A Phase 1, Open-Label, Randomized, Single-Dose, 5-Period Crossover Study to Determine the Bioavailability of Two Vonoprazan Orally Disintegrating Tablet Formulations Administered Without Water or Mixed With Water and Administered Via a Syringe Relative to the Vonoprazan Tablet in Healthy Subjects
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: Phathom Pharmaceuticals, Inc.

Protocol Number: VPED-105 
Official Title: A Phase 1, Open-label, Randomized, Single-dose, 5-Period 
Crossover Study to Determine The Bioavailability Of Two Vonoprazan 
Orally Disintegrating Tablet Formulations Administered Without Water or 
Mixed With Water And Administered Via A Syringe Relative To The 
Vonoprazan Tablet In Healthy Subjects
NCT Number: NCT06831344 
Document Date: 10 December 2024

Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-105 Version 1.0 
10 December 2024 
Page 2 
Protocol Approval – Sponsor Signatory 
Study Title 
A Phase 1, Open-Label, Randomized, Single-Dose, 5-Period Crossover 
Study to Determine the Bioavailability of Two Vonoprazan Orally 
Disintegrating Tablet Formulations Administered Without Water or Mixed 
With Water and Administered via a Syringe Relative to the Vonoprazan 
Tablet in Healthy Subjects 
Protocol Number 
VPED-105 
Protocol Version 
and Date 
Version 1.0 
10 December 2024 
PROTOCOL ACCEPTED AND APPROVED BY PHATHOM PHARMACEUTICALS: 
 
Date 
 
 
 
Date 
 
Date 
 
Docusign Envelope ID: 
10-Dec-2024 | 16:32 CST
10-Dec-2024 | 16:31 CST
10-Dec-2024 | 14:29 PST

Phathom Pharmaceuticals, Inc. 
vonoprazan 
Protocol: VPED-105 Version 1.0 
10 December 2024 
Page 3 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 1, Open-Label, 
Randomized, Single-Dose, 5-Period Crossover Study to Determine the Bioavailability of 
Two Vonoprazan Orally Disintegrating Tablet Formulations Administered Without Water or 
Mixed With Water and Administered via a Syringe Relative to the Vonoprazan Tablet in 
Healthy Subjects” and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 1.0, dated 10 December 2024, the International 
Council for Harmonisation harmonised tripartite guideline E6(R3): Good Clinical Practice, 
and all applicable government regulations. I will not make changes to the protocol before 
consulting with Phathom Pharmaceuticals, Inc. or implement protocol changes without 
Institutional Review Board approval except to eliminate an immediate risk to subjects. I 
agree to administer study drug only to subjects under my personal supervision or the 
supervision of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Phathom Pharmaceuticals, Inc. 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 

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Protocol: VPED-105 Version 1.0 
10 December 2024 
Page 4 
Table of Contents 
Table of Contents .......................................................................................................................4 
List of Tables ..............................................................................................................................7 
Protocol Synopsis.......................................................................................................................8 
List of Abbreviations................................................................................................................12 
1 
Introduction ......................................................................................................................15 
1.1 
Study Rationale .......................................................................................................15 
1.2 
Background .............................................................................................................16 
1.2.1 
Vonoprazan ..............................................................................................16 
1.3 
Justification for Dose ..............................................................................................17 
2 
Study Objectives and Endpoints.......................................................................................19 
3 
Investigational Plan ..........................................................................................................20 
3.1 
Study Design ...........................................................................................................20 
4 
Subject Selection and Withdrawal Criteria ......................................................................22 
4.1 
Selection of Study Population .................................................................................22 
4.1.1 
Inclusion Criteria .....................................................................................22 
4.1.2 
Exclusion Criteria ....................................................................................23 
4.1.3 
Screen Failures .........................................................................................25 
4.2 
Withdrawal of Subjects From Study Drug and/or Study Participation ...................25 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................25 
4.2.2 
Handling of Withdrawals .........................................................................26 
4.2.3 
Replacements ...........................................................................................26 
5 
Study Drugs ......................................................................................................................27 
5.1 
Method of Assigning Subjects to Treatment Groups ..............................................27 
5.2 
Treatments Administered ........................................................................................27 
5.3 
Identity of Investigational Product..........................................................................28 
5.4 
Management of Clinical Supplies ...........................................................................28 
5.4.1 
Study Drug Packaging and Storage .........................................................28 
5.4.2 
Study Drug Accountability ......................................................................29 
5.5 
Overdose Management ...........................................................................................29 

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10 December 2024 
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5.6 
Blinding ..................................................................................................................29 
5.7 
Study Compliance ...................................................................................................29 
5.7.1 
Treatment Compliance .............................................................................29 
5.8 
Prior and Concomitant Medications and Therapies ................................................30 
5.8.1 
Prior Medications .....................................................................................30 
5.8.2 
Concomitant Medications ........................................................................30 
6 
Study Assessments and Procedures ..................................................................................31 
6.1 
Pharmacokinetic Assessments ................................................................................31 
6.2 
Other Assessments ..................................................................................................32 
6.2.1 
Taste Assessment .....................................................................................32 
6.3 
Safety Assessments .................................................................................................32 
6.3.1 
Pretreatment Events and Adverse Events ................................................32 
6.3.1.1 
Definitions ...............................................................................................32 
6.3.1.2 
Documenting Adverse Events ..................................................................38 
6.3.1.3 
Time Period and Frequency for Collecting AE and SAE Information ....41 
6.3.2 
Pregnancy ................................................................................................44 
6.3.3 
Laboratory Analyses ................................................................................45 
6.3.4 
Physical Examinations .............................................................................47 
6.3.5 
Vital Signs ................................................................................................47 
6.3.6 
Electrocardiograms ..................................................................................47 
7 
Statistical and Analytical Plan ..........................................................................................48 
7.1 
Sample Size Calculations ........................................................................................48 
7.2 
Analysis Sets ...........................................................................................................48 
7.3 
Statistical Analysis Methodology ...........................................................................48 
7.3.1 
Pharmacokinetic Analyses .......................................................................48 
7.3.2 
Exploratory Analyses ...............................................................................49 
7.3.3 
Safety Analyses ........................................................................................49 
7.4 
Handling of Missing Data .......................................................................................50 
7.5 
Interim Analyses .....................................................................................................50 
8 
Data Quality Assurance ....................................................................................................51 
8.1 
Data Management ...................................................................................................51 
9 
Ethics ................................................................................................................................52 

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10 December 2024 
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9.1 
Institutional Review Board .....................................................................................52 
9.2 
Ethical Conduct of the Study ..................................................................................52 
9.3 
Subject Information and Consent ...........................................................................52 
10 Investigator’s Obligations ................................................................................................54 
10.1 Confidentiality ........................................................................................................54 
10.2 Financial Disclosure and Obligations .....................................................................54 
10.3 Investigator Documentation ....................................................................................55 
10.4 Study Conduct .........................................................................................................55 
10.5 Adherence to Protocol ............................................................................................56 
10.6 Adverse Events and Study Report Requirements ...................................................56 
10.7 Investigator’s Final Report .....................................................................................56 
10.8 Records Retention ...................................................................................................56 
10.9 Publications .............................................................................................................56 
11 Study Management ...........................................................................................................58 
11.1 Monitoring ..............................................................................................................58 
11.1.1 
Inspection of Records ..............................................................................58 
11.2 Management of Protocol Amendments and Deviations..........................................58 
11.2.1 
Modification of the Protocol ....................................................................58 
11.2.2 
Protocol Deviations .................................................................................59 
11.3 Study Termination ...................................................................................................59 
11.4 Final Report ............................................................................................................59 
12 Reference List...................................................................................................................61 
13 Appendices .......................................................................................................................63 
13.1 Appendix 1: Schedule of Events .............................................................................64 
13.2 Appendix 2: Contraceptive Guidance .....................................................................68 
13.3 Appendix 3: Liver Function Tests ...........................................................................69 
13.3.1 
Liver Function Test Monitoring ...............................................................69 
13.3.2 
Considerations for Temporary Discontinuation of Study Drug ...............69 
13.3.3 
Permanent Discontinuation of Study Drug ..............................................70 
13.3.4 
Re-initiation of Study Drug .....................................................................71 

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Protocol: VPED-105 Version 1.0 
10 December 2024 
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13.4 Appendix 4: Taste Assessment Questionnaire ........................................................72 
 
List of Tables 
Table 2-1 
Study Objectives and Endpoints ..................................................................... 19 
Table 3-1 
Study Treatment Sequence .............................................................................. 21 
Table 6-1 
Medically Significant Adverse Event List ...................................................... 34 
Table 6-2 
Adverse Events of Special Interest List .......................................................... 35 
Table 6-3 
Protocol-Required Safety Laboratory Assessments ........................................ 46 
Table 13-1 
Abnormal Liver Function Criteria for Permanent Discontinuation of Study 
Drug ................................................................................................................ 70 
 

