Clinical trial NCT06391177
Conditions: Erosive Esophagitis Heartburn Symptomatic Nonerosive Gasroesophageal Reflux Disease Helicobacter Pylori Infection
Keywords: Healthy participants Helicobacter pylori infection Erosive Esophagitis Symptomatic nonerosive gasroesophageal reflux disease Heartburn Breast milk Lactating women
Sponsor: Phathom Pharmaceuticals, Inc.
Start date: 2024-05-07; Completion date: 2024-09-19
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to determine the pharmacokinetics (PK) of vonoprazan in breast milk of healthy lactating women who have received vonoprazan administered once daily or vonoprazan 20 mg administered twice daily for 4 consecutive days.

Detailed description:

Arms: arm 1: Participants will be administered once-daily doses of vonoprazan 20 mg for 4 consecutive days (Days 1 through 4). arm 2: Participants will be administered twice-daily doses of vonoprazan 20 mg for 4 consecutive days (Days 1 through 4).
Interventions: intervention 1: Vonoprazan
Intervention descriptions: intervention 1: Oral tablet.

Protocol documents:
Prot_000.pdf: 
Protocol Number: VONO-401 
 
 Official Title: A Phase 1, Open-label Study to Evaluate Vonoprazan Concentrations in Breast Milk 
of Healthy Lactating Women Receiving Vonoprazan 20 mg Once Daily or Vonoprazan 20 mg Twice 
Daily 
 
NCT Number: NCT06391177 
 
Document Date: 18 July 2024 


 
CLINICAL STUDY PROTOCOL 
IND 143190/144399 
A PHASE 1, OPEN-LABEL STUDY TO EVALUATE VONOPRAZAN 
CONCENTRATIONS IN BREAST MILK OF HEALTHY LACTATING 
WOMEN RECEIVING VONOPRAZAN 20 MG ONCE DAILY OR 
VONOPRAZAN 20 MG TWICE DAILY 
PROTOCOL NO. VONO-401 
Sponsor: 
Phathom Pharmaceuticals, Inc. 
2150 E. Lake Cook Road 
Suite 800 
Buffalo Grove, IL 60089 USA 
Sponsor Contact: 
 
 
Telephone: 
 
Medical Monitor: 
 Medical Monitor 
 
 
SAE Hotline (24 hour): 
 
SAE Fax: 
 
Version of Protocol: 
Version 2.0 
Date of Protocol:  
18 July 2024 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Phathom Pharmaceuticals, Inc. 
The study will be conducted according to the International Council for Harmonisation 
Guideline E6(R2): Good Clinical Practice. 


Phathom Pharmaceuticals, Inc. 
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Protocol No. VONO-401 
Clinical Study Protocol 
Page 2  
 
SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Phase 1, Open-Label Study to Evaluate Vonoprazan 
Concentrations in Breast Milk of Healthy Lactating Women 
Receiving Vonoprazan 20 mg Once Daily or Vonoprazan 
20 mg Twice Daily 
PROTOCOL NUMBER: 
VONO-401 
 
 
Phathom Pharmaceuticals, Inc. 
 
 
 
 
Phathom Pharmaceuticals, Inc. 
 
 
 
Clinical Pharmacology Consultant 
Phathom Pharmaceuticals, Inc. 
 
 
Docusign Envelope ID:


Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VONO-401 
Clinical Study Protocol Amendment 1 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree to conduct the study as outlined in the protocol titled “A Phase 1, Open-Label Study 
to Evaluate Vonoprazan Concentrations in Breast Milk of Healthy Lactating Women 
Receiving Vonoprazan 20 mg Once Daily or Vonoprazan 20 mg Twice Daily” in accordance 
with the guidelines and all applicable government regulations including United States 
Title 21 of the Code of Federal Regulations Part 54. I have read and understand all sections 
of the protocol. 
 
 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ...........................................................................................................................1 
SIGNATURE PAGE ................................................................................................................2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ......................................................3 
TABLE OF CONTENTS .........................................................................................................4 
1. 
INTRODUCTION ................................................................................................7 
1.1 
BACKGROUND ................................................................................................7 
1.2 
RATIONALE FOR STUDY ..............................................................................7 
1.3 
RATIONALE FOR DOSE SELECTION ...........................................................8 
2. 
STUDY OBJECTIVES .........................................................................................9 
3. 
STUDY DESIGN ...................................................................................................9 
3.1 
SCHEDULE OF EVENTS ...............................................................................12 
4. 
STUDY POPULATION ......................................................................................15 
4.1 
INCLUSION CRITERIA .................................................................................15 
4.2 
EXCLUSION CRITERIA ................................................................................16 
4.3 
WITHDRAWAL CRITERIA ...........................................................................17 
4.4 
SUBJECT REPLACEMENT ...........................................................................17 
4.5 
SCREEN FAILURES .......................................................................................18 
5. 
STUDY TREATMENTS ....................................................................................18 
5.1 
TREATMENTS ADMINISTERED .................................................................18 
5.2 
INVESTIGATIONAL PRODUCTS ................................................................18 
5.2.1 
Study Drug Preparation and Storage ............................................................18 
5.2.2 
Study Drug Accountability ...........................................................................19 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS .........19 
5.4 
BLINDING .......................................................................................................19 
6. 
STUDY PROCEDURES ....................................................................................19 
6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS ......................20 
6.1.1 
Pharmacokinetic Sample Collection .............................................................20 
6.1.2 
Pharmacokinetic Sample Analysis ...............................................................20 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS ..............................................20 
6.2.1 
Adverse Events .............................................................................................21 
6.2.2 
Clinical Laboratory Assessments..................................................................21 
6.2.3 
Lactation Consultation and Breastfeeding Practice/Reinitiation ..................22 
7. 
STATISTICAL ANALYSIS PLANS .................................................................23 
7.1 
SAMPLE SIZE CALCULATIONS ..................................................................23 
7.2 
ANALYSIS SETS ............................................................................................23 
7.3 
STATISTICAL ANALYSES ............................................................................23 


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7.3.1 
Pharmacokinetic Analyses ............................................................................23 
7.3.2 
Safety Analyses ............................................................................................24 
7.4 
HANDLING OF MISSING DATA ..................................................................24 
7.5 
INTERIM ANALYSES ....................................................................................25 
8. 
REFERENCE LIST............................................................................................26 
9. 
APPENDICES .....................................................................................................27 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS ..................................................27 
9.2 
APPENDIX 2: STANDARD PROCEDURES .................................................29 
9.2.1 
Removal of Subjects From Therapy or Assessment .....................................29 
9.2.1.1 
General Criteria for Withdrawal ...............................................................29 
9.2.1.2 
Handling of Withdrawals ..........................................................................30 
9.2.2 
Prior and Concomitant Medications and Therapies .....................................30 
9.2.2.1 
Prior Medications ......................................................................................30 
9.2.2.2 
Concomitant Medications .........................................................................30 
9.2.3 
Treatment Compliance ..................................................................................30 
9.3 
APPENDIX 3: ADVERSE EVENT DEFINITIONS AND REPORTING ......32 
9.3.1 
Adverse Event Definitions ...........................................................................32 
9.3.2 
Eliciting and Documenting Adverse Events .................................................34 
9.3.3 
Reporting Adverse Events ............................................................................35 
9.3.4 
Additional Points to Consider for Pretreatment Events and Adverse Events
 ......................................................................................................................36 
9.3.5 
Assessment of Severity .................................................................................39 
9.3.6 
Assessment of Causality ...............................................................................39 
9.3.6.1 
Relationship to Study Procedures .............................................................40 
9.3.6.2 
Start Date ..................................................................................................40 
9.3.6.3 
Stop Date ..................................................................................................40 
9.3.6.4 
Frequency .................................................................................................40 
9.3.6.5 
Action Concerning Study Drug ................................................................40 
9.3.6.6 
Outcome ....................................................................................................41 
9.3.7 
Follow-up of Adverse Events .......................................................................41 
9.3.8 
Pregnancy .....................................................................................................42 
9.3.9 
Safety Reporting to Investigators, Institutional Review Boards, Independent 
Ethics Committees, and Regulatory Authorities ..........................................42 
9.4 
APPENDIX 4: STUDY GOVERNANCE .......................................................43 
9.4.1 
Data Quality Assurance ................................................................................43 
9.4.2 
Investigator Obligations ...............................................................................43 
9.4.2.1 
Confidentiality ..........................................................................................43 
9.4.2.2 
Institutional Review ..................................................................................44 


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9.4.2.3 
Subject Consent ........................................................................................44 
9.4.2.4 
Study Reporting Requirements .................................................................44 
9.4.2.5 
Financial Disclosure and Obligations .......................................................45 
9.4.2.6 
Investigator Documentation ......................................................................45 
9.4.2.7 
Study Conduct ..........................................................................................46 
9.4.2.8 
Case Report Forms and Source Documents .............................................46 
9.4.2.9 
Adherence to Protocol ..............................................................................46 
9.4.2.10 
Reporting Adverse Events ........................................................................47 
9.4.2.11 
Investigator’s Final Report .......................................................................47 
9.4.2.12 
Records Retention .....................................................................................47 
9.4.2.13 
Publications ...............................................................................................47 
9.4.3 
Study Management .......................................................................................48 
9.4.3.1 
Monitoring ................................................................................................48 
9.4.3.2 
Management of Protocol Amendments and Deviations ...........................48 
9.4.3.3 
Premature Termination or Suspension of the Study or Investigational Site
 ..................................................................................................................49 
9.4.3.4 
Study Termination .....................................................................................50 
9.4.3.5 
Final Report ..............................................................................................50 
 


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1. 
INTRODUCTION 
1.1 
BACKGROUND 
Vonoprazan (TAK-438) is a member of a class of compounds referred to as 
potassium-competitive acid blockers (PCABs) that suppress gastric acid secretion by 
competitively inhibiting gastric hydrogen, potassium–adenosine triphosphatase 
(H+, K+-ATPase). Vonoprazan is formulated and administered orally as its fumarate salt, 
vonoprazan fumarate. Following oral administration, the fumarate salt is rapidly converted to 
the free base form, and vonoprazan fumarate is not detectable in human plasma. 
Vonoprazan was developed by Takeda Pharmaceutical Company Limited. Phathom 
Pharmaceuticals, Inc. (Phathom) has licensed the exclusive rights from Takeda to develop 
and commercialize vonoprazan in the United States (US), Europe, and Canada.  
In the US, vonoprazan is 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 relief of heartburn associated with nonerosive 
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 other countries, vonoprazan has been studied in additional acid-related 
diseases including healing of gastric ulcer/duodenal ulcer and for the prevention of 
recurrence of peptic ulcer during nonsteroidal anti-inflammatory drugs or aspirin 
administration. Vonoprazan is approved in Japan and other countries in Asia, Latin America, 
and Russia for a variety of these indications in adults. 
Further information on the study drug can be found in the investigator’s brochure (Takeda 
Pharmaceutical 2024). 
1.2 
RATIONALE FOR STUDY 
Breastfeeding is crucial in child health and development (Lawrence and Lawrence 2011, 
Eidelman et al 2012). Immunological and anti-inflammatory agents that are passed on from 
mother to the infant via breast milk also facilitates development of protective mechanisms 
against several diseases (DHHS 2011). Despite these benefits, the conflict between the risks 
of maternal medications needed for postpartum health and ensuring optimal child nutrition 
through breastfeeding presents a complex challenge in the development of drugs for 
postpartum women (Clowse et al 2017). Approximately 72% of nursing mothers take 
medications. Although medication use is not the primary reason for most mothers avoiding or 


