaid on the same plots. Mean plasma 
concentrations will be plotted by nominal time on both linear and semi-logarithmic scales 
with all treatments overlaid on the same plots. 
8.3 
Plasma Pharmacokinetic Parameters 
Plasma concentration-time data will be analyzed by non-compartmental analysis using 
Phoenix® WinNonlin® Version 8.3 or higher (Certara USA, Inc., Princeton, NJ). The 
following PK parameters will be calculated for vonoprazan, where data permit: 
Cmax 
Maximum observed concentration. 
Tmax 
Time of maximum observed concentration. 
AUC0-t 
AUC from time 0 to the last measurable observed concentration (Clast), 
calculated using the linear trapezoidal rule. 
AUC0-inf 
AUC from time 0 extrapolated to infinity, calculated as [AUC0-t + (Clast 
/ λz)] where Clast is the last observed measurable concentration. 
%AUCext 
Percentage of AUC0-inf due to extrapolation; AUC0-inf, CL/F and Vz/F 
values will be flagged and excluded from summary statistics and 
statistical analysis (as applicable) where %AUCext > 20%. 
t1/2 
Apparent terminal elimination half-life, calculated as: ln (2) / λz. 
CL/F 
Apparent total body clearance after oral (extravascular) administration, 
calculated as: Dose / AUC0-inf. 
Vz/F 
Apparent volume of distribution during the terminal elimination phase 
after oral (extravascular) administration, calculated as: Dose / [λz * 
AUC0-inf]. 
In addition to the above PK parameters, which will be listed and summarized, the 
following parameters will also be listed and summarized to document the selection of data 
points used to estimate t1/2z using non-compartmental procedures: 
λz 
Apparent terminal elimination rate constant, where λz is the magnitude 
of the slope of the linear regression of the log concentration versus time 
profile during the terminal phase. 
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Number 
points 
Number of data points used to estimate λz; a minimum of 3 data points 
must be used, and Cmax must not be included. 
λz lower 
Lower bound used for the estimation of λz. 
λz upper 
Upper bound used for the estimation of λz. 
Rsq 
r2, the coefficient of determination (goodness of fit statistic); λz and all 
associated parameters will only be reported where r2 ≥ 0.80. 
Actual sampling times will be used for the estimation of all plasma PK parameters, and all 
concentrations will be included in the analysis (including concentrations collected outside 
predefined collection windows). 
Individual plasma PK parameters will be presented and summarized by treatment using 
descriptive statistics (number of observations, arithmetic mean, SD, CV, geometric mean, 
geometric CV, median, minimum, and maximum). Tmax will be summarized using number 
of observations, median, minimum, and maximum only. 
8.4 
Pharmacokinetic Statistical Analyses 
8.4.1 Bioequivalence Assessment 
A linear mixed model with fixed effects for treatment, sequence, and period and subject 
within sequence as a random effect will be performed on the natural log-transformed 
values of AUC0-t, AUC0-inf, and Cmax to assess the relative bioavailability (BA) of the test 
dose form (vonoprazan sprinkle capsule [either sprinkled on pudding, Treatment A, or on 
applesauce, Treatment B]) to the reference dose form (vonoprazan tablet, Treatment C). 
The geometric least square means and corresponding 90% confidence intervals (CIs) will 
be computed for AUC0-t, AUC0-inf, and Cmax by taking the antilog of the least square means 
from the linear mixed-effect model on the natural logarithms of the corresponding PK 
parameters. No adjustment will be made for multiplicity.  
Relative BA will be reported as the test to reference ratios (A/C or B/C) of the geometric 
means and its corresponding CIs for AUC0-t, AUC0-inf, and Cmax PK parameters. 
Bioequivalence will be concluded if the 90% CI for the geometric mean ratio (GMR) 
between the test treatments (20 mg sprinkle capsule, either sprinkled on pudding or on 
applesauce) and the reference treatment (20 mg tablet) are wholly contained within 0.80 
and 1.25 for the vonoprazan PK parameters AUC0-t, AUC0-inf, and Cmax.  