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vonoprazan 
Protocol: VPED-105 Version 1.0 
10 December 2024 
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Protocol Synopsis 
Protocol Number: VPED-105 
Title: 
A Phase 1, Open-Label, Randomized, Single-Dose, 5-Period Crossover 
Study to Determine the Bioavailability of Two Vonoprazan Orally 
Disintegrating Tablet Formulations Administered Without Water or 
Mixed With Water and Administered via a Syringe Relative to the 
Vonoprazan Tablet in Healthy Subjects 
Sponsor:  
Phathom Pharmaceuticals, Inc. 
2150 East Lake Cook Road, Suite 800 
Buffalo Grove, IL 60089 USA 
Study Phase: 
1 
Study Sites: 
1 site in the United States (US) 
Indication: 
Not applicable 
Rationale: 
Vonoprazan tablets are approved in the US for the healing of all grades 
of erosive esophagitis (EE) and relief of heartburn associated with EE, 
to maintain healing of all grades of EE and relief of heartburn 
associated with EE, for the relief of heartburn associated with non-
erosive gastroesophageal reflux disease (GERD), and in combination 
with amoxicillin or in combination with amoxicillin and clarithromycin 
for the treatment of Helicobacter pylori infection in adults.  
Phathom is developing an orally disintegrating tablet (ODT) 
formulation as an alternate formulation for the pediatric population and 
adults with difficulty swallowing tablets. 
The purpose of this study is to determine the bioavailability (BA) of 
two vonoprazan ODT formulations (ODT-1 and ODT-2) administered 
without water or mixed with water and administered via a syringe 
relative to the vonoprazan tablet.  
Objectives: 
Primary: 
• To assess the BA of a single oral dose of the vonoprazan ODT-1 or 
ODT-2 administered without water or mixed with water and 
administered via a syringe relative to the vonoprazan tablet in 
healthy subjects.  
Secondary: 
• To assess the pharmacokinetic (PK) profile of a single oral dose of 
vonoprazan when administered to healthy subjects as the ODT-1 or 
ODT-2 administered without water or mixed with water and 
administered via a syringe relative to the tablet. 

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Safety: 
• To assess the safety and tolerability of a single oral dose of 
vonoprazan when administered to healthy subjects as ODT-1, ODT-
2, or the tablet.  
Study Population: Healthy adult subjects, aged 18 to 55 years, inclusive  
Study Design:  
This is a Phase 1, randomized, open-label, single-dose, 5-period, 5-
sequence crossover study designed to assess the BA of the vonoprazan 
ODT-1 or ODT-2 administered without water or mixed with water and 
administered via a syringe relative to the vonoprazan tablet in healthy 
subjects. 
The study will include a Screening Period, 5 Treatment Periods and a 
Follow-up Period: 
Screening Period: Subjects will undergo screening assessments to 
determine study eligibility, and baseline assessments will be 
performed. If all eligibility criteria are met, the subject will be 
randomized and enter the Treatment Periods. 
Treatment Periods: Subjects will be randomly assigned to 1 of 5 
treatment sequences in a 1:1:1:1:1 ratio to receive the following:  
• Treatment A: Vonoprazan 10 mg ODT-1 without water  
• Treatment B: Vonoprazan 10 mg ODT-1 mixed with water and 
administered via a syringe  
• Treatment C: Vonoprazan 10 mg ODT-2 without water  
• Treatment D: Vonoprazan 10 mg ODT-2 mixed with water and 
administered via a syringe  
• Treatment E (reference): Vonoprazan 10 mg tablet 
The treatment periods will include administration of single doses of 
vonoprazan 10 mg on Day 1 of each period. There will be a washout 
interval of a minimum of 5 days between study drug dosing in each 
period. 
PK samples will be collected through 48 hours following dosing, and 
safety endpoints will be evaluated throughout the study. 
Follow-up Period: A safety follow-up phone call will occur on Day 28 
(±2 days) to assess adverse events (AEs). 
A subject will be considered to have completed the study if the subject 
completes all Treatment Periods and the safety follow-up phone call. 
Estimated Study 
Duration: 
The Screening Period is up to 28 days. Subjects will be confined to the 
clinical unit from Day –1 until discharge on Day 23. A follow-up 

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Protocol: VPED-105 Version 1.0 
10 December 2024 
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telephone call will occur on Day 28 (±2 days). The duration of the 
study, excluding Screening will be approximately 28 days. 
Pharmacokinetic 
Assessments: 
The primary vonoprazan PK endpoints will include the following PK 
parameters: 
• Maximum observed drug concentration (Cmax) 
• Area under the plasma concentration-time curve from time 0 to 
the last quantifiable concentration (AUC0-t) 
• Area under the plasma concentration versus time curve from 
time 0 extrapolated to infinity (AUC0-inf) 
The secondary PK endpoints will include tmax, tlag, λz, t1/2, CL/F, and 
Vz/F. 
Safety 
Assessments: 
Safety will be assessed by the following: 
• AEs 
• Laboratory test values (hematology, serum chemistry, 
urinalysis) 
• Electrocardiograms 
• Vital signs 
Study Drug, 
Dosage, and Route 
of Administration: 
Open-label vonoprazan ODT-1, ODT-2 or tablets will be administered 
orally. Vonoprazan ODT-1 and ODT-2 will be administered without 
water or mixed with 5 mL of room temperature water and administered 
via a syringe. Vonoprazan tablets will be administered with 240 mL of 
room temperature water. All study drug doses will be taken after a 10 
hour fast.  
Sample Size: 
This crossover study will enroll 25 subjects. The study will provide at 
least 95% power to conclude bioequivalence between a test treatment (A, 
B, C, or D) and the reference treatment (E). This assumes that the 
vonoprazan PK parameters Cmax, AUC0-t, and AUC0-inf are log-normally 
distributed, there is no more than a 5% difference between the true 
geometric means of a pair of treatments, and the intrasubject coefficient 
of variation is no greater than 16%. The sample size allows for up to 5 
dropouts in the study. Subjects will be randomly assigned to 1 of 5 
treatment sequences in a 1:1:1:1:1 ratio. 
Statistical 
Methods: 
Pharmacokinetic Endpoints: 
Individual PK parameter estimates will be summarized descriptively by 
vonoprazan treatment.  
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. The 
ratio of geometric least square means (Treatment A, Treatment B, 

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Protocol: VPED-105 Version 1.0 
10 December 2024 
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Treatment C, and Treatment D versus Treatment E) and corresponding 
90% CIs will be computed for AUC0-t, AUC0-inf, and Cmax, by taking the 
antilog of the difference of the least squares means and associated 90% 
confidence interval (CI) from the linear mixed effect model analyzing 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/E), (B/E), 
(C/E) and (D/E) of the geometric means and their 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 treatment (A, B, C, D) and the reference treatment (E) 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. 
Safety: 
Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of subjects 
experiencing treatment-emergent AEs will be summarized by MedDRA 
system organ class and preferred term overall, by severity, and by 
relationship to study drug for each treatment group.  
Clinical laboratory tests, electrocardiograms, and vital signs will be 
summarized with descriptive statistics at each time point by treatment 
group. 
Version and 
Date of Protocol: 
Version 1.0 
10 December 2024 

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10 December 2024 
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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
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 oral clearance 
Cmax 
maximum observed drug concentration  
COVID-19 
coronavirus disease 2019 
CV 
Coefficient of variation 
CYP 
cytochrome P450 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EE 
erosive esophagitis 
eGFR 
estimated glomerular filtration rate 
EOS 
End of study  
ET 
Early termination 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
GGT 
gamma-glutamyl transferase 
GMR 
geometric mean ratio 
H+, K+-ATPase 
hydrogen, potassium–adenosine triphosphatase 
HBsAg 
hepatitis B surface antigen 

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Protocol: VPED-105 Version 1.0 
10 December 2024 
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Abbreviation 
Definition 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
λz 
terminal elimination rate constant 
LFT 
liver function test 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
ODT 
Orally disintegrating tablet 
PCAB 
potassium-competitive acid blocker 
Phathom  
Phathom Pharmaceuticals, Inc. 
PK 
pharmacokinetic 
PPI 
Proton pump inhibitor  
PTE 
pretreatment adverse event 
QD 
once daily 
RBC 
Red blood cell 
SAE 
serious adverse event 
SD 
standard deviation 
SGPT 
serum glutamic-pyruvic transaminase 
SGOT 
serum glutamic-oxaloacetic transaminase 
SoE 
schedule of events 
SARS-Cov-2 
severe acute respiratory syndrome coronavirus 2 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal phase half-life 
Takeda 
Takeda Pharmaceutical Company Limited 
TEAE 
treatment-emergent adverse event 
tlag 
time until first measurable concentration in plasma 

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Protocol: VPED-105 Version 1.0 
10 December 2024 
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Abbreviation 
Definition 
tmax 
time to maximum observed plasma concentration 
ULN 
upper limit of normal 
US 
United States 
Vz/F 
apparent volume of distribution 
WBC 
White blood cell 