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stopping breastfeeding, it has been reported in up to 10% of mothers (Anderson and Momper 
2020). 
There are no data available to date on the presence of vonoprazan in human milk, the effects 
on the breastfed infant, or the effects on milk production. In animal studies, vonoprazan was 
shown to be excreted in milk. Although animal data cannot often be directly extrapolated to 
humans due to physiological differences between animals and humans for excretion into 
breast milk, there is a potential that the drug may also be present in human milk (Anderson 
and Momper 2020). 
In the US Prescribing Information for Voquezna Triple Pak and Voquezna Dual Pak 
(Voquezna 2024), it is advised that a woman should pump and discard human milk for the 
duration of Voquezna Triple Pak or Voquezna Dual Pak therapy, and for 2 days after therapy 
ends, and feed her infant stored human milk (collected prior to therapy) or formula due to the 
potential risk of adverse liver effects shown in animal studies with vonoprazan. This study is 
designed to assess the concentrations of vonoprazan in milk from healthy lactating women 
using a validated assay. 
Breastfeeding women receiving vonoprazan and their treating physicians would benefit from 
the availability of information about the transfer of vonoprazan into mature breast milk, to 
better assess the benefits and risks of breastfeeding in their individual situations. 
1.3 
RATIONALE FOR DOSE SELECTION 
Per the DHHS 2019 guidelines, this study has been designed to minimize the burden on the 
lactating mother for data collection while obtaining adequate data. 
Voquezna Triple Pak and Voquezna Dual Pak are approved for use in the US for treatment of 
H. pylori infection in adults. Voquezna is approved in the US for the healing of EE and relief 
of heartburn associated with EE, maintenance of healed EE and relief of heartburn associated 
with EE, and for relief of heartburn associated with GERD in adults. 
Vonoprazan is absorbed rapidly following oral administration, with median time to maximum 
observed plasma concentrations typically occurring 1.5 to 2 hours after once-daily dosing 
and 2.5 to 4 hours after twice-daily dosing. The rate of elimination from the plasma allows 
for once- or twice-daily dosing, with mean t1/2z values typically 7 to 8 hours. Vonoprazan 
exhibits time-independent pharmacokinetics (PK) and steady-state concentrations are 
achieved by Day 3 to 4. In this study, a once-daily dose of vonoprazan 20 mg or twice-daily 
dose of vonoprazan 20 mg will be administered for 4 consecutive days ensuring that 


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breast-milk sampling occurs when drug exposure in plasma is at steady state. A dose of 
vonoprazan 20 mg once daily is selected as it is the highest dose approved for the healing of 
EE and vonoprazan 20 mg twice daily is selected as it is the highest approved dose for the 
treatment of H. pylori infection. 
2. 
STUDY OBJECTIVES 
Table 2-1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To determine the PK of vonoprazan in breast milk 
of healthy lactating women who have received 
vonoprazan 20 mg administered once daily or 
vonoprazan 20 mg administered twice daily for 
4 consecutive days 
• 
AUC0-24, Cmax, Cmin, Cavg, and Tmax 
Secondary 
 
• 
To determine total drug excreted in milk 
• 
Total amount of drug excreted in milk (mg) 
• 
Amount of drug excreted in milk relative to 
the total dose received (%) 
• 
To estimate the relative infant dose of vonoprazan 
• 
Estimated infant daily dose (mg/kg/day) 
• 
Estimated relative infant dose to the total 
maternal dose received (%) 
Safety 
 
• 
To evaluate the safety and tolerability of 
vonoprazan 20 mg administered once daily or 
vonoprazan 20 mg administered twice daily for 
4 consecutive days 
• 
AEs 
• 
Clinical laboratory test values (hematology, 
serum chemistry, urinalysis) 
• 
Vital signs 
AEs: adverse events; AUC0-24: area under the milk drug concentration-time curve from time 0 to 24 hours 
following the morning dose on Day 4; Cavg: average drug concentration in milk; Cmax: maximum drug 
concentration in milk; Cmin: minimum drug concentration in milk; PK: pharmacokinetics; Tmax: time to 
maximum observed concentration in milk. 
3. 
STUDY DESIGN 
This is a Phase 1, nonrandomized, open-label study in healthy lactating women who have 
been actively breastfeeding or pumping for at least 4 weeks postpartum. Approximately 
15 subjects will be enrolled. No formal sample size estimation is planned. 
The study will consist of a Screening Period (up to 28 days prior to Baseline), Baseline 
(Day 1, predose), Treatment Period (4 days of treatment with study drug from 


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Days 1 through 4 and 24 hours of postdose assessments after the morning dose of study drug 
on Day 4), and a 7-day safety follow-up after the last dose. Since vonoprazan exhibits 
time-independent PK and steady-state concentrations are achieved by Days 3 to 4, a 
once-daily or twice-daily dose of vonoprazan 20 mg administered for 4 consecutive days will 
ensure that breast-milk sampling occurs when drug exposure in plasma is at steady state. 
During the Screening Period, subjects will be evaluated to determine if they meet the 
inclusion/exclusion criteria; information on their current breastfeeding practice will also be 
obtained. After screening, eligible subjects will visit the clinical research unit on Day 1 for 
the baseline assessment to confirm protocol eligibility and to obtain baseline data. 
Subjects must agree to discontinue breastfeeding for the duration of the Treatment Period and 
until at least 5 days after the last dose of the study drug to ensure that the infant is not 
exposed to vonoprazan (ie, the subject must agree to not breastfeed or use breast milk that is 
pumped from Day 1 of dosing with vonoprazan until 5 days after the last dose). Subjects will 
be encouraged to have stored breast milk available for feeding their infants for a duration of 
9 days. Subjects will be asked about their intentions for continuing breastfeeding after Day 9 
and information will be obtained regarding their current breastfeeding practices 
(eg, frequency, duration of feeds, use of formula supplementation). Subjects will have access 
to a lactation consultant throughout the duration of the study to provide lactation support. 
Subjects who complete the baseline assessment and meet the criteria for inclusion and 
exclusion will enter the Treatment Period and will be administered vonoprazan 20-mg tablet 
once daily or twice daily for 4 days (Days 1 through 4). On the mornings of Days 1 through 
3, subjects will present in the clinical research unit for an outpatient visit, and for 
administration of vonoprazan 20 mg orally with 240 mL of room temperature water, at 
approximately the same time each day and under direct observation of clinical research unit 
staff (without regard to food intake). Those assigned to receive vonoprazan 20 mg twice daily 
will self-administer a second dose of vonoprazan 20 mg orally with 240 mL of room 
temperature water at home approximately 12 hours after the first dose on Days 1 through 3. 
The evening dose should be taken at the time instructed by the clinic staff, but can be taken 
late if no more than 4 hours have elapsed since the prescribed dosing time. If more than 
4 hours have elapsed since the prescribed evening dosing time, the evening dose should not 
be taken. On Day 4, the morning and evening doses of vonoprazan 20 mg will be 
administered in the clinic. On Day 4, subjects will be admitted to the clinical research unit at 
least 2 hours prior to their scheduled dose administration for check-in procedures. Milk 
samples for PK assessments will be collected at prespecified intervals from predose (0 hour) 
and at pooled intervals up to 24 hours (0-4 hours, 4-8 hours, 8-12 hours, 12-18 hours, and 


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18-24 hours) after the morning dose of study drug on Day 4. During each sampling interval, 
the sample collections will be done using a standardized electric pump for efficient milk 
extraction, emptying both breasts. The time of starting and finishing milk expression will be 
recorded. All milk within each prespecified sampling interval will be carefully combined and 
mixed, and the total volume recorded. After recording the volume, each milk sample will be 
mixed with a stabilizing solution in 1:1 ratio to ensure stability of vonoprazan in the milk 
sample. Details of this process will be provided in a separate document. Two equal aliquots 
from each of these stabilized interval collections will be appropriately labelled and stored 
immediately at or below -70 °C until analyzed for vonoprazan concentrations. 
Safety will be assessed by monitoring adverse events (AEs), clinical laboratory test results 
(hematology, serum chemistry, and urinalysis), and vital signs. In the event of early 
termination, subjects should return to the clinical research unit for final safety assessments. 
These subjects may be replaced at the investigator’s discretion. 
Subjects will be confined to the clinical research unit from the morning of Day 4 until 
discharge on Day 5. All subjects will be followed up via a phone call on Day 11 (±2 days) for 
follow-up safety assessments of AEs, concomitant medication use, and to reassess 
breastfeeding practices (eg, frequency, duration of feeds, use of formula supplementation), 
along with a description of any challenges the subject experienced and any need for lactation 
consultation. Information will also be obtained to determine whether reinitiation of 
breastfeeding was established for subjects who planned to continue breastfeeding after 
Day 9. 
The duration of the study for individual subjects, excluding Screening Period, is 
approximately 13 days. All assessments will be conducted per the schedule of events (SOE, 
Section 3.1).


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3.1 
SCHEDULE OF EVENTS 
Period 
Screening 
Baseline 
Treatment 
Safety Follow-up Telephone Call/ 
EOS 
Procedure 
Day 
–28 to –1 
1  
(Predose) 
1 
2 
3 
4 
5/ET 
11 (±2 Days) 
Admission to clinical research unit 
 
 
 
 
 
X 
 
 
Discharge from clinical research 
unit (a) 
 
 
 
 
 
 
X 
 
Outpatient visit(b) 
X 
X 
X 
X 
X 
 
 
 
Telephone call(c) 
 
 
 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Serology(d) 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
Urine drug/alcohol/cotinine 
screen(e) 
X 
X 
 
 
 
X 
 
 
Height, weight, and BMI(f) 
X 
X 
 
 
 
 
X 
 
Physical examination(g) 
X 
X 
 
 
 
 
X 
 
Vital sign measurements(h) 
X 
X 
 
 
 
X 
X 
 
12-lead ECG(i) 
X 
X 
 
 
 
 
 
 
Clinical laboratory testing(j) 
X 
X 
 
 
 
 
X 
 
Pregnancy test(k) 
X 
X 
 
 
 
X 
X 
 
Study drug administration(l) 
 
 
X 
X 
X 
X 
 
 
Dispense study drug for at-home 
administration in the evenings of 
Days 1 to 3 (l) 
 
 
X 
 
 
 
 
 
Dispense Study Dosing Card (l) 
 
 
X 
 
 
 
 
 
Review Study Dosing Card/Drug 
Accountability 
 
 
 
X 
X 
X 
 
 
Milk PK sample collection(m) 
 
 
 
 
 
X 
X 
 
Lactation consultation(n) 
X 
X 
X 
X 
X 
X 
X 
X 
Breastfeeding discussion(o) 
X 
X 
 
 
 
 
 
X 
PTEs monitoring(p) 
X 
X 
 
 
 
 
 
 
AEs(q) 
 
 
X 
Prior/concomitant medications 
X 
Abbreviations: AEs, adverse events; BMI, body mass index; ECG, electrocardiogram; EOS, end of the study; ET, early termination; ICF, informed consent form; 
PK, pharmacokinetic; PTE, pretreatment event; QTcF, QT interval corrected for heart rate using Fridericia’s formula. 