In addition, the GMR and corresponding 90% CIs for AUC0-t, AUC0-inf, and Cmax will be 
summarized in forest plots to visually assess bioequivalence. 
Nonparametric methods (Wilcoxon signed-rank test) will be used to examine the 
differences in Tmax between treatments for vonoprazan. The Hodges-Lehmann estimate and 
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its 90% CI will be calculated for the median difference between treatments, and a p-value 
will be generated by the Wilcoxon signed-rank test. 
9. Safety Analysis
All safety summaries and analyses will be based upon the safety population.
9.1 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a subject enrolled in 
this study regardless of its causal relationship to study drug.   
A pre-treatment event (PTE) is defined as any untoward medical occurrence that has 
occurred prior to administration of any study drug in a clinical investigation subject who 
has signed informed consent to participate in a study; it does not necessarily have to have a 
causal relationship with study participation. 
A treatment-emergent AE (TEAE) is defined as any event that occurs after the first dose of 
study drug or any event at baseline that worsens in either intensity or frequency after the first 
dose of study drug. 
The AE’s relationship to study treatment will be evaluated as related or not related.  
The severity of AEs will be classified by the investigator as mild, moderate, or severe. 
An overall AE summary will be generated presenting the frequency and percentage of 
subjects and the number of AEs for the following: 
x Any AE 
x Any TEAE 
x Any PTE 
x Any treatment-related TEAE  
x Any mild TEAE 
x Any treatment-related mild TEAE  
x Any moderate TEAE 
x Any treatment-related moderate TEAE 
x Any severe TEAE 
x Any treatment-related severe TEAE 
x Any SAE 
x Any treatment-related SAE 
x Any TEAE leading to early discontinuation 
x Any death 
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All AEs will be coded using MedDRA (version 25.0). The TEAEs will also be summarized 
by system organ class (SOC), preferred term (PT), by severity and relationship to study 
treatment. Treatment-related TEAEs will be summarized by SOC and PT. 
The TEAE summary tables will be sorted by SOC and PT. System organ class will be 
displayed in descending order of overall frequency then alphabetically. Preferred term will 
be displayed in descending order of overall frequency and then alphabetically within SOC. 
A subject with 2 or more events within the same level of summarization will be counted 
only once in that level using the most severe incident or most related incident. Percentages 
will be based on the number of subjects in the safety population. 
In summaries of TEAEs by treatment, TEAEs will be summarized according to the most 
recent treatment received prior to the TEAE onset. For example, a TEAE that occurred on 
or after administration of the study drug on Day 1 of Period 1 but before the administration 
of study drug on Day 1 of Period 2 will be summarized for study drug administered in 
Period 1.  
All AEs will be presented in a data listing. Separate data listings will be generated for 
treatment-related AEs, SAEs, PTEs, and AEs leading to study discontinuation.  
9.2 
Clinical Laboratory Evaluations 
The hematology, serum chemistry, and urinalysis tests will be performed at the timepoints 
indicated in the schedule of assessments (schedules of assessments can be found in Section 
13). 
All clinical laboratory test results will be presented in the data listings and identified 
whether the test results are clinically significant or not. Laboratory values that are outside 
of the normal reference range will be flagged in the data listings. 
Actual results and change from baseline for continuous variables at each time point will be 
summarized for the safety population. Shift from baseline categorical variables will be 
summarized for the safety population.  
9.3 
Vital Sign Measurements 
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature, and will be measured at the timepoints indicated in the schedule of 
assessments (schedules of assessments can be found in Section 13). 
All vital sign, body weight, and height measurements will be presented in a data listing. 
The actual values and change from baseline values at each time point will be summarized 
for the safety population. 
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9.4 
Physical Examination 
A full physical examination will include, at minimum, assessment of skin, head, ears, eyes, 
nose, throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes, and 
musculoskeletal system/extremities. A brief physical examination will include, at 
minimum, assessment of skin, lungs, cardiovascular system, and abdomen (liver and 
spleen). 
Full physical examinations will be performed at Screening, and brief physical 
examinations will be performed at the timepoints indicated in the schedule of assessments 
(schedules of assessments can be found in Section 13). 
All physical examination results will be presented in a data listing. 