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Protocol: VPED-105 Version 1.0 
10 December 2024 
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1 
Introduction 
Vonoprazan belongs to a new class of gastric acid secretion inhibitory agents called 
potassium-competitive acid blockers (PCABs). In the United States (US), vonoprazan tablets 
are approved for the healing of all grades of erosive esophagitis (EE) and relief of heartburn 
associated with EE, to maintain healing of all grades of EE and relief of heartburn associated 
with EE, for the relief of heartburn associated with non-erosive gastroesophageal reflux 
disease (GERD), and in combination with amoxicillin or in combination with amoxicillin and 
clarithromycin for the treatment of Helicobacter pylori infection in adults. 
In countries other than the US, vonoprazan has been studied in other gastric acid-related 
diseases such as healing of gastric ulcer and duodenal ulcers, and for the prevention of 
recurrence of gastric or duodenal ulcer during nonsteroidal anti-inflammatory drug or aspirin 
administration. Vonoprazan has received regulatory approval in Japan, Russia, and other 
countries in Asia and Latin America for a variety of indications.  
Phathom Pharmaceuticals, Inc. (Phathom) licensed the exclusive rights from Takeda 
Pharmaceutical Company Limited (Takeda) to develop, manufacture, and commercialize 
vonoprazan in the US, Europe, and Canada. Phathom is developing an orally disintegrating 
tablet (ODT) formulation as an alternate formulation for the pediatric population and adults 
with difficulty swallowing tablets. 
1.1 
Study Rationale 
The purpose of this study is to determine the bioavailability (BA) of two vonoprazan ODT 
formulations (ODT-1 and ODT-2) administered without water or mixed with water and 
administered via a syringe relative to the vonoprazan tablet.  
The study will be conducted in accordance with the FDA Guidance for Industry (April 2022): 
“Bioavailability Studies Submitted in NDAs or INDs – General Considerations”. The use of 
healthy adult subjects is appropriate for the BA study. 
Relative BA will be based on the maximum observed drug concentration (Cmax), area under 
the plasma concentration versus time curve (AUC) from time 0 to the last quantifiable 
concentration (AUC0-t), and AUC from time 0 extrapolated to infinity (AUC0-inf). The 
pharmacokinetic (PK) profile following administration of the vonoprazan ODTs will be 
characterized relative to that of the vonoprazan tablet. 

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1.2 
Background 
1.2.1 
Vonoprazan 
The gastric hydrogen, potassium–adenosine triphosphatase (H+, K+-ATPase), also known as 
the proton pump, is responsible for acid secretion from parietal cells in the stomach. It is 
inactive in the cytosol but relocates from the cytosol to the secretory membrane of the 
parietal cells when food is present in the stomach, thereby becoming active and pumping 
H+ ions out of the cells and into the canaliculi in exchange for K+ ions. It represents an 
attractive pharmacological target since it is the final step of the acid secretion process.  
Two classes of pharmaceuticals, with distinct mechanisms of action for inhibiting the gastric 
proton pump, have been developed for clinical application: Proton pump inhibitors (PPIs) 
and PCABs. As a PCAB, vonoprazan has a unique mechanism of action and 
pharmacokinetics relative to PPIs: 
• Acid activation and stability: Conventional PPIs are prodrugs, which are activated by 
acid and covalently bind to the H+, K+-ATPase; however, activated PPIs are not 
stable in acidic conditions. In contrast, vonoprazan does not require acid activation, is 
stable in acidic conditions, and has a more durable effect. Further, vonoprazan is 
rapidly protonated in the parietal cell canaliculi, which concentrates the drug 
proximal to the H+, K+-ATPase [Scarpignato 2019]. 
• Activity against proton pumps: Vonoprazan inhibits acid secretion by competitively 
inhibiting the binding of potassium ions to the H+, K+-ATPase. Vonoprazan may 
selectively concentrate in the parietal cells in both the resting and stimulated states 
and binds to the active pumps in a noncovalent and reversible manner. In contrast, 
PPIs covalently bind H+, K+-ATPase only when the pump is active, as an acidic 
environment is required for the activation and accumulation of PPIs in the parietal 
cell [Scott 2015].  
• Vonoprazan maintains acid control over 24 hours with once daily (QD) dosing 
[Engevik 2020]. Vonoprazan can also be dosed in the presence or absence of food, 
while most PPIs require dosing before a meal to optimize their acid suppressant effect 
because activated pumps are at their highest level post-prandially due to activation of 
pumps by the meal [Shin 2013]. 

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• Extended half-life: The mean plasma half-life is typically 7 to 8 hours after single and 
multiple QD administration of vonoprazan 20 mg (TAK-438_107). This is 
significantly longer than the half-life of conventional PPIs (<2 hours) [Shin 2013]. 
• Metabolism: Vonoprazan is metabolized by a combination of cytochrome P450 (CYP) 
isoforms including CYP3A4/5, which does not have a high degree of genetic 
polymorphism as compared with CYP2C19, which is the primary enzyme responsible 
for the metabolism of PPIs [Shin 2013]. 
These unique aspects of the vonoprazan mechanism of action and pharmacokinetics relative 
to PPIs translate into greater magnitude and duration of gastric acid suppression, which are 
reflected in the pharmacodynamic profile [Jenkins 2015; Sakurai 2015; Laine 2022]. 
The efficacy and safety of vonoprazan for the healing of all grades of EE and relief of 
heartburn associated with EE, to maintain healing of all grades of EE and relief of heartburn 
associated with EE and for relief of heartburn associated with non-erosive GERD has been 
established in adults. The most common adverse events were gastritis, diarrhea, abdominal 
distention, abdominal pain, nausea, dyspepsia, constipation, hypertension, and urinary tract 
infection [VOQUEZNA 2024]. 
Vonoprazan has been studied in an extensive nonclinical pharmacology and toxicology 
program as well as in a large global clinical program in multiple indications. The nonclinical 
pharmacology data are consistent with the pharmacological effect observed in humans. The 
nonclinical toxicology studies support repeated doses up to 40 mg in humans without 
significant toxicology findings. The safety profile of vonoprazan in Phase 3 studies of adults 
across indications showed no evidence of a dose-related increase in adverse effects with 
vonoprazan from 5 mg to 40 mg QD. As of 25 December 2023, the global cumulative post-
marketing patient exposure to vonoprazan is estimated to be approximately 129 million 
patients.  
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
and the applicable regulatory requirement(s). 
1.3 
Justification for Dose 
A single 10 mg dose of vonoprazan was selected because this is the highest currently 
developed ODT dosage strength. Oral dosing will be used as this is the intended route of 

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Protocol: VPED-105 Version 1.0 
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clinical administration for both vonoprazan formulations. Multiple oral doses of vonoprazan 
20 mg tablet formulations have been shown to be safe and well tolerated in patients and at a 
single dose of up to 120 mg in healthy adult subjects. 

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2 
Study Objectives and Endpoints 
Study objectives with corresponding endpoints are presented in Table 2-1. 
Table 2-1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To assess the BA of a single oral dose of the 
vonoprazan ODT-1 or ODT-2 administered 
without water or mixed with water and 
administered via a syringe relative to the 
vonoprazan tablet in healthy subjects. 
• 
Cmax, AUC0-t, AUC0-inf 
Secondary 
• 
To assess the PK profile of a single oral dose of 
vonoprazan when administered to healthy 
subjects as the ODT-1 or ODT-2 administered 
without water or mixed with water and 
administered via a syringe relative to the tablet. 
• 
tmax, tlag, λz, t1/2, CL/F, Vz/F 
Safety 
• 
To assess the safety and tolerability of a single 
oral dose of vonoprazan when administered to 
healthy subjects as ODT-1, ODT-2, and as the 
tablet 
• 
Adverse events 
• 
Laboratory test values (hematology, serum 
chemistry, urinalysis) 
• 
Electrocardiograms (ECG) 
• 
Vital signs 
AUC0-inf: area under the drug concentration-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; CL/F: apparent oral clearance; Cmax: maximum observed plasma concentration; ECG: 
electrocardiogram; ODT: orally disintegrating tablet; PK: pharmacokinetic; t1/2: terminal phase half-life; tlag: 
time until first measurable concentration in plasma; tmax: time to maximum observed plasma concentration; 
Vz/F: apparent volume of distribution, λz: terminal elimination rate constant. 
 