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Notes: 
(a) Discharge on Day 5 following 24-hour milk PK sample collection. Note: Subjects who withdraw before completion of the study should return to the clinical research 
unit for ET assessments. 
(b) Outpatient visits will occur at the clinical research unit at Screening and on Days 1 through 3; subjects will be administered vonoprazan tablet in the morning at the same 
time each day. 
(c) Safety follow-up/EOS telephone call: Subjects will receive a telephone call from the clinical research unit 7 days (±2 days) after their last dose of study drug to assess 
for AEs and concomitant medication use. Information will also be obtained to determine whether reinitiation of breastfeeding was established for subjects who planned 
to continue breastfeeding after Day 9). Breastfeeding practices (eg, frequency, duration of feeds, use of formula supplementation) will be reassessed, along with a 
description of any challenges the subject experienced and any need for a lactation consultant. 
(d) Serology testing will include hepatitis B surface antigen, hepatitis C virus antibody, and HIV types 1 and 2 antibodies. For COVID-19 screening, SARS-CoV-2 testing 
will be conducted as per clinical research unit’s standard processes. 
(e) Urine drug/alcohol/cotinine screen will occur at Screening, Baseline, and Day 4/Check-in per the clinical research unit’s standard procedures. 
(f) Height and weight will be measured, and BMI calculated at Screening only. Only weight will be measured at Baseline and Day 5/ET. 
(g) A full physical examination will be performed at Screening (at a minimum, assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, cardiovascular 
system, abdomen, lymph nodes, and musculoskeletal system/extremities). A brief physical examination will be performed at Baseline and Day 5/ET (at a 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. 
(h) Vital signs will be measured at Screening and Baseline; within 60 minutes prior to study drug dosing on Day 4; and on the day of discharge (Day 5)/ET. Vital signs will 
be measured after the subject has been in the seated position for at least 5 minutes and will include systolic and diastolic blood pressure, heart rate, respiratory rate, and 
body temperature. 
(i) Single 12-lead ECG recordings will be made at Screening and Baseline after the subject has been in the supine position for at least 5 minutes. A single repeat 
measurement is permitted at Screening for eligibility determination. Measurements of the following intervals will be reported: RR interval, PR interval, QRS width, QT 
interval, and QTcF. Assessments should include comments on whether the tracings are normal or abnormal; rhythm; presence of arrhythmia or conduction defects; 
morphology; any evidence of myocardial infarction; or ST-segment, T-Wave, and U-Wave abnormalities. 
(j) Clinical laboratory testing will occur at Screening, Baseline, and on the day of discharge (Day 5)/ET. A complete list of assessments is provided in Section 6.2.2. Blood 
and urine samples will be collected under fasted conditions and prepared per the clinical research unit’s standard procedures. 
(k) All subjects will undergo a pregnancy test at Screening, Baseline, and Day 4/Check-in, or ET. A serum pregnancy test will be performed at Screening and urine 
pregnancy test at Baseline and on Day 4/Check-in or ET. 
(l) Subjects will be assigned to either once-daily or twice-daily doses of vonoprazan. Each subject will receive vonoprazan 20-mg tablet in the morning from Day 1 through 
Day 4 at the clinic. Those assigned to receive vonoprazan 20 mg twice daily will self-administer a second dose of vonoprazan 20 mg at home approximately 12 hours 
after the first dose on Days 1 through 3. Date and time of self-administered doses will be documented on the Study Dosing Card. The evening dose should be taken at 
the time instructed by the clinic staff, but can be taken late if no more than 4 hours have elapsed since the prescribed dosing time. If more than 4 hours have elapsed 
since the prescribed evening dosing time, the evening dose should not be taken. On Day 4, the the morning and evening doses of vonoprazan 20 mg will be administered 
in the clinic. All doses of vonoprazan will be administered with 240 mL of room temperature water. 
(m) Breast milk samples for PK analyses will be collected predose on Day 4, and at regularly scheduled intervals through 24 hours after the morning dosing (0-4 hours, 
4-8 hours, 8-12 hours, 12-18 hours, and 18-24 hours). During each collection interval, all milk will be collected and at the conclusion of each interval both breasts will 
be completely emptied using an electric breast pump and milk will be carefully combined with any milk collected previously within that interval. The combined sample 
will be mixed, and the total volume recorded. After recording the volume, each milk sample will be mixed with a stabilizing solution in a 1:1 ratio to ensure stability of 
vonoprazan in the milk sample. Aliquots from each of these interval collections will be stored and analyzed for vonoprazan concentrations. 
(n) Subjects will have access to a lactation consultant throughout the study to provide lactation support as needed. 
(o) At Screening and Baseline, subjects will be encouraged to have stored breast milk available for feeding their infants for the duration of approximately 9 days (from 
Day 1 till 5 days after the last dose). Subjects will be asked about their intentions for continuing breastfeeding after Day 9 and information will be obtained regarding 
their current breastfeeding practices (eg, frequency, duration of feeds, use of formula supplementation). At the safety follow-up telephone call, subjects will be asked 


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whether reinitiation of breastfeeding was established for subjects who planned to continue breastfeeding after Day 9. Breastfeeding practices will be reassessed, along 
with a description of any challenges the subject experienced and any need for a lactation consultant. 
(p) Collection of PTEs will start after the subject has signed the ICF. 
(q) Adverse events will be assessed from the time of the first study drug dosing until EOS and should be followed until they are resolved, stable, or judged by the 
investigator to be not clinically significant. 
 


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4. 
STUDY POPULATION 
Up to 15 healthy lactating women subjects will be enrolled at a single center in the US. 
4.1 
INCLUSION CRITERIA 
Each subject must meet all the following criteria to be enrolled in this study: 
1. The subject is a healthy lactating woman at least 18 years of age at the time of signing the 
informed consent form (ICF). 
2. The subject has delivered a normal term infant (at least 37 weeks gestation) and has been 
breastfeeding or actively pumping breast milk for at least 4 weeks postpartum prior to the 
first dose. 
3. The subject is willing to not breastfeed or otherwise use her breast milk during 
administration of vonoprazan and until at least 5 days after the last dose of the study 
drug. 
4. The subject has confirmed that her breastfed infant is able to feed from a bottle. 
5. The subject agrees to collect all breast milk from predose to 24 hours after the morning 
dose administration on Day 4, using an electric pump. 
6. The subject is considered by the investigator to be in good general health as determined 
by medical history, clinical laboratory test results, vital sign measurements, 12-lead 
electrocardiogram (ECG) results, and physical examination findings at Screening. 
7. Subjects of childbearing 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) or be surgically sterile (ie, hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy). All subjects must have a negative 
pregnancy test at Screening and before the first dose of study drug (Baseline). 
8. The subject agrees to comply with all protocol requirements. 
9. The subject is able to provide written informed consent. 


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4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. The subject has a positive pregnancy test at Screening or Baseline, is planning to become 
pregnant before, during, or within 4 weeks after participating in this study, or intends to 
donate ova during this time period, or is of childbearing potential and not using an 
effective contraceptive method. 
2. The subject has a history of breast implants, breast augmentation, or breast reduction 
surgery that significantly impacts breastfeeding or collection of milk from one or both 
breasts. 
3. The subject has signs or symptoms of mastitis or other condition that would prevent the 
collection of milk from one or both breasts. 
4. The subject has undergone prior esophageal and/or gastrointestinal surgeries that may 
affect study drug absorption. 
5. The subject has undergone surgery (other than cesarean section) within 30 days before 
the first dose of study drug. 
6. The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus 
antibody, or HIV types 1 or 2 antibodies at Screening. 
7. The subject has any other clinically significant findings on physical examination, clinical 
laboratory abnormalities, or ECG results that preclude participation in the study, as 
deemed by the investigator. 
8. The subject has used any prescription (excluding hormonal birth control) and/or 
over-the-counter medications (including cytochrome P450 3A4 inducers), including 
herbal or nutritional supplements, within 14 days before the first dose of study drug, 
and/or is expected to require any such medication during the course of the study until end 
of the Treatment Period. Use of multivitamins and acetaminophen (up to 2 g per day) is 
permissible. 
9. The subject has consumed grapefruit and/or grapefruit juice, Seville orange, or Seville 
orange-containing products (eg, marmalade) 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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10. The subject is a smoker 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. 
11. The subject has a history of alcohol abuse or drug dependency within 12 months before 
the first dose of study drug. 
12. The subject has a positive test result for drugs of abuse, alcohol, or cotinine (indicating 
active current smoking) at Screening, Baseline, or Day 4 (Check-in). 
13. The subject is involved in strenuous activity or contact sports within 24 hours before the 
first dose of study drug and during the study. 
14. The subject has a history of relevant drug and/or food allergies (ie, any significant food 
allergy that could preclude a standard diet in the clinical research unit). 
15. The subject has received study drug in another investigational study (including 
vonoprazan) within 30 days prior to start of the Screening Period. 
16. The subject has a history of hypersensitivity or allergies to vonoprazan or any of its 
formulation excipients (D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose, 
fumaric acid, ascorbic acid, croscarmellose sodium, magnesium stearate, hypromellose, 
polyethylene glycol 8000, titanium dioxide, or ferric oxide red). 
17. In the opinion of the investigator, the subject is not suitable for entry into the study. 
4.3 
WITHDRAWAL CRITERIA 
General criteria for subject withdrawal and the handling of withdrawals can be found in 
Appendix 2. 
4.4 
SUBJECT REPLACEMENT 
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 up 
to 15 subjects. 


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4.5 
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 events (PTEs), AEs, and any serious adverse 
events (SAEs). Subjects may be rescreened at the discretion of principal investigator with 
consultation of the medical monitor and/or the sponsor. 
5. 
STUDY TREATMENTS 
5.1 
TREATMENTS ADMINISTERED 
All subjects will receive the study treatment as described in Section 3 and according to the 
SOE (Section 3.1). Five subjects will receive vonoprazan 20 mg once daily and 10 subjects 
will receive vonoprazan 20 mg twice daily (total daily dose of 40 mg). 
5.2 
INVESTIGATIONAL PRODUCTS 
The study drug that will be used is as follows: 
Product 
Supplied Formulation 
Vonoprazan 
20-mg tablet 
Vonoprazan tablets contain 20 mg vonoprazan free base (MW 345.39) and the following 
inactive excipients: D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose, fumaric 
acid, ascorbic acid, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene 
glycol 8000, titanium dioxide, and ferric oxide red. 
Further information on the study drug can be found in the investigator’s brochure 
(Takeda Pharmaceutical 2024). 
5.2.1 
Study Drug Preparation and Storage 
Phathom will provide the investigator and clinical research unit with adequate quantities of 
vonoprazan tablets. The tablets will be packaged in high-density polyethylene bottles. The 
clinical research unit pharmacy will provide the study drug for each subject according to the 
SOE (Section 3.1) and the pharmacy standard procedures for in-clinic dosing. The clinical 


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research unit pharmacy will provide the study drug for each subject who will self-administer 
the evening dose at home. 
At the clinical site, all study drugs must be stored according to the labeled instructions in a 
secure cabinet or room with access restricted to necessary clinical research unit personnel. 
The site will be required to keep a temperature log to establish a record of compliance with 
storage conditions. For study drug dispensed for at-home administrations, subjects should 
follow the labeled storage conditions. 
5.2.2 
Study Drug Accountability 
The investigator will maintain accurate records of receipt of all study drugs, including dates 
of receipt. Accurate records will be kept regarding when and how much study drug is 
dispensed and used by each subject in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, and to satisfy 
regulatory requirements regarding drug accountability, all study drugs will be reconciled and 
retained or destroyed according to applicable regulations. 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT 
GROUPS 
This is a nonrandomized study. Subjects who meet all inclusion and none of the exclusion 
criteria will receive study treatments according to their assigned treatment and the SOE 
(Section 3.1). The first 5 subjects will be assigned to receive vonoprazan 20 mg once daily 
and the next 10 subjects will be assigned vonoprazan 20 mg twice daily. 
5.4 
BLINDING 
This is an open-label study. 
6. 
STUDY PROCEDURES 
Before performing any study procedures, all potential subjects will sign an ICF as outlined in 
Section 9.4.2.3. 
Details of additional standard study procedures can be found in Appendix 2. 
The total amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed 500 mL. 


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6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS 
The following milk PK parameters for vonoprazan will be estimated (if data permit) as 
endpoints for each subject using standard noncompartmental methods: AUC0-24, Cmax, Cmin, 
Cavg, and Tmax. In addition, the total amount of drug excreted in milk (mg), the amount of 
drug excreted in milk relative to the total dose received (%), the estimated infant daily dose 
(mg/kg/day), and the estimated relative infant dose to the total maternal dose received (%) 
will be derived. 
The timing and frequency of PK sample collection is listed in the SOE (Section 3.1). 
6.1.1 
Pharmacokinetic Sample Collection 
Details for the collection, processing, storage, and shipping of PK samples will be provided 
to the clinical research unit separately. 
6.1.2 
Pharmacokinetic Sample Analysis 
Pharmacokinetic samples will be analyzed using a validated liquid chromatography coupled 
with tandem mass spectrometry assay for vonoprazan in human milk. Assay results and 
validation details will be provided in a separate bioanalytical report. 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS 
The timing and frequency of all safety assessments is listed in the SOE (Section 3.1). 
Safety and tolerability endpoints will include monitoring and recording of AEs, clinical 
laboratory test results (hematology, serum chemistry, and urinalysis), and vital sign 
measurements. 
For all safety assessments, the investigator will determine whether results are clinically 
significant, which is defined as any variation in a result that has medical relevance and may 
result in an alteration in medical care (eg, active observation, diagnostic measures, or 
therapeutic measures). If clinical significance is noted, the result and reason for significance 
will be documented and an AE reported on the AE page of the subject’s electronic case report 
form (eCRF). The investigator will monitor the subject until the result has reached the 
reference range or the result at Screening, or until the investigator determines that follow-up 
is no longer medically necessary. 