9.5 
Electrocardiograms 
Single 12-lead ECGs will be obtained after the subject has been in the supine position for 
at least 5 minutes.  
Heart rate, PR interval, QRS width, RR interval, QT interval, QT interval corrected for 
heart rate using Fridericia’s formula (QTcF), and interpretation of ECG will be captured on 
the eCRF. 
Single 12-lead ECG will be performed at the timepoints indicated in the schedule of 
assessments (schedules of assessments can be found in Section 13). 
Actual values and changes from baseline for numeric ECG data will be summarized by 
visit and treatment sequence for subjects in the safety population. 
All ECG data will be presented in a data listing.  
9.6 
Other Tests 
A serology test, COVID-19 test, urine drug screen, pregnancy test (female only) and serum 
follicle stimulating hormone (FSH) test (female only) will be performed at the timepoints 
indicated at schedules of assessments (schedules of assessments can be found in Section 
13).  
The test results will be presented in a data listing. 
9.7 
COVID-19 Vaccine, Infection History and Impact 
The status of coronavirus disease 2019 (COVID-19) including vaccine and infection 
history will be collected and presented in a data listing. 
The visits impacted by COVID-19 will also be presented in a data listing. 
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10. Interim Analysis.
No formal interim analyses are planned.
11. Changes in the Planned Analysis
Any changes from this statistical analysis plan will be documented in the CSR for this
study.
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12.
References
1.
Department of Health and Human Services (DHHS), Food and Drug Administration
(FDA), Center for Drug Evaluation and Research (CDER). Guidance for industry.
Bioavailability Studies Submitted in NDAs or INDs – General Considerations. April
2022. Available from: https://www.fda.gov/media/121311/download.
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13.
Schedule of Assessments
Phase Screening Check-in 
Treatment Periods 1 to 3(b) 
Follow-up 
(Phone 
Call)/EOS 
Day –28 to –2
–1
Day 1 
Day 2 
Day 3 
(ET) 
Day 31 
(±2) 
Procedure(a) 
Hours 
— 
— 
Predose 
0 0.25 0.5 1 1.5 2 
4 
6 
8 10 12 16 24 36 
48 
Admission to clinic 
X 
Discharge from clinic(c) 
X 
Telephone call 
X 
Informed consent 
X 
Demographics 
X 
Serology(d) 
X 
COVID-19 screening 
X 
X 
Serum FSH(e) 
X 
Inclusion/exclusion criteria
X 
X 
Medical history 
X 
X 
Urine drug/alcohol/cotinine screen(f) 
X 
X 
Height, weight, and BMI(g) 
X 
X 
X 
Physical examination(h) 
X 
X
X 
Vital sign measurements(i) 
X 
X 
X 
X 
12-lead ECG(j) 
X 
X 
X 
Clinical laboratory testing(k) 
X 
X 
X 
Pregnancy test(l) 
X 
X 
X 
Guidance on avoidance of pregnancy 
X 
X 
X 
Randomization(m) 
X 
Study drug administration(n) 
X 
PK sample collection(o) 
X 
X 
X 
X 
X 
X X X X X 
X 
X X 
X 
X 
CYP genotyping 
X 
Fasting period(p) 
X 
X 
X 
X 
X 
X 
X 
X X 
Non-fasting period(q) 
X X X 
X 
X X 
X 
X 
PTEs monitoring(r) 
X 
X 
X 
AEsError! Reference source not found. 
X 
Prior/concomitant medications 
X 
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Abbreviations: AE, adverse event; BMI, body mass index; COVID-19, coronavirus disease 2019; CYP, cytochrome P450; ECG, electrocardiogram; EOS, end of 
study; ET, end-of-treatment period phase; FSH, follicle stimulating hormone; ICF, informed consent form; PK, pharmacokinetic; PTE, pre-treatment event; 
QTcF, QT interval corrected for heart rate using Fridericia’s formula. 
Notes: 
(a) When procedures overlap or occur at the same time point, all blood draws should follow vital signs or ECGs, and PK sampling should be timed to
occur last and as close to the scheduled time window as possible.