 
 

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3 
Investigational Plan 
3.1 
Study Design 
This is a Phase 1, randomized, open-label, single-dose, 5-period, 5-sequence crossover study 
designed to assess the BA of two vonoprazan ODT formulations (ODT-1 and ODT-2) 
administered without water or mixed with water and administered via a syringe relative to the 
vonoprazan tablet in healthy subjects. 
The study will consist of a screening period, a Check-in, 5 treatment periods, and a follow-up 
(telephone call). Each treatment period will include administration of a single dose of 
vonoprazan 10 mg (See treatments and Table 3-1) on Day 1 of each treatment period. There 
will be a washout interval of a minimum of 5 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 5 treatment sequences in a 1:1:1:1:1 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 10 mg ODT-1 without water  
• Treatment B: Vonoprazan 10 mg ODT-1 mixed with water and administered via a 
syringe 
• Treatment C: Vonoprazan 10 mg ODT-2 without water 
• Treatment D: Vonoprazan 10 mg ODT-2 mixed with water and administered via a 
syringe 
• Treatment E (reference): Vonoprazan 10 mg tablet 

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Table 3-1 
Study Treatment Sequence   
Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
Period 5 
1 
A 
B 
C 
D 
E 
2 
B 
D 
E 
C 
A 
3 
C 
E 
B 
A 
D 
4 
D 
C 
A 
E 
B 
5 
E 
A 
D 
B 
C 
Treatment A: vonoprazan 10 mg ODT-1 without water 
Treatment B: vonoprazan 10 mg ODT-1 mixed with water and administered via a syringe 
Treatment C: vonoprazan 10 mg ODT-2 without water 
Treatment D: vonoprazan 10 mg ODT-2 mixed with water and administered via a syringe 
Treatment E: vonoprazan 10 mg tablet 
 
Pharmacokinetic samples will be collected through 48 hours following dosing, taste 
assessments will be conducted for Treatments A, B, C and D, and safety endpoints will be 
evaluated throughout the study. 
Subjects will be confined to the clinical unit from Day -1 until discharge on Day 23.  
A safety follow-up phone call will occur on Day 28 (±2 days) to assess adverse events (AEs). 
A subject will be considered to have completed the study if the subject completes all 
Treatment Periods and the safety follow-up phone call. 
 

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4 
Subject Selection and Withdrawal Criteria 
4.1 
Selection of Study Population 
In this study, 25 healthy male and female subjects will be enrolled at a single center in the US 
to achieve at least 20 evaluable subjects.  
4.1.1 
Inclusion Criteria 
Subjects are eligible for enrollment in the study if they meet all of the following inclusion 
criteria: 
1. The subject is 18 to 55 years of age, inclusive, at Screening. 
2. The subject has a body mass index (BMI) 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 ECG results, and physical examination findings at Screening. 
4. 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 signing the informed consent 
form (ICF) until 4 weeks after the last dose of study drug or be surgically sterile (ie, 
hysterectomy 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). See Section 13.2 for more details. 
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. 

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4.1.2 
Exclusion Criteria 
Subjects are not eligible for study participation if they meet any of the following exclusion 
criteria: 
1. The subject has 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 Check-in. 
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 the end of confinement on Study Day 23. 
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 before the first dose of study drug and/or is expected to be unable to abstain 
through the study. 

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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 ½ 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. 
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 (Section 5.3) 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 5-times the 
plasma half-life (t1/2) of the study drug or 30 days of dosing, whichever is longer. 
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. 

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4.1.3 
Screen Failures 
Screen failures are defined as subjects who signed the ICF to participate in the clinical study 
but are not subsequently entered in the Treatment Period of the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure subjects to 
meet the Consolidated Standards of Reporting Trials publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, pretreatment adverse events (PTEs), AEs, and any serious 
adverse events (SAEs). 
Subjects may be allowed to be rescreened upon discussion with and approval by the medical 
monitor.  
4.2 
Withdrawal of Subjects From Study Drug and/or Study Participation  
4.2.1 
Reasons for Withdrawal/Discontinuation 
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 is 3x upper 
limit of normal [ULN] or total bilirubin is >2 × 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 

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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 PTE/AE, 
the investigator will confer with the sponsor Medical Monitor. 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. 
4.2.2 
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 electronic case report form (eCRF). Whenever 
possible, any subject who prematurely withdraws from the study will undergo all Early 
Termination (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. 
4.2.3 
Replacements 
Subjects may be rescreened at the discretion of the investigator and the sponsor, after 
consultation with the sponsor 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 20 evaluable 
subjects. Any replacement subject will be assigned to receive the same treatment sequence as the 
subject he or she is replacing.  

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5 
Study Drugs 
5.1 
Method of Assigning Subjects to Treatment Groups 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomly assigned to a treatment sequence in a 1:1:1:1:1 ratio as described in Table 3-1. 
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. 
5.2 
Treatments Administered 
In each period, subjects will fast overnight (nothing to eat or drink except water) for at least 
10 hours before study drug administration in the morning. Subjects will remain fasted for 
4 hours after dosing with study drug and thereafter receive standardized meals scheduled at 
the same time throughout the study. Water (other than the water consumed with the 
administration of vonoprazan Treatment B, D and E) is permitted as desired except for 1 hour 
before and 1 hour after administration of vonoprazan.  
• The subject should not chew the vonoprazan ODT or tablet. 
• The subject should remain in an upright (seated or standing) position for at least 4 
hours following dosing. 
Treatment A and C 
Administer the vonoprazan ODT on the tongue, allow it to disintegrate and swallow without 
water.  
Treatment B and D 
Prepare the dose just prior to administration and administer the vonoprazan ODT as follows:  
1. Place one vonoprazan ODT in a 20 mL oral syringe and draw up 5 mL of room 
temperature water. 
2. Swirl the syringe gently to dissolve.  
3. After the ODT has dissolved, administer the entire contents of the syringe 
immediately into the mouth.  

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Treatment E 
Administer the vonoprazan tablet whole with 240 mL of room temperature water and 
swallow immediately. 
5.3 
Identity of Investigational Product  
Vonoprazan study medication will be supplied as 10 mg ODT-1, 10 mg ODT-2 and 10 mg 
tablets. 
manufactures the vonoprazan 
fumarate drug substance. The vonoprazan ODTs are manufactured and packaged by 
 
. The vonoprazan tablets are 
manufactured and packaged by 
 
 applies the clinical labels and distributes to the clinical 
site. 
Vonoprazan ODT-1 contains 10 mg vonoprazan free base (MW 345.39) and the following 
inactive excipients: 
 
 
Vonoprazan ODT-2 contains 10 mg vonoprazan free base (MW 345.39) and the following 
inactive excipients: 
 
Vonoprazan tablets contain 10 mg vonoprazan free base (MW 345.39) and the following 
inactive excipients: 
 
 
 
5.4 
Management of Clinical Supplies 
5.4.1 
Study Drug Packaging and Storage 
Phathom will provide the investigator and clinical unit with adequate quantities of 
vonoprazan ODT-1, ODT-2, and vonoprazan tablets for the conduct of the study plus required 
retention samples [DHHS 2024]. The vonoprazan ODT-1 will be supplied in 6-count blisters. 
The vonoprazan ODT-2 will be supplied in 10-count blisters.  The vonoprazan tablets will be 
provided in 30-count high-density polyethylene bottles. The clinical unit pharmacy will 
prepare the study treatments for each subject according to the SoE (Section 13.1). 

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Study supplies must be stored in a secure area (eg, a locked cabinet), protected from 
moisture, and kept at a controlled room temperature (20°C to 25°C [68°F to 77°F]; 
excursions are allowed between 15°C and 30°C [59°F to 86°F]) until they are used or 
returned to the sponsor or designee for destruction. Study drug must be stored under the 
conditions specified on the label and remain in the original container until dispensed. 
5.4.2 
Study Drug Accountability 
The investigator will maintain accurate records of receipt of all study drug, including dates of 
receipt. In addition, accurate records will be kept regarding when and how much study drug 
is dispensed and used by each subject in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study drug will be reconciled and 
retained or destroyed according to applicable regulations. 
5.5 
Overdose Management 
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. 
Cases of overdose without manifested signs or symptoms are not considered AEs. Adverse 
events associated with an overdose will be documented on the AE eCRF(s) according to 
Section 6.3.1.3.1. The SAEs associated with overdose should be reported according to the 
procedure outlined in Section 6.3.1.3.2. 
5.6 
Blinding 
This is an open-label study. 
5.7 
Study Compliance 
5.7.1 
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 by conducting a hand and mouth check for 
each treatment administered. 

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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. 
5.8 
Prior and Concomitant Medications and Therapies 
Restrictions for prior and concomitant medications and therapies are provided in 
Section 4.1.2. 
5.8.1 
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. 
5.8.2 
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. 