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6.2.1 
Adverse Events 
Definitions and procedures for reporting of AEs can be found in Appendix 3. For this study, 
the following contact information is to be used for SAE reporting: 
 Medical Monitor: 
 
 
 
SAE Hotline (24 hour): 
 
SAE: 
 
Safety Email Address: 
 
6.2.2 
Clinical Laboratory Assessments 
The following clinical laboratory assessments will be performed: 
Hematology 
Absolute neutrophil count and differential count, hematocrit, 
hemoglobin, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, leukocytes count (basophils, 
eosinophils, lymphocytes, monocytes, neutrophils), mean 
corpuscular volume, platelet count, red blood cell count, and red 
blood cell distribution width 
Serum chemistry 
Alanine aminotransferase (ALT), albumin, alkaline phosphatase, 
aspartate aminotransferase (AST), bilirubin (total), blood urea 
nitrogen, calcium, carbon dioxide, chloride, cholesterol (total, high-
density lipoprotein, and calculated low-density lipoprotein), 
creatinine, gamma-glutamyltransferase, globulin, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total protein, 
triglycerides, and uric acid 
Urinalysis 
Appearance, bilirubin, color, glucose, ketones, leukocyte esterase, 
reflex microscopy (performed if dipstick is positive for protein or 
the blood value is 1+ or greater; and includes bacteria, casts, 
crystals, epithelial cells, red blood cells, and white blood cells), 
nitrites, occult blood, pH, protein, specific gravity, turbidity, and 
urobilinogen 
Serology 
Hepatitis B surface antigen, hepatitis C virus antibody, and HIV 
antibody types 1 and 2 (Screening only) 


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Other analyses 
Urine drug screen (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine metabolites, cotinine, methamphetamines, 
methylenedioxymethamphetamine, and opiates [including heroin, 
codeine, and oxycodone]), COVID-19 screening (SARS-CoV-2 
testing will be conducted as per clinical research unit’s standard 
processes), serum and urine pregnancy test (human chorionic 
gonadotropin), international normalized ratio (INR) (to be done 
when follow-up laboratory tests are required for elevated ALT or 
AST levels per Section 9.3.1), and an alcohol breath test 
The clinical laboratory that performs the tests will provide the reference ranges for all clinical 
laboratory parameters. 
Clinical laboratory tests may be repeated at the discretion of the investigator, if necessary, for 
assessment of inclusion and exclusion criteria or evaluation of clinical laboratory 
abnormalities. 
6.2.3 
Lactation Consultation and Breastfeeding 
Practice/Reinitiation 
Subjects will have access to a lactation consultant throughout the duration of the study, to 
provide lactation support, as needed. 
At Screening, subjects will be encouraged to have stored breast milk available for feeding 
their infants for the duration of the Treatment Period and until at least 5 days after the last 
dose of the study drug. Subjects will be asked about their intentions for continuing 
breastfeeding after Day 9 and information will be obtained regarding their current 
breastfeeding practices (eg, frequency, duration of feeds, use of formula supplementation). 
At the Day 11 (±2 days) safety follow-up telephone call, information will be obtained to 
determine whether reinitiation of breastfeeding was established for subjects who planned to 
continue breastfeeding after Day 9. Breastfeeding practices will be reassessed, along with a 
description of any challenges the subject may have experienced and any need for a lactation 
consultant. 


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7. 
STATISTICAL ANALYSIS PLANS 
7.1 
SAMPLE SIZE CALCULATIONS 
The number of subjects is based on clinical and practical considerations and not on a formal 
statistical power calculation. The total sample size of 15 subjects is considered sufficient for 
the objectives of the study. 
7.2 
ANALYSIS SETS 
The analysis populations are as follows: 
• 
The PK population will include subjects who receive sufficient doses of vonoprazan and 
have sufficient concentration data in milk to support accurate estimation of at least 1 PK 
parameter in milk. 
• 
The safety population will include all subjects who receive at least 1 dose of study drug. 
7.3 
STATISTICAL ANALYSES 
Details of all statistical analyses will be described in a separate statistical analysis plan. All 
data collected will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings but not included in the calculation of 
summary statistics. 
For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of subjects, mean, median, 
standard deviation [SD], minimum, and maximum). 
Baseline demographic and background variables will be summarized. The number of subjects 
who enroll in the study and the number and percentage of subjects who complete the study 
will be presented. Frequency and percentage of subjects who withdraw or discontinue from 
the study, and the reason for withdrawal or discontinuation, will also be summarized. 
7.3.1 
Pharmacokinetic Analyses 
The PK analysis will be based on the PK population. Noncompartmental analysis to 
determine the milk PK parameters of vonoprazan will be performed. All parameters will be 
calculated using the latest version of Phoenix® WinNonlin® (Certara USA Inc., Princeton, 
New Jersey) or SAS® software (SAS Institute Inc., Cary, North Carolina). 


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Individual milk concentration-time data will be presented and summarized for each treatment 
(once daily and twice daily), both graphically and in tabular form with descriptive statistics 
(n, arithmetic mean, SD, percent coefficient of variation [CV%], median, minimum, 
maximum, geometric mean, and geometric CV%). Concentration data will be summarized 
according to nominal time windows. 
The following milk PK parameters will be estimated (if data permit) for each subject: 
AUC0-24, Cmax, Cmin, Cavg, and Tmax. Pharmacokinetic parameters will be summarized for each 
treatment (once daily and twice daily) using descriptive statistics (n, arithmetic mean, SD, 
CV%, median, minimum, maximum, geometric mean, and geometric CV%). A listing of 
individual PK parameters for each subject will be provided. 
In addition, the total amount of drug excreted in milk (mg), the total amount of drug excreted 
in milk relative to the total dose received (%), the estimated infant dose (mg/kg/day), and the 
estimated relative infant dose to the total maternal dose received (%) will be calculated for 
each subject and summarized for each treatment (once daily and twice daily) using 
descriptive statistics. Additional PK analyses may be performed as appropriate. 
7.3.2 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the Medical 
Dictionary for Regulatory Activities (MedDRA). All AE data will be presented in a data 
listing. Treatment-emergent AEs (TEAEs) will be summarized overall, as well as by severity 
and relationship to study drug. Serious AEs, AEs leading to discontinuation of study drug, 
and PTEs will also be presented in the data listings. 
Actual values and changes from Baseline for clinical laboratory test results and vital sign 
measurements results will be summarized at each time point using descriptive statistics 
(number of subjects, mean, SD, median, minimum, and maximum). Shift tables will be 
generated for clinical laboratory test results. 
7.4 
HANDLING OF MISSING DATA 
Vonoprazan concentrations in milk 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. 


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7.5 
INTERIM ANALYSES 
No formal interim analyses will be performed in this study. 


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8. 
REFERENCE LIST 
Anderson PO, Momper JD. Clinical lactation studies and the role of pharmacokinetic 
modeling and simulation in predicting drug exposures in breastfed infants. J Pharmacokinet 
Pharmacodyn. 2020;47(4):295-304. 
Clowse ME, Förger F, Hwang C, et al. Minimal to no transfer of certolizumab pegol into 
breast milk: results from CRADLE, a prospective, postmarketing, multicentre, 
pharmacokinetic study. Ann Rheum Dis. 2017;76- (11):1890–96. 
Department of Health and Human Services (DHHS). Office of the Surgeon General. The 
Surgeon General’s Call to Action to Support Breastfeeding. Rockville (MD); 2011 [cited 
2022 Nov 07]. Available from: The Surgeon General's Call to Action to Support 
Breastfeeding - NCBI Bookshelf (nih.gov) 
Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), 
Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER). Guidance for Industry: Clinical Lactation Studies: Considerations for 
Study Design Guidance for Industry; 2019 [cited 2022 Nov 07]. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-
lactation-studies-considerations-study-design 
Eidelman AI, Schanler RJ, Johnston M, et al. Breastfeeding and the use of human milk. 
Pediatrics. 2012;129(3):e827-41. 
Lawrence RM, Lawrence RA. Breastfeeding: more than just good nutrition. Pediatr Rev. 
2011;32 (7):267-80. 
Takeda Pharmaceutical Company, Ltd. Vonoprazan fumarate (TAK-438). Global 
Investigator’s Brochure, 14th ed. 2024. 
Voquezna Triple Pak (vonoprazan tablets; amoxicillin capsules; clarithromycin tablets) and 
Voquezna Dual Pak (vonoprazan tablets; amoxicillin capsules) [prescribing information]. 
Phathom Pharmaceuticals, Inc. Buffalo Grove, IL; 2024. 


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9. 
APPENDICES 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the milk concentration versus time curve 
AUC0-24 
area under the milk drug concentration-time curve from time 0 to 
24 hours following the morning dose on Day 4 
BLQ 
below the limit of quantification 
BMI 
body mass index 
Cavg 
average drug concentration in milk 
CFR 
Code of Federal Regulations 
Cmax 
maximum drug concentration in milk 
Cmin 
minimum drug concentration in milk 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EE 
erosive esophagitis 
EOS 
end of the study 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
H+, K+ ATPase 
hydrogen, potassium–adenosine triphosphatase 
H. pylori 
Helicobacter pylori 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCAB 
potassium competitive acid blocker 
PK 
pharmacokinetic(s) 
PTE 
pretreatment event 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SD 
standard deviation 
SOE 
schedule of events 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum observed concentration in milk 


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Abbreviation 
Term 
ULN 
upper limit of normal 
US 
United States 
 


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


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9.2.1.2 
Handling of Withdrawals 
When a subject withdraws from the study, the reason(s) for withdrawal shall be recorded by 
the investigator on the relevant page of the eCRF. Whenever possible, any subject who 
prematurely withdraws from the study will undergo all early termination assessments. Any 
subject who fails to return for final assessments will be contacted by the site in a reasonable 
attempt to have them comply with the protocol. The status of subjects who fail to complete 
final assessments will be documented in the eCRF. 
9.2.2 
Prior and Concomitant Medications and Therapies 
Restrictions for prior and concomitant medications and therapies are provided in Section 4.2. 
Prior and concomitant medications and therapies will be coded using the WHODrug Global 
dictionary. 
9.2.2.1 
Prior Medications 
Information regarding prior medications taken by the subject within the 30 days before 
signing the ICF will be recorded in the subject’s eCRF. 
9.2.2.2 
Concomitant Medications 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. If a concomitant medication is taken, 
except for those specified in the protocol, a joint decision will be made by the investigator 
and the sponsor to continue or discontinue the subject based on the time the medication was 
administered, its pharmacology and PK, and whether the use of the medication will 
compromise the safety of the subject or the interpretation of the data. The investigator is 
responsible for ensuring that details regarding the medication are adequately recorded in the 
eCRF. 
9.2.3 
Treatment Compliance 
All morning doses of study drug and the evening dose on Day 4 (as applicable, for subjects 
assigned to twice-daily dosing) will be administered in the clinical research unit under direct 
observation of clinical research unit personnel and will be recorded in the eCRF. Evening 
doses of study drug on Days 1 through 3 will be self-administered by the subject at home for 
subjects assigned to twice-daily dosing. Subjects will be provided a Study Dosing Card to 
record the date and time the evening dose was taken on Study Days 1 to 3. 


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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. 


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9.3 
APPENDIX 3: ADVERSE EVENT DEFINITIONS AND 
REPORTING 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF 
and reported to the sponsor, regardless of their relationship to study drug or clinical 
significance. If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported. 
9.3.1 
Adverse Event Definitions 
A PTE is defined as any untoward medical occurrence that has occurred prior to 
administration of any study drug in a clinical investigation subject who has signed ICF to 
participate in a study; it does not necessarily have to have a causal relationship with study 
participation. 
An AE is defined as any untoward medical occurrence in a subject enrolled in this study 
regardless of its causal relationship to study drug. An AE can therefore be an unfavorable 
sign or symptom, or a disease temporally associated with the use of study drug. 
A 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 the study drug. 
An SAE is defined as any untoward medical occurrence at any dose that meets one of the 
following criteria: 
1. Results in death. 
2. Is life-threatening. The term “life-threatening” refers to an event in which the subject was 
at risk of death at the time of the event; it does not refer to an event that hypothetically 
might have caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. 
4. Results in persistent or significant disability/incapacity. 
5. Is a congenital anomaly/birth defect. 


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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 9-1) 
• Exposes the subject to danger, even though the event is not immediately 
life-threatening or fatal or does not result in hospitalization 
Table 9-1 
Medically Significant Adverse Event List 
Term 
Acute respiratory failure/acute respiratory distress syndrome 
Torsade de pointes/ventricular fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizures 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/Stevens-Johnson syndrome 
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis 
Confirmed or suspected endotoxin shock 
Confirmed or suspected transmission of infectious agent by a medicinal product 
Neuroleptic malignant syndrome/malignant hyperthermia 
Spontaneous abortion/stillbirth and fetal death 
COVID-19 pneumonia 
COVID-19–related disease 
Abbreviation: COVID-19, coronavirus disease 2019. 
The PTEs that fulfill one or more of the serious criteria above are also considered SAEs and 
should be reported and followed up in the same manner. 