(b) There will be a washout interval of a minimum of 7 days between study drug dosing in each period.
(c) Discharge will occur following the last study assessment on Day 17 (ET, ie, Day 3 of Period 3).
(d) Serology testing will include hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus types 1 and 2 antibodies.
The testing will be conducted at Screening.
(e) Females with at least 12 months of amenorrhea should have a serum FSH test performed at Screening, if required, to confirm postmenopausal
status per Inclusion Criterion #4 (FSH level >40 IU/mL).
(f) A urine drug/alcohol/cotinine screen will occur at Screening and Check-in.
(g) Height and weight will be measured, and BMI (kg/m2) will be calculated at Screening only. Only weight will be measured at Check-in and ET.
(h) A full physical examination will be performed at Screening (at minimum, assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs,
heart, cardiovascular, abdomen, lymph nodes, and musculoskeletal system/extremities). A brief physical examination will be performed at Check-in
and ET (at minimum, assessment of skin, lungs, cardiovascular system, and abdomen [liver and spleen]). Interim physical examinations may be
performed at the discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities.
(i) Vital signs will be measured at Screening and Check-in, within 15 minutes prior to vonoprazan dosing in each period, and at ET. Vital signs will be
measured after the subject has been in the seated position for at least 5 minutes and will include systolic and diastolic blood pressure, pulse rate,
respiratory rate, and body temperature.
(j) Single 12-lead ECG recordings will be made at Screening, Check-in, and ET after the subject has been in the supine position for at least 5 minutes.
A single repeat measurement is permitted at Screening for eligibility determination. Measurements of the following intervals will be reported: RR
interval, PR interval, QRS width, QT interval, and QTcF. Assessments should include comments on whether the tracings are normal or abnormal;
rhythm; presence of arrhythmia or conduction defects; morphology; any evidence of myocardial infarction; or ST-segment, T-wave, and U-wave
abnormalities.
(k) Clinical laboratory testing will occur at Screening, Check-in, and ET. A complete list of assessments is provided in Section Error! Reference
source not found.. Blood and urine samples will be collected and prepared per the clinic’s standard procedures; blood sample will be collected
under fasted conditions.
(l) All women will have a serum pregnancy test performed at Screening. At Check-in and ET, a urine pregnancy test will be performed, and if the test
result is positive, a serum pregnancy test will be performed for confirmation.
(m) Subjects will be randomized only on Day 1 of Period 1.
(n) The time of vonoprazan dosing will be called “0” hour in each period and is denoted with gray shading. Vonoprazan sprinkle capsule sprinkled on
1 tablespoon of pudding will be swallowed and will be followed with swish/swallow of 240 mL of room temperature water; vonoprazan sprinkled
on 1 tablespoon of applesauce will be swallowed and will be followed with swish/swallow of 240 mL of room temperature water. Vonoprazan
tablet will be administered and swallowed whole with 240 mL of room temperature water. Subjects will maintain an upright (ie, seated or standing)
position for at least 4 hours after dosing.
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(o) Blood samples for PK analysis of vonoprazan in plasma will be collected within 15 minutes prior to vonoprazan dosing in each period and at 0.25,
0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours following vonoprazan dosing in each period. The window for PK sample collection up to 4
hours following vonoprazan dosing will be ±5 minutes; from 6 hours up to 12 hours post dose will be ±10 minutes; and from 16 hours up to 48
hours will be ±30 minutes.
(p) During fasting periods, subjects should have nothing to eat or drink except water for 10 hours prior to vonoprazan dosing until 4 hours after dosing.
Water (other than the water consumed with the administration of vonoprazan tablet or sprinkle capsule) is permitted as desired except for 1 hour
before and 1 hour after administration of vonoprazan.
(q) During non-fasting periods, subjects should receive standardized meals per the clinic’s standard procedures that will be scheduled at the same time
in each period of the study.
(r) Collection of PTEs will start after the subject has signed the ICF.
(s) Adverse events will be assessed from the time of the first vonoprazan dosing until the follow-up telephone call or withdrawal from the study and
should be followed until they are resolved, stable, or judged by the investigator to be not clinically significant.
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