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6 
Study Assessments and Procedures 
Prior to undergoing any protocol-specific procedures or assessments, all potential subjects 
must sign and date the ICF. Subjects will have the opportunity to have any questions 
answered before signing the ICF. The investigator must address all questions raised by the 
subject. The investigator or designee will also sign and date the ICF. 
Study procedures and their timing are summarized in the Schedule of Events (SoE) 
(Section 13.1). Adherence to the study design requirements, including those specified in the 
SoE, is essential and required for study conduct. All safety concerns should be discussed with 
the principal investigator and medical monitor immediately to determine if any active 
intervention is needed, including action taken with study drug. All screening evaluations 
must be completed and reviewed to confirm that potential subjects meet all eligibility criteria. 
The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
6.1 
Pharmacokinetic Assessments 
The following PK parameters for vonoprazan will be calculated as endpoints using standard 
noncompartmental methods: AUC0-t, AUC0-inf, Cmax, the time to maximum observed plasma 
concentration (tmax), time until first measurable concentration in plasma (tlag), terminal 
elimination rate constant (λz), terminal phase half-life (t1/2), apparent oral 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. The secondary 
endpoints will be tmax, tlag, λz, t1/2, CL/F, and Vz/F of vonoprazan. 
The timing and frequency of PK sample collection is listed in the SOE (Section 13.1). 
Blood samples will be collected into sodium heparin vacutainer collection tubes and 
processed into plasma. Details of collection, processing, storage and shipping will be 
contained in the Clinical Laboratory Manual. 
Bioanalytical Methods 
Plasma concentrations of vonoprazan will be measured at 
 
 using a validated liquid chromatography/mass spectrometry 

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method with an analytical range of 0.1 to 100 ng/mL and will be used for the calculation of 
the plasma vonoprazan PK parameters. 
6.2 
Other Assessments  
6.2.1 
Taste Assessment 
After receiving each of Treatments A, B, C, and D, subjects will complete a taste assessment 
(Section 13.4).  
6.3 
Safety Assessments 
6.3.1 
Pretreatment Events and Adverse Events 
6.3.1.1 Definitions  
6.3.1.1.1 Definitions of Pretreatment Adverse Events 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject 
whose informed consent to participate in a study has been signed, which has occurred prior to 
administration of any study drug; it does not necessarily have to have a causal relationship 
with study participation. 
6.3.1.1.2 
Definitions of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to study drug. An AE can therefore be an unfavorable 
sign or symptom, or a disease temporally associated with the use of study drug. 
A treatment-emergent adverse event (TEAE) is defined as any event that occurs after the first 
dose of study drug or any event at baseline that worsens in either intensity or frequency after 
the first dose of study drug until 30 days after the last dose of study drug. 

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

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Table 6-1 
Medically Significant Adverse Event List 
Term 
Acute respiratory failure / acute respiratory distress syndrome 
Torsade de pointes / ventricular fibrillation / ventricular tachycardia 
Malignant hypertension 
Convulsive seizure  
Agranulocytosis  
Aplastic anemia  
Toxic epidermal necrolysis/Stevens-Johnson syndrome  
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis 
Confirmed or suspected endotoxin shock 
Confirmed or suspected transmission of infectious agent by a medicinal product 
Neuroleptic malignant syndrome / malignant hyperthermia 
Spontaneous abortion / stillbirth and fetal death 
 
The PTEs that fulfill one or more of the serious criteria above are also to be considered SAEs 
and should be reported and followed up in the same manner (see Section 6.3.1.3.2 and 
Section 6.3.1.3.3). 
If a subject is noted to have an alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) value >3 × the upper limit of normal (ULN) and a total bilirubin value >2 × ULN, for 
which an alternative etiology has not been identified, the event should be recorded as an SAE 
and reported as per Section 6.3.1.3.2. The investigator must contact the medical monitor for 
discussion of the relevant subject details and possible alternative etiologies, such as acute 
viral hepatitis A or B or other acute liver disease or medical history or concurrent medical 
conditions. Follow-up laboratory tests, as described in Section 6.3.3, must also be performed. 
In addition, if the LFT increases are SAEs, a Liver Function Test Increase Form must be 
completed and transmitted (see Section 13.3). 

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6.3.1.1.4 
Adverse Events of Special Interest 
An AE of special interest is a noteworthy event for the particular product or class of products 
that a sponsor may wish to monitor carefully. It could be serious or nonserious (eg, hair loss, 
loss of taste, impotence), and could include events that might be potential precursors or 
prodromes for more serious medical conditions in susceptible individuals. 
Adverse events of special interest include any event listed in Table 6-2. 
Table 6-2 
Adverse Events of Special Interest List 
Term 
Hepatotoxicity  
Severe cutaneous adverse reactions, including hypersensitivity 
Clostridium difficile infections and pseudomembranous colitis 
Hypersensitivity reactions (anaphylaxis)  
Acute interstitial nephritis/tubulointerstitial nephritis   
Bone fracture 
Hematologic abnormalities 
Gastric cancer 
Vitamin B-12 deficiency 
Hypomagnesemia 
Lupus erythematosus 
 
For additional details on liver function monitoring, see Section 13.3. 
6.3.1.1.5 
Additional Points to Consider for PTEs and AEs 
An untoward finding generally may involve the following: 
• Indicates a new diagnosis or unexpected worsening of a pre-existing condition. 
(Intermittent events for pre-existing conditions or underlying disease should not be 
considered PTEs or AEs.) 
• Necessitates therapeutic intervention. 
• Requires an invasive diagnostic procedure. 

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• Requires discontinuation or a change in dose of study drug or a concomitant 
medication. 
• Is considered unfavorable by the investigator for any reason.  
• Is caused by a study procedure (eg, a bruise after blood collection); these events 
should be recorded as a PTE/AE. 
Diagnoses versus signs and symptoms: 
• Each event is required to be recorded to represent a single diagnosis or disorder using 
standard medical terminology rather than individual symptoms. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should 
be recorded appropriately as a PTE(s) or as an AE(s).  
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG parameters are only considered to be PTEs or 
AEs if they are judged to be clinically significant (eg, if some action or intervention is 
required or if the investigator judges the change to be beyond the range of normal 
physiologic fluctuation). A laboratory retest and/or continued monitoring of an 
abnormal value are not considered an intervention. In addition, repeated or additional 
noninvasive testing for verification, evaluation, or monitoring of an abnormality is 
not considered an intervention. 
• If abnormal laboratory values or ECG findings are the result of a pathology for which 
there is an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis 
only should be reported as a PTE or as an AE. 
Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing informed consent) are 
considered concurrent medical conditions and should NOT be recorded as PTEs or 
AEs. Abnormal findings identified at baseline evaluations and screening assessments 
(eg, laboratory tests, ECG, endoscopy, or X-rays) should NOT be recorded as PTEs 
unless related to study procedures. However, if the subject experiences a worsening or 

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complication of a concurrent condition, the worsening or complication should be 
recorded appropriately as a PTE (worsening or complication occurs before start of 
study drug) or an AE (worsening or complication occurs after start of study drug). 
Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”). 
• If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any 
occurrence of an episode should only be captured as a PTE/AE if the episodes 
become more frequent, serious, or severe in nature, that is, investigators should 
ensure that the AE term recorded captures the change in the condition from baseline 
(eg “worsening of…”).  
• If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be captured as a PTE/AE if 
occurring to a greater extent than that which would be expected. Again, investigators 
should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”). 
Worsening of PTEs or AEs: 
• If the subject experiences a worsening or complication of a PTE after starting 
administration of the study drug, the worsening or complication should be recorded 
appropriately as an AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).  
• If the subject experiences a worsening or complication of an AE after any change in 
study drug, the worsening or complication should be recorded as a new AE. 
Investigators should ensure that the AE term recorded captures the change in the 
condition (eg, “worsening of…”). 
• At each required study visit, all AEs that have occurred since the previous visit or 
AEs that have changed in severity since the previous visit must be recorded in the AE 
record of the eCRF. 
Changes in severity of AEs/serious PTEs: 

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• If the subject experiences change in severity of an AE/serious PTE, the event should 
be captured once with the maximum severity recorded. 
Preplanned procedures:  
• Preplanned procedures that were scheduled prior to signing of informed consent are 
not considered PTEs or AEs. However, if a preplanned procedure is performed early 
(eg, as an emergency) due to a worsening of the pre-existing condition, the worsening 
of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned procedure should be reported as AEs. 
Elective surgeries or procedures:  
• Elective procedures performed where there is no change in the subject’s medical 
condition should not be recorded as PTEs or AEs but should be documented in the 
subject’s source documents. Complications resulting from an elective surgery should 
be reported as AEs. 
Overdose: 
• Any manifested side effects will be considered AEs and will be recorded on the AE 
page of the eCRF. 
6.3.1.2 Documenting Adverse Events 
6.3.1.2.1 Assessment of Severity 
The severity or intensity of an AE refers to the extent to which an AE affects the subject’s 
daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual 
activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
 

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Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of onset and duration of each episode. 
6.3.1.2.2 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The relationship or association of each AE to study drug(s) will be assessed using the 
following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of study 
drug (including the course after withdrawal of the drug), or for which possible 
involvement of the drug cannot be ruled out, although factors other than the 
study drug, such as underlying diseases, complications, concomitant drugs, and 
concurrent treatments, may also be responsible. 
Not 
Related: 
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant drugs, and concurrent 
treatments. 
 
6.3.1.2.3 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as not related. 
6.3.1.2.4 Start Date and Time 
The start date and time of the AE/PTE is the date and time that the first signs/symptoms were 
noted by the subject and/or physician. 