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A special interest AE (serious or nonserious) is one of scientific and medical concern specific 
to the study drug or program for which ongoing monitoring and rapid communication by the 
investigator to Phathom may be appropriate. Such events may require further investigation in 
order to characterize and understand them and would be described in protocols and 
instructions provided for investigators as to how and when they should be reported to 
Phathom. 
Reporting of Abnormal Liver Function Tests: 
If a subject is noted to have an ALT or AST value >3 × ULN and a total bilirubin value 
>2 × ULN during the treatment or follow-up period for which an alternative etiology has not 
been identified, the event should be reported as an SAE. The investigator must contact the 
medical monitor for discussion of the relevant subject details and possible alternative 
etiologies, such as acute viral hepatitis A or B, other acute liver disease, medical history, or 
concurrent medical conditions. Study drug should be discontinued immediately as per 
Section 9.2.1.1. Laboratory tests should be followed up as described in Section 6.2.2. In 
addition, a Liver Function Test Increase eCRF must be completed and transmitted with the 
SAE form. 
If subjects with normal baseline ALT or AST levels experience ALT or AST >3 × ULN and a 
2-fold increase above baseline, follow-up laboratory tests (at a minimum, serum alkaline 
phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase, and INR) should be 
repeated within a maximum of 7 days and preferably within 48 to 72 hours after the 
abnormality is found. 
If subjects with elevated baseline ALT or AST levels experience ALT or AST >5 × ULN, 
follow-up laboratory tests (at a minimum, serum alkaline phosphatase, ALT, AST, total 
bilirubin, gamma-glutamyl transferase, and INR) should be repeated within a maximum of 
7 days and preferably within 48 to 72 hours after the abnormality is found. 
If subjects with either normal or elevated baseline ALT or AST levels experience ALT or AST 
>8 × ULN, follow-up laboratory tests (at a minimum, serum alkaline phosphatase, ALT, AST, 
total bilirubin, gamma-glutamyl transferase, and INR) should be repeated within a maximum 
of 48 hours after the abnormality is found. 
9.3.2 
Eliciting and Documenting Adverse Events 
Collection of PTEs will commence at the time the subject signs the ICF to participate in the 
study and will continue until the subject is first administered study drug or until screen 


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failure. For subjects who discontinue prior to study drug administration, PTEs will be 
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 telephone call or withdrawal from the study. 
On each study day, the investigator will assess whether any subjective AEs have occurred. A 
neutral question such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing 
a serious PTE must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline or there is a satisfactory explanation 
for the change. Nonserious PTEs, related or unrelated to the study procedure, do not need to 
be followed up for the purposes of the protocol. All subjects experiencing AEs, whether 
considered associated with the use of the study drug or not, must be monitored until the 
symptoms subside and any clinically relevant changes in laboratory values have returned to 
baseline or until there is a satisfactory explanation for the changes observed. 
In addition to subject observations, AEs will be documented from any data collected on the 
AE page of the eCRF (eg, laboratory values, physical examination findings, and ECG 
changes) or other documents that are relevant to subject safety. 
9.3.3 
Reporting Adverse Events 
All PTEs and AEs will be documented on the PTE/AE page of the eCRF, regardless of 
whether the investigator concludes that the event is related to drug treatment. Information to 
be collected includes event term, start and stop date, seriousness, severity, investigator’s 
opinion of the causal relationship between the event and administration of study drug(s) 
(related or not related; not applicable for PTEs), action concerning study drug (not applicable 
for PTEs), any required treatment or evaluations, and the outcome of the event. 
Any AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported. All AEs will 
be followed until they are resolved, stable, or judged by the investigator to be not clinically 
significant. Any medical condition that is present at the time that the subject is screened but 
does not deteriorate should not be reported as an AE. However, if the medical condition 
deteriorates at any time during the study, it should be recorded as an AE. Section 9.3.4 
provides additional details. The MedDRA will be used to code all AEs. 
Any AE that is considered serious by the investigator or that meets SAE criteria 
(Section 9.3.1) must be reported to the sponsor within 24 hours (after the investigator has 


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confirmed the occurrence of the SAE). The investigator will assess whether there is a 
reasonable possibility that the study drug(s) caused the SAE. The sponsor will be responsible 
for notifying the relevant regulatory authorities of any SAE as outlined in US Title 21 Code 
of Federal Regulations (CFR) Parts 312 and 320. The investigator is responsible for notifying 
the institutional review board (IRB) directly. Contact information to be used for SAE 
reporting can be found in Section 6.2.1. 
Any SAE spontaneously reported to the investigator following the AE collection period 
should be reported to the sponsor if it is considered related to study participation. 
Investigators are not obligated to actively seek information regarding new AEs or SAEs after 
the conclusion of study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a subject has been discharged from the study and he or 
she considers the event to be reasonably related to the study drug or study participation, the 
investigator must promptly notify the sponsor. Reporting of serious PTEs will follow the 
same procedure as SAE reporting. 
9.3.4 
Additional Points to Consider for Pretreatment Events and 
Adverse Events 
An untoward finding generally may involve the following: 
• 
Indicates a new diagnosis or unexpected worsening of a preexisting condition 
(preexisting conditions or underlying disease should not be considered PTEs or AEs) 
• 
Necessitates therapeutic intervention 
• 
Requires an invasive diagnostic procedure 
• 
Requires discontinuation or a change in dose of study drug or a concomitant medication 
• 
Is considered unfavorable by the investigator for any reason 
Pretreatment events/AEs caused by a study procedure (eg, a bruise after blood draw) should 
be recorded as a PTE/AE. 


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Diagnoses versus signs and symptoms: 
• 
Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, signs or symptoms should be 
recorded appropriately as PTEs or as AEs. 
Laboratory values and ECG findings: 
• 
Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if 
they are judged to be clinically significant (ie, if some action or intervention is required 
or if the investigator judges the change to be beyond the range of normal physiologic 
fluctuation). A laboratory or ECG retest or continued monitoring of an abnormal value or 
finding is not considered an intervention. In addition, repeated or additional noninvasive 
testing for verification, evaluation, or monitoring of an abnormality is not considered an 
intervention. 
• 
If abnormal laboratory values or ECG findings are the result of pathology for which there 
is an overall diagnosis (eg, increased creatinine in renal failure), only the diagnosis 
should be reported as a PTE or an AE. 
Preexisting conditions: 
• 
Preexisting conditions (present at the time of signing the ICF) are considered concurrent 
medical conditions and should NOT be recorded as PTEs or AEs. Baseline evaluations 
(eg, laboratory tests, ECGs) should NOT be recorded as PTEs unless related to study 
procedures. However, if the subject experiences a worsening or complication of such a 
concurrent medical condition, the worsening or complication should be recorded 
appropriately as a PTE (if the worsening or complication occurs before administration of 
study drug) or an AE (if the worsening or complication occurs after administration of 
study drug). Investigators should ensure that the recorded event term captures the change 
in the condition (eg, “worsening of…”). 
• 
If a subject has a preexisting episodic concurrent medical condition (eg, asthma, 
epilepsy), any occurrence of an episode should be captured as a PTE/AE only if the 
condition becomes more frequent, serious, or severe in nature. Investigators should 
ensure that the recorded AE term captures the change in the condition from baseline (eg, 
“worsening of…”). 


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• 
If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE/AE if it occurs to 
a greater extent than would be expected. Investigators should ensure that the recorded AE 
term captures the change in the condition (eg, “worsening of…”). 
Worsening of PTEs or AEs: 
• 
If the subject experiences a worsening or complication of a PTE after the start of study 
drug, the worsening or complication should be recorded as an AE. Investigators should 
ensure that the recorded AE term captures the change in the PTE (eg, “worsening of…”). 
• 
If the subject experiences a worsening or complication of an AE after any change in 
study drug, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the recorded AE term captures the change in the condition 
(eg, “worsening of…”). 
Changes in intensity of AEs/serious PTEs: 
• 
If the subject experiences a change in the intensity of an AE/serious PTE, the event 
should be captured once with the maximum intensity recorded. 
Preplanned procedures (surgeries or interventions): 
• 
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing the 
ICF are not considered PTEs or AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the preexisting condition, the 
worsening of the condition should be recorded as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
• 
Elective procedures performed when there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs. 


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Overdose: 
Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs but instead will be documented on the overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the eCRF. 
9.3.5 
Assessment of Severity 
The severity (or intensity) of an AE refers to the extent to which it affects the subject’s daily 
activities and will be classified as mild, moderate, or severe using the following criteria: 
• Mild: These events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• Moderate: These events result in a low level of inconvenience or require minor 
therapeutic measures. Moderate events may cause some interference with normal 
functioning. 
• Severe: These events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
Changes in the severity of an AE should be documented to allow the duration of the event at 
each level of intensity to be assessed. An AE characterized as intermittent does not require 
documentation of the onset and duration of each episode. 
9.3.6 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process but is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The investigator will assess causality (ie, whether there is a reasonable possibility that the 
study drug caused the event) for all AEs and SAEs. The relationship will be classified as 
follows: 
• Not related: An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant drugs, and concurrent treatments. 


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


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9.3.6.6 
Outcome 
• 
Recovered/resolved: The subject returns to the first assessment status with respect to the 
AE/PTE. 
• 
Recovering/resolving: The intensity is decreased by 1 or more stages, the diagnosis or 
signs/symptoms have almost disappeared, the abnormal laboratory value has improved 
but has not returned to the normal range or to baseline, or the subject dies from a cause 
other than the particular AE/PTE with the condition remaining “recovering/resolving.” 
• 
Not recovered/not resolved: There is no change in the diagnosis, signs, or symptoms; the 
intensity of the diagnosis, signs/symptoms, or laboratory value on the last day of the 
observed study period is worse than when it started; the condition is an irreversible 
congenital anomaly; or the subject died from another cause while the particular AE/PTE 
state was “not recovered/not resolved.” 
• 
Resolved with sequelae: The subject recovers from an acute AE/PTE but is left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis). 
• 
Fatal: AEs/PTEs that are considered the cause of death. 
• 
Unknown: The course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
9.3.7 
Follow-up of Adverse Events 
All AEs must be reported in detail on the appropriate page of the eCRF and followed until 
they are resolved, stable, or judged by the investigator to be not clinically significant. 
For SAEs, if information is 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, ECG results, 
laboratory test results, discharge summary, postmortem results) should be provided, if 
requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 


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


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9.4 
APPENDIX 4: STUDY GOVERNANCE 
9.4.1 
Data Quality Assurance 
This study will be conducted using the quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and 
will comply with current International Council for Harmonisation (ICH) guidance on quality 
and risk management. All aspects of the study will be monitored for compliance with 
applicable government regulatory requirements, current Good Clinical Practice (GCP), the 
protocol, and standard operating procedures. The monitor will maintain current personal 
knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the investigator and staff. 
Electronic CRFs and electronic data capture will be utilized. The electronic data capture 
system is validated and compliant with US Title 21 CFR Part 11. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. 
Important protocol deviations, should they occur during the study, will be presented in the 
clinical study report. 
9.4.2 
Investigator Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study and may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB 
but will not result in protocol amendments. 
9.4.2.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject, except as necessary for monitoring and auditing by the sponsor, its 
designee, the FDA, or the IRB. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 


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


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


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


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9.4.2.10 
Reporting Adverse Events 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB as appropriate. The investigator also agrees to 
provide the sponsor with an adequate report, if applicable, shortly after completion of the 
investigator’s participation in the study. 
9.4.2.11 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the study’s 
outcome and the sponsor and regulatory authorities with any reports required. 
9.4.2.12 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study drug. These documents should be 
retained for a longer period, however, if required by applicable regulatory requirements or by 
an agreement with the sponsor. The sponsor is responsible for informing the 
investigator/institution when these documents no longer need to be retained. 
9.4.2.13 
Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and any other related issues. The sponsor has final approval authority over 
all such issues. 
Data are the property of the sponsor and cannot be published without their prior 
authorization, but data and any publication thereof will not be unduly withheld. 