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6.3.1.2.5 Stop Date and Time 
The stop date and time of the AE/PTE is the date and time at which the subject recovered, the 
event resolved but with sequelae, or the subject died. 
6.3.1.2.6 Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of 
consecutive days are considered intermittent. All other events are considered continuous. 
6.3.1.2.7 Action Concerning Study Drug 
• Drug withdrawn: A study drug is stopped due to the particular AE. 
• Dose not changed: The particular AE did not require stopping a study drug. 
• Unknown: Only to be used if it has not been possible to determine what action has 
been taken. 
• Not applicable: A study drug was stopped for a reason other than the particular AE, 
eg, the study has been terminated, the subject died, or dosing with the study drug was 
already stopped before the onset of the AE. 
• Dose interrupted: The dose was interrupted/held due to the particular AE. 
6.3.1.2.8 Outcome 
• Recovered/resolved: Subject returned to baseline status with respect to the AE/PTE. 
• Recovering/resolving: The intensity is lowered by one or more stages: the diagnosis 
or signs/symptoms have lessened/improved; the abnormal laboratory value improved 
but has not returned to the normal range or to baseline; or the subject died from a 
cause other than the particular AE/PTE with the condition remaining 
“recovering/resolving.” 
• Not recovered/not resolved: There is no change in the diagnosis, signs, or symptoms; 
the intensity of the diagnosis, signs/symptoms, or laboratory value on the last day of 
the observed study period has worsened from when it started; is an irreversible 

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congenital anomaly; or the subject died from another cause with the particular 
AE/PTE state remaining “Not recovered/not resolved.” 
• Resolved with sequelae: Subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but 
with some persisting paresis). 
• Fatal: The AEs/PTEs are considered the cause of death. 
• Unknown: The course of the AE/PTE cannot be followed up due to a hospital change 
or residence change at the end of the subject’s participation in the study. 
6.3.1.3 Time Period and Frequency for Collecting AE and SAE 
Information 
6.3.1.3.1 Collection and Reporting of Adverse Events 
Collection of PTEs will commence from the time the informed consent to participate in the 
study has been signed and will continue until the subject is first administered study drug or 
until screen failure. For subjects who discontinue the study prior to study drug 
administration, PTEs are collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered study 
drug (Day 1). Routine collection will continue until the follow-up phone call or withdrawal 
from the study. 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing 
a serious PTE must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline or there is a satisfactory explanation 
for the change. Nonserious PTEs, related or unrelated to the study procedure, need not be 
followed up for the purposes of the protocol. All subjects experiencing AEs, whether 
considered associated with the use of the study drug or not, must be monitored until the 
symptoms subside and any clinically relevant changes in laboratory values have returned to 
baseline or until there is a satisfactory explanation for the changes observed. 

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All PTEs and AEs will be documented in the PTE/AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event: 
• Event term 
• Start and stop date and time 
• Severity 
• Investigator’s opinion of the causal relationship between the event and administration 
of study drug(s) (related or not related) (not completed for PTEs) 
• Investigator’s opinion of the causal relationship to study procedure(s), including the 
details of the suspected procedure 
• Action concerning study drug (not applicable for PTEs) 
• Outcome of event 
• Seriousness 
6.3.1.3.2 Collection and Reporting of Serious Adverse Events 
When an SAE occurs through the AE collection period, it should be reported according to the 
following procedure:  
An SAE eCRF must be completed and submitted via Medidata Rave immediately or within 
24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious 
• Subject identification number 
• Investigator’s name 
• Name of the study drug(s) 

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• Causality assessment 
If the Medidata Rave system is not functioning for any reason, a paper SAE case report form 
must be completed (in English), signed by the investigator, and faxed to the contact listed 
below. 
The SAE form should be transmitted within 24 hours to 
 Pharmacovigilance. 
 
 24-Hour Safety Contact Information 
 
SAE Hotline: 
 
SAE Fax: 
 
 
Any SAE spontaneously reported to the investigator following the AE collection period 
should be reported to the sponsor if considered related to study participation. 
Investigators are not obligated to actively seek information regarding new AEs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a subject has been discharged from the study, and he/she 
considers the event to be reasonably related to the study drug or study participation, the 
investigator must promptly notify the sponsor. Reporting of serious PTEs will follow the 
procedure described for SAEs. 
6.3.1.3.3 Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator should update the SAE eCRF and transmit it immediately within 24 hours of 
receipt. Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, 
discharge summary, postmortem results) should be provided, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 

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6.3.1.3.4 Safety Reporting to Investigators, IRB/IECs, 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 the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC), as applicable in 
accordance with the national regulations in the countries 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 study. The study 
site also will forward a copy of all expedited reports to their IRB or IEC in accordance with 
local regulations.  
6.3.2 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 13.2). 
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 6.3.1.3.2. If the female subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject was 
participating in a clinical study at the time she became pregnant and provide details of the 
treatment the subject received. All pregnancies in subjects receiving study drug will be 
reported using the pregnancy form and will be followed up to final outcome. The outcome, 
including any premature termination, must be reported to the sponsor. An evaluation after the 
birth of the child will also be conducted. 

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6.3.3 
Laboratory Analyses 
See Table 6-3 for the list of clinical laboratory tests to be performed and the SoE 
(Section 13.1) for the timing and frequency. 
• The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Abnormal 
laboratory findings that are expected with the underlying disease should not be 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the subject’s condition. 
• All laboratory tests with abnormal values considered clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the 
sponsor notified. 
o All protocol-required laboratory assessments, as defined in Table 6-3, must be 
conducted in accordance with the laboratory manual and the SoE. 
 If laboratory values from non–protocol-specified laboratory 
assessments performed at the institution’s local laboratory require a 
change in subject management or are considered clinically significant 
by the investigator (eg, SAE, AE, or dose modification), then the 
results must be recorded in the unscheduled laboratory eCRF. 
All samples will be collected in accordance with acceptable laboratory procedures. Details of 
these procedures and required safety monitoring will be provided in the laboratory manual. 
All study-required laboratory assessments will be performed by a central laboratory. 

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Table 6-3 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
• 
Platelet count 
• 
RBC count 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC indices: MCV, MCH 
• 
WBC count with differential: neutrophils, lymphocytes, monocytes, eosinophils, 
basophils 
Clinical 
chemistry a 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Total and direct bilirubin 
• 
ALT/SGPT 
• 
AST/SGOT 
• 
Alkaline phosphatase 
• 
Magnesium 
• 
Total protein 
• 
Potassium 
• 
Sodium 
• 
Calcium 
• 
Glucose  
• 
GGT 
• 
eGFR 
Routine 
urinalysis 
• 
Specific gravity, appearance, color, turbidity 
• 
pH, glucose, protein, occult blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase 
• 
Microscopic examination (if blood or protein is abnormal) 
Other 
screening tests 
• 
COVID-19 
• 
FSH if menopause is suspected b 
• 
Serology (HIV antibody type 1 and 2, HBsAg, and HCV antibody) 
• 
Urine alcohol, cotinine and drug screen including amphetamines (including 
methamphetamine), barbiturates, benzodiazepines, cocaine, opiates, methadone, and 
phencyclidine 
• 
Serum hCG pregnancy test at Screening and Check-in 
• 
Urine hCG pregnancy test at Check-out/Early Termination  
ALT: alanine aminotransferase; AST: aspartate aminotransferase; eGFR: estimated glomerular filtration rate; 
FSH: follicle stimulating hormone; GGT: gamma-glutamyl transferase; HBsAg: hepatitis B surface antigen; 
hCG: human chorionic gonadotropin; HCV: hepatitis C virus; HIV: human immunodeficiency virus; 
MCH: mean corpuscular hemoglobin; MCV: mean corpuscular volume; RBC: red blood cell; SGOT: serum 
glutamic-oxaloacetic transaminase; SGPT: serum glutamic-pyruvic transaminase; WBC: white blood cell 
a 
See Section 13.3 for the appropriate guidance on reporting of abnormal liver function tests. For liver 
function test monitoring, see Section 13.3.1. For temporary and permanent discontinuation of study 
drugs due to abnormal liver function tests, see Section 13.3.2 and Section 13.3.3, respectively. 
b 
Required only for confirmation of postmenopausal females. Female subjects whose duration of 
(consecutive) amenorrhea is borderline or open to doubt and where the investigator believes the subject 
to be menopausal by history should have confirmatory FSH drawn. 
 
Investigators must document their review of each laboratory safety report. 

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6.3.4 
Physical Examinations 
Refer to the SoE (Section 13.1) for the timing and frequency for full and brief physical 
examinations, as well as height and body weight. BMI equals a subject’s weight in kilograms 
divided by the height in meters squared.  
A complete physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and body 
weight will also be measured and recorded. The subject should be dressed in light clothing 
and without shoes when the body weight is being measured. 
A brief physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, and gastrointestinal systems. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
6.3.5 
Vital Signs 
Refer to the SoE (Section 13.1) for the timing and frequency of vital sign assessments.  
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and 
temperature.  
6.3.6 
Electrocardiograms 
Refer to the SoE (Section 13.1) for the timing and frequency of ECG assessments.  
A single, standard 12-lead ECG recording will be made after the subject has been in the 
supine position for at least 5 minutes. A single repeat measurement is permitted during the 
screening period for eligibility determination. Assessments will include whether the tracings 
are normal or abnormal (if abnormal, whether clinically significant or not clinically 
significant). 

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7 
Statistical and Analytical Plan 
This section describes the statistical and analytical methods to be used for the study.  
7.1 
Sample Size Calculations 
This crossover study will enroll 25 subjects to ensure 20 evaluable subjects, assuming an 
approximate dropout rate of 20%. With 20 evaluable subjects, the study will provide at least 
95% power to conclude bioequivalence between the test treatments (A, B, C, and D) and the 
reference treatment (E). This assumes that the vonoprazan PK parameters Cmax, AUC0-t, and 
AUC0-inf are log-normally distributed, there is no more than a 5% difference between the true 
geometric means, and the intrasubject coefficient of variation is no greater than 16%.  
Subjects will be randomly assigned to 1 of 5 treatment sequences in a 1:1:1:1:1 ratio. 
7.2 
Analysis Sets 
The PK population will include subjects who receive at least 1 dose of study drug and have 
sufficient concentration data to support accurate estimation of at least 1 PK parameter. 
Subjects who experience vomiting within 4 hours after study drug dosing will be excluded 
from the PK analysis for that treatment. 
The safety population will include all subjects who receive at least 1 dose of study drug. 
7.3 
Statistical Analysis Methodology 
7.3.1 
Pharmacokinetic Analyses 
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, standard deviation 
(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 Phoenix® WinNonlin® (Certara USA Inc., 
Princeton, New Jersey) or SAS® (SAS Institute Inc., Cary, North Carolina). The individual 
PK parameters will be presented in data listings and summarized by treatment using the 

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following descriptive statistics: number of subjects, mean, SD, CV, geometric mean, 
geometric CV, median, minimum, and maximum. For tmax and tlag only median, minimum, 
and maximum will be reported. 
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 AUC0t, AUC0-inf, and Cmax. The ratio of geometric least square means (Treatment A, 
Treatment B, Treatment C, and Treatment D versus Treatment E) and corresponding 90% CIs 
will be computed for AUC0-t, AUC0-inf, and Cmax by taking the antilog of the difference of 
least square means and associated 90% confidence intervals (CI) from the linear mixed effect 
model analyzing 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/E), (B/E), (C/E) and (D/E) of 
the geometric means and their corresponding CIs for AUC0-t, AUC0-inf, and Cmax. Relative BA 
will also be reported for the comparison of each ODT mixed with water to the ODT without 
water (B/A and D/C). Bioequivalence will be concluded if the 90% CI for the geometric 
mean ratio (GMR) between the test treatment (A, B, C or D) and the reference treatment (E) 
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 
Exploratory Analyses 
Individual responses to the taste assessment (Section 13.4) will be presented in a data listing. 
Responses will be tabulated and summarized with histograms for each question and 
formulation assessed.  Responses for each question will also be summarized by treatment 
using the following descriptive statistics: number of subjects, arithmetic mean, SD, CV, 
median, minimum, and maximum. Additional summaries or analyses may be performed if 
appropriate. 
7.3.3 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent 
AEs will be summarized by treatment and overall, as well as by severity and relationship to 

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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, standard deviation, median, minimum, and 
maximum). Shift tables will be generated for clinical laboratory test results. 
7.4 
Handling of Missing Data 
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero 
for descriptive statistics.  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. 
7.5 
Interim Analyses 
No formal interim analyses will be performed in this study. 
 

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8 
Data Quality Assurance 
This study will be conducted according to the International Council for Harmonisation (ICH) 
E6(R3) risk and quality processes described in the applicable procedural documents. The 
quality management approach to be implemented in this study will be documented and will 
comply with the current ICH guidance on quality and risk management [DHHS 2023]. The 
sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). 
8.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include laboratory reports and ECG 
strips.  
Investigative site personnel will enter subject data into electronic data capture. The analysis 
data sets will be a combination of these data and data from other sources (eg, laboratory 
data). 
Clinical data management will be performed in accordance with applicable sponsor’s 
standards and data cleaning procedures to ensure the integrity of the data, eg, correcting 
errors and inconsistencies in the data. Adverse event terms will be coded using the MedDRA, 
and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. 
After the database lock, each study site will receive a file containing all of their site-specific 
eCRF data as entered into Medidata Rave for the study, including full discrepancy and audit 
history. Additionally, a file of all of the study site’s data from the study will be created and 
sent to the sponsor for storage. 
 will maintain a duplicate file for their records. In all 
cases, subject initials will not be collected or transmitted to the sponsor. 

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9 
Ethics 
9.1 
Institutional Review Board 
Federal regulations, national regulations, and the ICH guidelines require that approval be 
obtained from an IRB/IEC before participation of human subjects in research studies. Before 
study onset, the protocol, informed consent, advertisements to be used for the recruitment of 
study subjects, and any other written information regarding this study to be provided to the 
subject must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and of 
the IRB/IEC compliance with ICH GCP will be maintained by the site and will be available 
for review by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairperson or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
9.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
All potential serious breaches must be reported to the sponsor or designee immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the 
study or the protocol which is likely to affect to a significant degree the safety or physical or 
mental integrity of the subjects of the study or the scientific value of the study. 
9.3 
Subject Information and Consent 
A written informed consent in compliance with regulatory authority regulations shall be 
obtained from each subject before the entering the subject in the study or performing any 
unusual or nonroutine procedure that involves risk to the subject. Participating subjects will 
provide assent as applicable. An informed consent template may be provided by the sponsor 

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to investigative sites. If any institution-specific modifications to study-related procedures are 
proposed or made by the site, the consent and assent materials should be reviewed by the 
sponsor or its designee or both before IRB/IEC submission. Once reviewed, the consent and 
assent materials will be submitted by the investigator to his or her IRB/IEC for review and 
approval before the start of the study. If the ICF or assent form is revised during the course of 
the study, the active participating subject must sign the revised form as applicable. 
Before recruitment and enrollment, each prospective subject will be given a full explanation 
of the study and be allowed to read the approved ICF and assent form (if applicable). Once 
the investigator is assured that the subject understands the implications of participating in the 
study, the subject will be asked to give consent to participate in the study by signing the ICF. 
If applicable, the subject will be asked to give assent by signing the assent form. 
The investigator shall retain the signed original form(s) and give a copy of the signed original 
form(s) to the subject. 

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

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Neither the sponsor nor 
 is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor 
 is financially responsible for 
further treatment of the subject’s disease. 
10.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6 Section II 
and Title 21 of the CFR by providing the following essential documents, including but not 
limited to the following: 
• IRB/IEC approval 
• Original investigator-signed investigator agreement page of the protocol 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 for US sites and equivalent form for non-US sites 
• Curriculum vitae for the investigator and each subinvestigator listed on Form 
FDA 1572 or equivalent form for non-US sites 
• Financial disclosure information to allow the sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR 54. In addition, 
the investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study. 
• IRB/IEC-approved informed consent and assent (if applicable), samples of site 
advertisements for recruitment for this study, and any other written information 
regarding this study that is to be provided to the subject  
• Laboratory certifications and normal ranges for any local laboratories used by the 
site, in accordance with 42 CFR 493 
10.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6. The investigator will conduct all aspects of this study in accordance with all 

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

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will be submitted, and other related issues. The sponsor has final approval authority over all 
such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 

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11 Study Management 
11.1 Monitoring 
The clinical monitor, acting as the main line of communication between the sponsor (or 
designee) and the investigator and as a representative of the sponsor, has the obligation to 
follow the study closely. In doing so, the monitor will visit the investigator and study site at 
periodic intervals, in addition to maintaining necessary telephone and letter contact. The 
monitor will maintain current personal knowledge of the study through observation, review 
of study records and source documentation, and discussion of the conduct of the study with 
the investigator and personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.1 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, representatives 
of the sponsor, or a regulatory agency access to all study records. 
The investigator should promptly notify the sponsor and 
 of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB/IEC for approval before subjects can be enrolled into an amended protocol. 

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11.2.2 Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review, to the sponsor for agreement, and to the 
regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
subject or investigator that results in a significant additional risk to the subject. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, or nonadherence to 
FDA regulations or ICH GCP guidelines, and may lead to the subject being withdrawn from 
the study (Section 4.2). 
Protocol deviations will be documented by the investigative site staff, the clinical monitor, 
and/or the contract research organization throughout the course of the study. Principal 
investigators will be notified in writing by the monitor of any deviations discovered during a 
monitoring visit. The IRB/IEC should be notified of all protocol deviations they consider 
reportable in a timely manner. 
11.3 Study Termination 
Although the sponsor has every intention of completing the study, the sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last subject completes the follow-up 
phone call. 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 

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reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
The sponsor will submit to clinical trial registries a summary of the results of the clinical trial 
and where applicable a summary that is understandable to a layperson, and the clinical study 
report health authorities, within 6 months after the end of the study. The investigator is 
encouraged to share the summary results with study subjects, as appropriate.  