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9.4.3 
Study Management 
9.4.3.1 
Monitoring 
9.4.3.1.1 
Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, is obligated to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals 
in addition to maintaining necessary telephone and email contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the investigator and 
staff. 
All aspects of the study will be carefully monitored by the sponsor or its designee for 
compliance with applicable government regulation with respect to current ICH E6(R2) 
guidelines and standard operating procedures. 
9.4.3.1.2 
Inspection of Records 
The investigator and institution involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the investigator agrees to allow the sponsor, their representatives, the 
FDA, or other regulatory agencies access to all study records. 
The investigator should promptly notify the sponsor and study site(s) of any audits scheduled 
by any regulatory authorities and promptly forward copies of any audit reports received to 
the sponsor. 
9.4.3.2 
Management of Protocol Amendments and Deviations 
9.4.3.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent 
immediate hazard to the subject, must be reviewed and approved by the sponsor or designee. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB for 
approval before subjects are enrolled into an amended protocol. 


Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VONO-401 
Clinical Study Protocol Amendment 1 
 
Page 49 
 
9.4.3.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB for review and approval, to the sponsor for agreement, and to 
the regulatory authorities, if required. 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important deviation (sometimes referred to as a major 
or significant deviation) is a subset of protocol deviations that leads to a subject being 
discontinued from the study, or significantly affects the subject’s rights, safety, or well-being 
and/or the completeness, accuracy, and reliability of the study data. An important deviation 
can include nonadherence to inclusion or exclusion criteria or nonadherence to FDA 
regulations or ICH E6(R2) guidelines. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The investigator will be notified in writing by the monitor of deviations. 
The IRB should be notified of all protocol deviations, if appropriate, in a timely manner. 
9.4.3.3 
Premature Termination or Suspension of the Study or 
Investigational Site 
9.4.3.3.1 
Criteria for Premature Termination or Suspension of the 
Study 
The study will be completed as planned unless one or more of the following criteria that 
require temporary suspension or premature termination of the study are met: 
• 
New information or other evaluation regarding the safety or efficacy of the study 
medication that indicates a change in the known risk/benefit profile for the compound 
such that the risk/benefit is no longer acceptable for subjects participating in the study. 
• 
Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety. 


Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VONO-401 
Clinical Study Protocol Amendment 1 
 
Page 50 
 
9.4.3.3.2 
Criteria for Premature Termination or Suspension of 
Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the 
investigator) is found in significant violation of GCP, the protocol, or contractual agreement 
or is unable to ensure adequate performance of the study or as otherwise permitted by the 
contractual agreement. 
9.4.3.3.3 
Procedures for Premature Termination or Suspension of 
the Study or the Participation of Investigational Sites 
In the event that the sponsor, an IRB, or regulatory authority elects to terminate or suspend 
the study or the participation of an investigational site, a study-specific procedure for 
premature termination or suspension will be provided by the sponsor; the procedure will be 
followed by applicable investigational sites during the course of termination or study 
suspension. 
9.4.3.4 
Study Termination 
Although the sponsor has every intention of completing the study, they reserve the right to 
discontinue it at any time for clinical or administrative reasons. 
The end of the study (EOS) is defined as the date on which the last subject completes the last 
visit (including the EOS follow-up telephone call and any additional long-term follow-up). 
Any additional long-term follow-up that is required for monitoring of the resolution of an AE 
or finding may be appended to the clinical study report. 
9.4.3.5 
Final Report 
Regardless of whether the study is completed or prematurely terminated, the sponsor will 
ensure that clinical study reports are prepared and provided to regulatory agency(ies) as 
required by the applicable regulatory requirement(s). The sponsor will also ensure that 
clinical study reports in marketing applications meet the standards of the ICH harmonised 
tripartite guideline E3: Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review complete study results. 


Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VONO-401 
Clinical Study Protocol Amendment 1 
 
Page 51 
 
Upon completion of the clinical study report, the investigator(s) will be provided with the 
final approved clinical study report, as appropriate. 
 
 
 
 
 

SAP_001.pdf: 
Protocol Number: VONO-401 
 
Official Title: A Phase 1, Open-label Study to Evaluate Vonoprazan Concentrations in Breast Milk of 
Healthy Lactating Women Receiving Vonoprazan 20 mg Once Daily or Vonoprazan 20 mg Twice 
Daily 
 
NCT Number: NCT06391177 
 
Document Date: 30 August 2024 
 


Phathom Pharmaceuticals, Inc. 
 
Vonoprazan 
Protocol No. VONO-401 
 
Clinical Study Report 
 
16.1.9 
Documentation of Statistical Methods 
 
 
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Phathom Pharmaceuticals, Inc. 
 
Vonoprazan 
Protocol No. VONO-401 
 
Clinical Study Report 
 
16.1.9.1 
Statistical Analysis Plan 
This section contains the following document: 
Final Statistical Analysis Plan Version 1.0, dated 28 August 2024  
 
 
Page 2


 
Confidential 
 
 
 
 
 
 
 
 
 
Phathom Pharmaceuticals, Inc. 
 
 
VONO-401 
 
 
A PHASE 1, OPEN-LABEL STUDY TO EVALUATE VONOPRAZAN 
CONCENTRATIONS IN BREAST MILK OF HEALTHY LACTATING 
WOMEN RECEIVING VONOPRAZAN 20 MG ONCE DAILY OR 
VONOPRAZAN 20 MG TWICE DAILY 
 
28Aug2024 
Final Statistical Analysis Plan 
 
Version 1.0 
 
Prepared by: 
 
 
 
 
 
 
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Phathom Pharmaceuticals, Inc.
Final Statistical Analysis Plan, Version 1.0
Protocol: VONO-401
Date Issued: 28/08/2024
Page 2 of 20 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 4 
1.
INTRODUCTION ............................................................................................................ 5 
2.
OBJECTIVES AND ENDPOINTS ................................................................................. 5 
2.1 PRIMARY OBJECTIVE AND ENDPOINTS ................................................................................. 5 
2.2 SECONDARY OBJECTIVES AND ENDPOINTS .......................................................................... 5 
2.3 SAFETY OBJECTIVES AND ENDPOINTS ................................................................................. 6 
3.
STUDY DESIGN ............................................................................................................... 6 
4.
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 7 
4.1. SAMPLE SIZE ........................................................................................................................ 8 
4.2. RANDOMIZATION AND BLINDING ......................................................................................... 8 
4.3. ANALYSIS POPULATION ....................................................................................................... 8 
5.
SUBJECT DISPOSITION ............................................................................................... 9 
5.1 DISPOSITION ........................................................................................................................ 9 
5.2 PROTOCOL DEVIATIONS ....................................................................................................... 9 
5.3 INCLUSION AND EXCLUSION CRITERIA ................................................................................ 9 
6.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................... 9 
6.1 DEMOGRAPHICS ................................................................................................................... 9 
6.2 MEDICAL HISTORY ............................................................................................................ 10 
7.
TREATMENTS AND MEDICATIONS ....................................................................... 10 
7.1 PRIOR AND CONCOMITANT MEDICATIONS ......................................................................... 10 
7.2 STUDY TREATMENT ........................................................................................................... 10 
8.
PHARMACOKINETICS ............................................................................................... 10 
8.1 BREAST MILK CONCENTRATIONS AND AMOUNTS ............................................................. 10 
8.2 BREAST MILK PHARMACOKINETIC PARAMETERS AND INFANT EXPOSURE MEASURES ...... 11 
8.3 DATA HANDLING ............................................................................................................... 12 
8.3.1 
Pharmacokinetic Profile Exclusions ......................................................................... 12 
8.3.2 
Data Rounding .......................................................................................................... 12 
8.3.3 
Below the Limit of Quantification ............................................................................. 12 
8.3.4 
Missing Data ............................................................................................................. 12 
8.3.5 
Summary Statistics .................................................................................................... 12 
9.
SAFETY ANALYSIS ..................................................................................................... 13 
9.1 ADVERSE EVENTS .............................................................................................................. 13 
9.2 CLINICAL LABORATORY EVALUATIONS ............................................................................. 15 
9.3 VITAL SIGN MEASUREMENTS ............................................................................................ 16 
9.4 PHYSICAL EXAMINATION ................................................................................................... 16 
9.5 ELECTROCARDIOGRAMS .................................................................................................... 16 
9.6 BREASTFEEDING ................................................................................................................ 17 
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Date Issued: 28/08/2024
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10.
INTERIM ANALYSIS ................................................................................................... 17 
11.
CHANGES IN THE PLANNED ANALYSIS .............................................................. 17 
12.
REFERENCES ................................................................................................................ 18 
13.
SCHEDULE OF ASSESSMENTS ................................................................................ 19 
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Date Issued: 28/08/2024
 
Page 4 of 20 
 
List of Abbreviations 
 
AE 
adverse event 
AUC 
area under the drug concentration-time curve 
AUC0-24 
area under the drug concentration-time curve from time 0 to 24 hours following 
the last dose 
BLQ 
below the limit of quantification 
BMI 
body mass index 
Cavg 
average drug concentration in milk 
Cmax 
maximum drug concentration in milk 
Cmin 
minimum drug concentration in milk 
CSR 
clinical study report 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
ICF 
informed consent form 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic(s) 
PT 
preferred term 
PTE 
pretreatment event 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum observed milk concentration 
WHODrug
World Health Organization Drug Dictionary 
 
 
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1. Introduction 
Vonoprazan (TAK-438) is a member of a class of compounds referred to as 
potassium-competitive acid blockers (PCABs) that suppress gastric acid secretion by 
competitively inhibiting gastric hydrogen, potassium–adenosine triphosphatase (H+, K+-
ATPase). Vonoprazan is formulated and administered orally as its fumarate salt, vonoprazan 
fumarate. Following oral administration, the fumarate salt is rapidly converted to the free base 
form, and vonoprazan fumarate is not detectable in human plasma. 
Further information on the study drug can be found in the investigator’s brochure. 
The purpose of this statistical analysis plan (SAP) is to define the planned statistical analysis of 
the study data consistent with the study objectives. This SAP is written based on protocol 
VONO-401, version 2.0, dated 18 July 2024 . 
2. Objectives and Endpoints 
2.1 
Primary Objective and Endpoints 
Primary objective 
Endpoint 
 
To determine the pharmacokinetics 
(PK) of vonoprazan in breast milk of 
healthy lactating women who have 
received vonoprazan 20 mg 
administered once daily or vonoprazan 
20 mg administered twice daily for 
4 consecutive days 
 
Area under the drug concentration-time 
curve from time 0 to 24 hours 
following the morning dose (AUC0-24) 
on Day 4, maximum drug 
concentration in milk (Cmax), minimum 
drug concentration in milk (Cmin), and 
average drug concentration in milk 
(Cavg), time to maximum observed 
concentration in milk (Tmax)
2.2 
Secondary Objectives and Endpoints 
Secondary objective 
Endpoints 
 
To determine total drug excreted in 
milk 
 
Total amount of drug excreted in milk 
(mg) 
 
Amount of drug excreted in milk 
relative to the total dose received (%)
 
To estimate the relative infant dose of 
vonoprazan 
 
Estimated infant daily dose (mg/kg/day)
 
Estimated relative infant dose to the 
total maternal dose received (%) 
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Date Issued: 28/08/2024
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2.3 
Safety Objectives and Endpoints 
Safety objective 
Endpoint 

To evaluate the safety and tolerability of
vonoprazan 20 mg administered once
daily or vonoprazan 20 mg administered
twice daily for 4 consecutive days

Adverse events (AEs)

Clinical laboratory test values
(hematology, serum chemistry,
urinalysis)

Vital signs
3. Study Design
This is a Phase 1, nonrandomized, open-label study in healthy lactating women who have been
actively breastfeeding or pumping for at least 4 weeks postpartum. Approximately 15 subjects
will be enrolled. No formal sample size estimation was performed.
The study will consist of a Screening Period (up to 28 days prior to Baseline), Baseline (Day 1, 
predose), Treatment Period (4 days of treatment with study drug from Days 1 through 4 and 
24 hours of postdose assessments after the morning dose of study drug on Day 4), and a 7-day 
safety follow-up after the last dose. Since vonoprazan exhibits time-independent PK and steady-
state concentrations are achieved by Days 3 to 4, a once-daily or twice daily dose of vonoprazan 
20 mg administered for 4 consecutive days will ensure that breast-milk sampling occurs when 
drug exposure in plasma is at steady state.  
During the Screening Period, subjects will be evaluated to determine if they meet the 
inclusion/exclusion criteria; information on their current breastfeeding practice will also be 
obtained. After screening, eligible subjects will visit the clinical research unit on Day 1 for the 
baseline assessment to confirm protocol eligibility and to obtain baseline data. 
Subjects who complete the baseline assessment and meet the criteria for inclusion and exclusion 
will enter the Treatment Period and will be administered vonoprazan 20-mg tablet once daily or 
twice daily for 4 days (Days 1 through 4). On the mornings of Days 1 through 3, subjects will 
present in the clinical research unit for an outpatient visit, and for administration of vonoprazan 
20 mg orally with 240 mL of room temperature water, at approximately the same time each day 
and under direct observation of clinical research unit staff (without regard to food intake). Those 
assigned to receive vonoprazan 20 mg twice daily will self-administer a second dose of 
vonoprazan 20 mg orally with 240 mL of room temperature water at home approximately 12 
hours after the first dose on Days 1 through 3. The evening dose should be taken at the time 
instructed by the clinic staff, but can be taken late if no more than 4 hours have elapsed since the 
prescribed dosing time. If more than 4 hours have elapsed since the prescribed evening dosing 
time, the evening dose should not be taken. On Day 4, the morning and evening doses of 
vonoprazan 20 mg will be administered in the clinic. On Day 4, subjects will be admitted to the 
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Date Issued: 28/08/2024
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clinical research unit at least 2 hours prior to their scheduled dose administration for check-in 
procedures. Milk samples for PK assessments will be collected at prespecified intervals from 
predose (0 hour) and at pooled intervals up to 24 hours (0-4 hours, 4-8 hours, 8-12 hours, 12-18 
hours, and 18-24 hours) after the morning dose of study drug on Day 4. During each sampling 
interval, the sample collections will be done using a standardized electric pump for efficient milk 
extraction, emptying both breasts. The time of starting and finishing milk expression will be 
recorded. All milk within each prespecified sampling interval will be carefully combined and 
mixed, and the total volume recorded. After recording the volume, each milk sample will be 
mixed with a stabilizing solution in 1:1 ratio to ensure stability of vonoprazan in the milk 
sample. Details of this process will be provided in a separate document. Two equal aliquots from 
each of these stabilized interval collections will be appropriately labelled and stored immediately 
at or below -70 °C until analyzed for vonoprazan concentrations. 
Safety will be assessed by monitoring AEs, clinical laboratory test results (hematology, serum 
chemistry, and urinalysis), and vital signs. In the event of early termination, subjects should 
return to the clinical research unit for final safety assessments. These subjects may be replaced at 
the investigator’s discretion. 
Subjects will be confined to the clinical research unit from the morning of Day 4 until discharge 
on Day 5. All subjects will be followed up via a phone call on Day 11 (±2 days) for follow-up 
safety assessments of AEs, concomitant medication use, and to reassess breastfeeding practices 
(eg, frequency, duration of feeds, use of formula supplementation), along with a description of 
any challenges the subject experienced and any need for lactation consultation. Information will 
also be obtained to determine whether reinitiation of breastfeeding was established for subjects 
who planned to continue breastfeeding after Day 9. 
The duration of the study for individual subjects, excluding Screening Period, is approximately 
13 days. 
Schedules of assessments can be found in Section 13. 
4. General Statistical Considerations
All statistical analyses will be conducted using statistical analysis system (SAS®) Version 9.4 or
higher (SAS Institute, Cary, NC).
Descriptive statistics for continuous variables will include number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum, unless otherwise noted. For categorical 
variables, frequencies and percentages will be presented. 
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All tables, listings, and figures will be presented by treatment. The treatments below will be used 
for presentations: 
Vonoprazan 20 mg tablet once daily; 
Vonoprazan 20 mg tablet twice daily; 
All data listings will be sorted by treatment and subject number. 
No algorithm for imputation of missing data will be employed. 
Study days are calculated with respect to the first dose date as below: 
 If the assessment/observation date is on or after the first dose date, then  
Study Day = Assessment/Observation Date – First Dose Date + 1; 
 Otherwise, Study Day = Assessment/Observation Date – First Dose Date 
Baseline will be defined as the last non-missing assessment (including repeated and unscheduled 
assessments) before the first dose of study drug, unless otherwise specified. 
For summary of safety assessments, if there are repeated measurements at a time point, the first 
non-missing assessment at that time point will be used in the summary tables. 
Unscheduled results will not be included in the summary tables, except for determining Baseline, 
but will be presented in data listings. 
The methodology and data handling specifications for PK data are detailed in Section 8. 
4.1. 
Sample Size 
The number of subjects is based on clinical and practical considerations and not on a formal 
statistical power calculation. The total sample size of 15 subjects is considered sufficient for the 
objectives of the study. 
4.2. 
Randomization and Blinding 
This is a nonrandomized and open-label study. The first 5 subjects will be assigned to receive 
vonoprazan 20 mg once daily and the next 10 subjects will be assigned vonoprazan 20 mg twice 
daily.  
4.3. 
Analysis Population 
The safety population will include all subjects who received at least 1 dose of study drug. 
The PK population will include all subjects who received sufficient doses of vonoprazan and 
have sufficient concentration data in milk to support accurate estimation of at least 1 PK 
parameter in milk. 
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5. Subject Disposition 
5.1 
Disposition 
The screened population will include all subjects who signed informed consent form (ICF). 
The following will be summarized for the screened population for all: 
 
The number of subjects who screen failed (both overall and according to reason for 
screen failure) 
 
The number of subjects who received treatment 
 
The number of subjects who completed the study 
 
The number of subjects treated who did not complete the study (both overall and 
according to reasons for discontinuation from the study) 
 
The number of subjects in each analysis population 
Subject disposition data will be presented in a data listing. 
5.2 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. An important deviation (sometimes referred to as a major or significant 
deviation) is a subset of protocol deviations that leads to a subject being discontinued from the 
study, or significantly affects the subject’s rights, safety, or well-being and/or the completeness, 
accuracy, and reliability of the study data. 
Significant protocol deviations will be summarized in a table and all protocol deviations will be 
presented in a data listing. 
5.3 
Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria deviations will be presented in a data listing. 
6. Demographics and Baseline Characteristics 
6.1 
Demographics 
Demographic information collected at screening will be presented in a data listing. 
Descriptive statistics will be calculated for the following continuous demographic characteristics:  
 
Age (years) 
 
Weight (kg) 
 
Height (cm) 
 
Body mass index (BMI) (kg/m2) 
Frequency counts and percentages will be tabulated for the categorical variables: 
 
Sex 
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
Race

Ethnicity
The summaries will be presented by treatment and overall for the safety population. 
6.2 
Medical History 
The medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, version 27.0) and presented in a data listing. 
7. Treatments and Medications
7.1 
Prior and Concomitant Medications
Medications that stop prior to the first dose of Vonoprazan will be classified as prior medication.
Medications that start on or after the first dose of study drug will be classified as concomitant. If
a medication starts before the first dose of study drug and stops on or after the first dose of study
drug, then the medication will be classified as both prior and concomitant.
All prior and concomitant medications will be coded according to the World Health Organization 
Drug Dictionary (WHODrug, version 2024-March (Global B3)) and presented in a data listing. 
7.2 
Study Treatment 
The study drug administration data as collected on electronic case report form (eCRF) will be 
presented in a data listing. 
8. Pharmacokinetics
All PK listings will be presented using the safety population, and subjects not included in the PK
population will be highlighted. Individual PK concentrations, amounts, and parameters will be
presented using the safety population, and subjects not included in the PK population will be
highlighted. Subjects without any estimable PK parameters will not be presented in the listing of
PK parameters. PK tables and mean figures will be presented using the PK population.
8.1 
Breast Milk Concentrations and Amounts 
Breast milk samples will be collected at the following time points for PK assessment: 
Prior to the morning dose on Day 4 and at regularly scheduled intervals through 24 hours 
after the morning dose (0-4 hours, 4-8 hours, 8-12 hours, 12-18 hours, and 18-24 hours) 
Individual breast milk concentrations, amounts (concentration * volume), and cumulative 
amounts will be presented in data listings and summarized separately by dosing scheme (once 
daily or twice daily) and collection interval. 
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Individual breast milk concentrations will be plotted by actual mid-point of the collection 
interval on a linear scale. Arithmetic mean breast milk concentrations will be plotted by nominal 
mid-point of the collection interval on a linear scale. Individual and arithmetic mean amounts, 
and cumulative amounts will be plotted by collection interval on a linear scale. 
8.2 
Breast Milk Pharmacokinetic Parameters and Infant Exposure Measures 
Breast milk vonoprazan concentration-time data and excretion parameters will be derived from 
vonoprazan amount data using SAS® (SAS Institute Inc., Cary, North Carolina) Version 9.4 or 
higher. The following PK parameters and infant exposure measures will be calculated for 
vonoprazan, where data permit: 
Parameter 
Definition 
Cmin 
Minimum observed concentration. 
Cmax 
Maximum observed concentration. 
Cavg 
Average concentration, calculated as: AUC0-24 / tau (tau = 24 hours) 
Tmax 
Time to maximum observed concentration (actual midpoint of the interval in 
which Cmax is observed). 
AUC0-24 
AUC from time 0 to 24 hours post-dose, calculated as: the sum of the product 
of the concentration of the interval and the width of the interval 
i.e. Σ interval concentration × interval width
The actual interval width will be used in the derivation.
Total amount 
of drug 
excreted (mg)
Total amount of drug excreted in breast milk over 24 hours; calculated as the 
sum of drug concentration × expressed milk volume in each collection 
interval over 24-hour period. 
Relative 
amount 
excreted (%) 
Total amount of drug excreted over 24 hours relative to total dose 
administered; calculated as the sum of (total amount of drug excreted in each 
collection interval / total dose received over 24-hour period) * 100. 
Daily 
maternal dose 
(mg/kg) 
Maternal dose received; calculated as: 
20 mg / mother’s body weight in kg (once daily dosing) or 40 mg / mother’s 
body weight in kg (twice daily dosing). 
Daily infant 
dose 
(mg/kg/day) 
Estimated weight adjusted daily dose consumed by the infant through breast 
milk; calculated as total amount of drug excreted over 24-hour period / weight 
of infant. 
Calculation will use the nominal infant weight of 6.0 kg which is the 
approximate 50th percentile for a 3-month old infant. 
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Relative 
infant dose 
(%) 
Daily infant dose relative to the daily maternal dose; calculated as (daily 
infant dose / daily maternal dose) * 100. 
Actual sampling times will be used for the estimation of all breast milk PK parameters, and all 
concentrations associated with scheduled sampling times will be included in the analysis. 
Unscheduled PK samples will not be included in the estimation of PK parameters. 
Breast milk PK parameters and exposure measures will be presented in data listings and 
summarized descriptively by dosing scheme (once daily or twice daily). 
8.3 
Data Handling 
8.3.1 Pharmacokinetic Profile Exclusions 
Where subjects experience issues pertaining to a specific administration of study drug which 
may affect exposure to study drug during PK sample collections (eg, dosing errors, etc), 
individual PK results will be reviewed and evaluated by the study pharmacokineticist on a case-
by-case basis for potential exclusion from treatment summaries and/or the PK population. All 
exclusions will be documented throughout the affected data listings. 
8.3.2 Data Rounding 
Concentration data will be reported in the listings to the same precision as received in the raw 
bioanalytical data. Amounts, PK parameter estimates, and infant exposure measures will be 
reported to 3 significant figures. Associated concentration, amount, parameter, and measure 
summary statistics will be reported to 3 significant figures except number of non-missing 
observations (n), which will be reported as an integer.  
8.3.3 Below the Limit of Quantification 
Breast milk concentrations that are below the limit of quantification (BLQ) will be treated as 
zero for the calculation of amounts, concentration descriptive statistics, and estimation of all PK 
parameters.  
8.3.4 Missing Data 
All missing concentration data will be presented as missing in concentration data listings and 
excluded from the estimation of amounts, concentration summary statistics, and PK parameters. 
No imputation for missing data will be performed. 
8.3.5 Summary Statistics 
Summary statistics to be presented for each output are as follows: 
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Breast milk concentrations and amounts: n, arithmetic mean, standard deviation (SD), 
percent coefficient of variation (CV), geometric mean, geometric CV, median, minimum, 
and maximum. 
Breast milk concentration and amount data will be summarized according to nominal time 
windows. 
Breast milk PK parameters and infant exposure measures: n, arithmetic mean, SD, CV, 
geometric mean, geometric CV, median, minimum, and maximum; only n, median, 
minimum, and maximum will be presented for Tmax. 
Where only one observation is observed (ie, n=1), only the number of observations, arithmetic 
mean, median, minimum, and maximum will be presented. 
Where breast milk concentrations are BLQ (handled as zero for amount calculation, summary 
statistics, and parameter generation), geometric mean and geometric CV will be reported as not 
applicable (NA). 
9. Safety Analysis 
All safety summaries and analyses will be based upon the safety population. 
9.1 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related. 
A pretreatment event (PTE) is defined as any untoward medical occurrence that has occurred 
prior to administration of any study drug in a clinical investigation subject who has signed ICF to 
participate in a study; it does not necessarily have to have a causal relationship with study 
participation. 
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 the study drug. 
A serious AE (SAE) is defined as any untoward medical occurrence at any dose that meets one of 
the following criteria: 
1. Results in death. 
2. Is life-threatening. The term “life-threatening” refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. 
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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 9.1 of protocol) 
 