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12 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). Draft Guidance for industry: E6(R3) Good Clinical Practice (GCP) June 
2023. [cited 2024 Jul 08] Available from: https://www.fda.gov/media/169090/download  
Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), 
Health and Human Services (HHS), Handling and Retention of BA and BE Testing Samples; 
Draft Guidance for Industry; March 2024. [cited 2024 Oct 21] Available from: 
https://www.fda.gov/media/71393/download. 
Engevik AC, Kaji I, Goldenring JR. The physiology of the gastric parietal cell. Physiol 
Rev 2020;100(2):573-602. 
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):636-648. 
Laine L, Sharma P, Mulford D, et al. Pharmacodynamics and pharmacokinetics of the 
potassium-competitive acid blocker vonoprazan ad the proton pump inhibitor lansoprazole in 
US subjects. Am J Gastroentrol. 2022; 117(7): 1158-1161. 
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):719-730. 
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):344–355. 
Scott DR, Munson KB, Marcus EA, Lambrecht NW, Sachs G. The binding selectivity of 
vonoprazan (TAK-438) to the gastric H+, K+ -ATPase. Aliment Pharmacol Ther 
2015;42(11-12):1315-1326. 
Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. 
J Neurogastroenterol Motil 2013;19(1):25-35. 

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VOQUEZNA® (vonoprazan) Tablets [package insert] Buffalo Grove, Illinois. Phathom 
Pharmaceuticals, Inc.; July 2024.  
 

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13 Appendices

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13.1 Appendix 1: Schedule of Events  
 
 
 
 
 
 
 
 

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Abbreviations: AE: adverse event; BMI: body mass index; COVID-19: coronavirus disease 2019; ECG: electrocardiogram; EOS: end of study; ET: Early 
Termination; 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 5 days between study drug dosing in each period. 
(c) Discharge will occur following the last study assessment on Day 23 (ie, Day 3 of Period 5). 
(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) Female subjects 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 Check-out (Day 
23/Early Termination. 
(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 Check-out 
(Day 23)/Early Termination (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 Check-out (Day 23)/Early 
Termination. 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 Check-out (Day 23)/Early Termination 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; 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 Check-out (Day 23)/Early Termination. A complete list of assessments is provided in 
Section 6.3.2. Blood and urine samples will be collected and prepared per the clinic’s standard procedures; blood samples will be collected under fasted 
conditions. 
(l) All female subjects will have a serum pregnancy test performed at Screening and Check-in. At Check-out (Day 23)/Early Termination, a urine pregnancy test 
will be performed, and if the test result is positive, a serum pregnancy test will be performed for confirmation. 
(m) Guidance on pregnancy avoidance at Screening, Check-in and Check-out (Day 23)/Early Termination  
(n) Subjects will be randomized only on Day 1 of Period 1. 
(o) The time of vonoprazan dosing will be called “0” hour in each period and is denoted with gray shading. Study drug will be administered as outlined in 
Section  3.1.  Subjects will maintain an upright (ie, seated or standing) position for at least 4 hours after dosing. 

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(p) 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 post dose will be ±30 
minutes. 
(q) Subjects assigned to each treatment will undergo fasting period. Further details are provided in Section 5.2.  
(r) Taste assessment should be completed between the 15-minute and the 30-minute PK sample collections. Completion of the taste assessment should not 
interfere with the timing of the PK sample collections. 
(s) Collection of PTEs will start after the subject has signed the ICF. 
(t) 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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13.2 Appendix 2: Contraceptive Guidance 
Contraception Guidance: 
From signing of informed consent, throughout the duration of the study, and for 4 weeks after 
the last dose of study drug, female subjects of childbearing potential who are sexually active 
must use adequate contraception.  
Birth Control: Birth control methods considered acceptable for this study include: 
Barrier methods (each time that you have intercourse): 
• Male condom PLUS spermicide 
• Cap (plus spermicidal cream or jelly) PLUS male condom and spermicide 
• Diaphragm (plus spermicidal cream or jelly) PLUS male condom and spermicide 
Intrauterine Devices  
• Copper T PLUS condom or spermicide 
• Progesterone T PLUS condom or spermicide 
Hormonal Contraceptives 
• Implants 
• Hormone shot/injection 
• Combined pill 
• Minipill 
• Patch 
• Vaginal ring PLUS male condom and spermicide 
During the course of the study, serum human chorionic gonadotropin (hCG) will be 
performed at Screening and regular urine hCG pregnancy tests will be performed for all 
female subjects. Subjects will receive continued guidance with respect to the avoidance of 
pregnancy as part of the study procedures (Section 13.1). Female subjects must have a 
negative serum hCG pregnancy test on Day -1 prior to study drug dispensation. 

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13.3 Appendix 3: Liver Function Tests 
13.3.1 Liver Function Test Monitoring 
Liver function will be carefully monitored throughout the study. Additional monitoring may 
be necessary and is recommended for subjects with abnormal LFTs. 
If subjects with normal baseline ALT or AST levels experience ALT or AST >3 × ULN and a 
2-fold increase above baseline, follow-up laboratory tests (at a minimum, serum alkaline 
phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase (GGT), and international 
normalized ratio [INR]) should be repeated within a maximum of 7 days and preferably 
within 48 to 72 hours after the abnormality was found. 
If subjects with normal ALT or AST levels experience ALT or AST >8 × ULN, follow-up 
laboratory tests (at a minimum, serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, 
and INR) should be repeated within a maximum of 48 hours after the abnormality was found. 
13.3.2 Considerations for Temporary Discontinuation of Study Drug 
If the ALT or AST levels remain elevated >3 × ULN in subjects with normal baseline ALT or 
AST levels and a 2-fold increase above baseline OR if the ALT or AST levels remain 
elevated >5 × ULN in subjects with elevated baseline ALT or AST levels on 2 consecutive 
occasions, the investigator must contact the medical monitor to discuss additional testing, 
recommended monitoring, possible temporary discontinuation of study drug, and possible 
alternative etiologies. 

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13.3.3 Permanent Discontinuation of Study Drug 
If any of the circumstances occur as mentioned in Table 13-1 at any time during treatment, 
the study drug should be permanently discontinued: 
Table 13-1 
Abnormal Liver Function Criteria for Permanent Discontinuation of 
Study Drug 
Criteria for Discontinuation of Study Drug 
• 
ALT or AST >8 × ULN  
• 
ALT or AST >5 × ULN and persists for more than 2 weeks 
• 
ALT or AST >3 × ULN AND a 2-fold increase above baseline value in conjunction with elevated 
total bilirubin >2 × ULN or INR >1.5 
• 
ALT or AST >3 × ULN AND a 2-fold increase above baseline value with appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; INR: international normalized ratio; 
ULN: upper limit of normal 
 
In each of these instances, appropriate clinical follow-up should be instituted (including 
repeat laboratory tests) until a satisfactory conclusion (ie, until the AE resolves, the 
laboratory value returns to baseline, or the condition becomes stable). 
If a subject meets the liver safety criteria and must be discontinued from study drug, the 
subject will continue to be followed per the protocol schedule until the study is completed. 
If the subject refuses to return for the study visits, telephone visits may be conducted; 
however, this is not preferred or recommended. The reason for discontinuation of study drug 
should be listed as an LFT abnormality. 

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If any of the above circumstances occur at any time during the study, the abnormality should 
be documented as an SAE, and a Liver Function Test Increase Form completed and sent to:  
Pharmacovigilance 
. 
 
 
24-Hour Safety Contact Information 
SAE Hotline: 
 
SAE Fax: 
 
 
13.3.4 Re-initiation of Study Drug 
If the study drug is discontinued due to any of the scenarios provided above, study drug must 
not be re-initiated without consultation with the medical monitor.  
 
 

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13.4 Appendix 4: Taste Assessment Questionnaire 
Taste Assessment Questionnaire 
Fill this out with respect to your opinion of today’s dose of study medication.  Mark only one 
response for each question. 
Subject Number:  __________________ 
Date (DD/MMM/YYYY): _________________________ 
Time (HH:MM): ___________________     __ AM       __ PM 
Please rate the TASTE of the study medication: 
____5 = totally acceptable 
____4 = quite acceptable 
____3 = somewhat acceptable 
____2 = slightly acceptable 
____1 = not at all acceptable 
 
Please rate the BITTERNESS of the study medication:  
____5 = not at all bitter  
____4 = slightly bitter  
____3 = moderately bitter  
____2 = very bitter  
____1 = extremely bitter 
 
Please rate the SWEETNESS of the study medication:  
____5 = extremely sweet  
____4 = very sweet  
____3 = moderately sweet 
____2 = slightly sweet 
____1 = not at all sweet 
 
Please rate the AFTERTASTE of the study medication:  
____5 = no aftertaste  
____4 = slight aftertaste  
____3 = moderate aftertaste  
____2 = strong aftertaste 
____1 = extreme aftertaste 
 

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Based on taste and acceptability, please rate your WILLINGNESS to take the study 
medication daily: 
____5 = I would take this medication daily 
____4 = I would likely take this medication daily 
____3 = I would possibly take this medication daily 
____2 = I would not likely take this medication daily 
____1 = I would not take this medication daily