Exposes the subject to danger, even though the event is not immediately life-threatening 
or fatal or does not result in hospitalization 
The AE’s relationship to study treatment will be evaluated by the investigator. The following 
relationships will be collected on eCRF: related or not related. 
The AEs that are evaluated as related will be considered treatment-related AEs for summary 
purpose. 
The severity of AEs will be classified by the investigator as mild, moderate, or severe. 
An overall TEAE summary will be generated presenting the frequency and percentage of 
subjects and the number of AEs for the following: 
Any AE 
Any PTE  
Any TEAE 
Any treatment-related TEAE 
Any Mild TEAE 
Any treatment-related Mild TEAE 
Any moderate TEAE 
Any treatment-related moderate TEAE 
Any severe TEAE 
Any treatment-related severe TEAE 
Any SAE 
Any treatment-related SAE 
Any TEAE leading to early discontinuation 
Any death  
All AEs will be coded using MedDRA (version 27.0). The TEAEs will also be summarized by 
system organ class (SOC), preferred term (PT), by severity and relationship to study treatment. 
The TEAE summary tables will be sorted by SOC and PT. System organ class will be displayed 
in descending order of overall frequency then alphabetically. Preferred term will be displayed in 
descending order of overall frequency and then alphabetically within SOC. A subject with 2 or 
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more events within the same level of summarization will be counted only once in that level using 
the most severe incident or most related incident. Percentages will be based on the number of 
subjects in the safety population. 
All AEs will be presented in a data listing. Separate data listings will be generated for 
treatment-related AEs, treatment-emergent AEs, PTEs, and SAEs, and AEs leading to study 
treatment discontinuation. 
9.2 
Clinical Laboratory Evaluations 
The following laboratory tests will be performed: 
Hematology 
Absolute neutrophil count and differential count, hematocrit, 
hemoglobin, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, leukocytes count (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), mean corpuscular volume, 
platelet count, red blood cell count, and red blood cell distribution 
width
Serum chemistry 
Alanine aminotransferase (ALT), albumin, alkaline phosphatase, 
aspartate aminotransferase (AST), bilirubin (total), blood urea 
nitrogen, calcium, carbon dioxide, chloride, cholesterol (total, high-
density lipoprotein, and calculated low-density lipoprotein), 
creatinine, gamma-glutamyltransferase, globulin, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total protein, 
triglycerides, and uric acid
Urinalysis 
Appearance, bilirubin, color, glucose, ketones, leukocyte esterase, 
reflex microscopy (performed if dipstick is positive for protein or the 
blood value is 1+ or greater; and includes bacteria, casts, crystals, 
epithelial cells, red blood cells, and white blood cells), nitrites, occult 
blood, pH, protein, specific gravity, turbidity, and urobilinogen
Serology 
Hepatitis B surface antigen, hepatitis C virus antibody, and HIV 
antibody types 1 and 2 (Screening only)
Other analyses 
Urine drug screen (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine metabolites, cotinine, methamphetamines, 
methylenedioxymethamphetamine, and opiates [including heroin, 
codeine, and oxycodone]), COVID-19 screening (SARS-CoV-2 
testing will be conducted as per clinical research unit’s standard 
processes), serum and urine pregnancy test (human chorionic 
gonadotropin), international normalized ratio (INR) (to be done when 
follow-up laboratory tests are required for elevated ALT or AST levels 
per Section 9.3.1 of protocol), and an alcohol breath test
The clinical laboratory tests will be performed at the timepoints indicated in the schedule of 
assessments (schedules of assessments can be found in Section 13). 
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All clinical laboratory test results will be presented in the data listings. Laboratory values that are 
outside of the normal reference range will be flagged in the data listings. 
Actual results and change from baseline for hematology, serum chemistry, and urinalysis 
quantitative data at post-dose time point will be summarized for the safety population. Shift from 
baseline in terms of low/normal/high for hematology and serum chemistry tests, and in terms of 
normal/abnormal for urinalysis tests will be summarized for the safety population.  
9.3 
Vital Sign Measurements 
Vital signs will include systolic and diastolic blood pressure, heart rate, respiratory rate, and 
body temperature will be measured at the timepoints indicated in the schedule of assessments 
(schedules of assessments can be found in Section 13). 
All vital sign, body weight, and height measurements will be presented in a data listing. The 
actual values and change from baseline values at each time point will be summarized for the 
safety population. 
9.4 
Physical Examination 
A full physical examination will include, at minimum, assessment of skin, head, ears, eyes, nose, 
throat, neck, thyroid, lungs, cardiovascular, abdomen, lymph nodes, and musculoskeletal 
system/extremities. A brief physical examination will include, at minimum, assessment of skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
Full physical examinations will be performed at Screening (Visit 1), and abbreviated physical 
examinations will be performed at the timepoints indicated in the schedule of assessments 
(schedules of assessments can be found in Section 13). 
A data listing will indicate the performance of the physical exams. 
9.5 
Electrocardiograms 
Single 12-lead (electrocardiogram) ECGs will be obtained 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. Assessments will include comments on whether the tracings are normal 
or abnormal, rhythm, presence of arrhythmia or conduction defects, morphology, any evidence of 
myocardial infarction, or ST-segment, T-Wave, and U-Wave abnormalities. 
Heart rate, PR interval, QRS width, RR interval, QT interval, QT interval corrected for heart rate 
using Fridericia’s formula (QTcF), and interpretation of ECG will be captured on the eCRF. 
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Single 12-lead ECG will be performed at the timepoints indicated in the schedule of assessments 
(schedules of assessments can be found in Section 13). 
All ECG data will be presented in a data listing. 
9.6 
Breastfeeding 
Subjects will be asked about their intentions for continuing breastfeeding and information will be 
obtained regarding their current breastfeeding practices (eg, frequency, duration of feeds, use of 
formula supplementation). 
Breastfeeding practices will be reassessed, along with a description of any challenges the subject 
experienced and any need for a lactation consultant. (schedules of assessments can be found in 
Section 13). 
All breastfeeding data will be presented in a data listing. 
10. Interim Analysis 
No formal interim analyses are planned. 
11. Changes in the Planned Analysis 
Any changes from this statistical analysis plan will be documented in the clinical study report 
(CSR) for this study. 
 
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12. 
References 
None. 
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13.
Schedule of Assessments
Period
Screening 
Baseline 
Treatment 
Safety Follow-up Telephone Call/ 
EOS 
Procedure 
Day
–28 to –1
1 
(Predose) 
1 
2 
3 
4 
5/ET 
11 (±2 Days) 
Admission to clinical research 
unit
X 
Discharge from clinical research 
unit (a)
X 
Outpatient visit(b)
X
X
X
X
X
Telephone call(c)
X
Informed consent
X
Demographics
X
Serology(d)
X
Inclusion/exclusion criteria 
X
X
Medical history
X
X
Urine drug/alcohol/cotinine 
screen(e)
X 
X 
X 
Height, weight, and BMI(f) 
X
X
X
Physical examination(g) 
X
X 
X
Vital sign measurements(h)
X
X
X
X
12-lead ECG(i)
X
X
Clinical laboratory testing(j) 
X
X
X
Pregnancy test(k) 
X
X
X
X
Study drug administration(l) 
X
X
X
X
Milk PK sample collection(m) 
X
X
Lactation consultation(n)
X
X
X
X
X
X
X
X
Breastfeeding discussion(o)
X
X
X
PTEs monitoring(p)
X
X
AEs(q)
X
Prior/concomitant medications
X
Abbreviations: AEs, adverse events; BMI, body mass index; ECG, electrocardiogram; EOS, end of the study; ET, early termination; ICF, informed consent form; PK, 
pharmacokinetic; PTE, pretreatment event; QTcF, QT interval corrected for heart rate using Fridericia’s formula. 
Notes: 
(a) Discharge on Day 5 following 24-hour milk PK sample collection. Note: Subjects who withdraw before completion of the study should return to the clinical
research unit for ET assessments.
(b) Outpatient visits will occur at the clinical research unit at Screening and on Days 1 through 3; subjects will be administered vonoprazan tablet in the morning at
the same time each day.
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(c) Safety follow-up/EOS telephone call: Subjects will receive a telephone call from the clinical research unit 7 days (±2 days) after their last dose of study drug to 
assess for AEs and concomitant medication use. Information will also be obtained to determine whether reinitiation of breastfeeding was established for subjects 
who planned to continue breastfeeding after Day 9). Breastfeeding practices (eg, frequency, duration of feeds, use of formula supplementation) will be reassessed, 
along with a description of any challenges the subject experienced and any need for a lactation consultant. 
(d) Serology testing will include hepatitis B surface antigen, hepatitis C virus antibody, and HIV types 1 and 2 antibodies. For COVID-19 screening, SARS-CoV-2 
testing will be conducted as per clinical research unit’s standard processes. 
(e) Urine drug/alcohol/cotinine screen will occur at Screening, Baseline, and Day 4/Check-in per the clinical research unit’s standard procedures. 
(f) Height and weight will be measured, and BMI calculated at Screening only. Only weight will be measured at Baseline and Day 5/ET. 
(g) A full physical examination will be performed at Screening (at a minimum, assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, cardiovascular 
system, abdomen, lymph nodes, and musculoskeletal system/extremities). A brief physical examination will be performed at Baseline and Day 5/ET (at a 
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. 
(h) Vital signs will be measured at Screening and Baseline; within 60 minutes prior to study drug dosing on Day 4; and on the day of discharge (Day 5)/ET. Vital 
signs will be measured after the subject has been in the seated position for at least 5 minutes and will include systolic and diastolic blood pressure, heart rate, 
respiratory rate, and body temperature. 
(i) Single 12-lead ECG recordings will be made at Screening and Baseline after the subject has been in the supine position for at least 5 minutes. A single repeat 
measurement is permitted at Screening for eligibility determination. Measurements of the following intervals will be reported: RR interval, PR interval, 
QRS width, QT interval, and QTcF. Assessments should include comments on whether the tracings are normal or abnormal; rhythm; presence of arrhythmia or 
conduction defects; morphology; any evidence of myocardial infarction; or ST-segment, T-Wave, and U-Wave abnormalities. 
(j) Clinical laboratory testing will occur at Screening, Baseline, and on the day of discharge (Day 5)/ET. A complete list of assessments is provided in Section 6.2.2 
of protocol. Blood and urine samples will be collected under fasted conditions and prepared per the clinical research unit’s standard procedures. 
(k) All subjects will undergo a pregnancy test at Screening, Baseline, and Day 4/Check-in, or ET. A serum pregnancy test will be performed at Screening and urine 
pregnancy test at Baseline and on Day 4/Check-in or ET. 
(l) Each subject will receive vonoprazan 20-mg tablet in the morning from Day 1 through Day 4. All doses of vonoprazan will be administered with 240 mL of room 
temperature water. Subjects will maintain an upright (ie, seated or standing) position for at least 4 hours after dosing. 
(m) Breast milk samples for PK analyses will be collected predose on Day 4, and at regularly scheduled intervals through 24 hours after dosing (0-4 hours, 4-8 hours, 
8-12 hours, 12-18 hours, and 18-24 hours). During each collection interval, all milk will be collected and at the conclusion of each interval both breasts will be 
completely emptied using an electric breast pump and milk will be carefully combined with any milk collected previously within that interval. The combined 
sample will be mixed, and the total volume recorded. After recording the volume, each milk sample will be mixed with a stabilizing solution in a 1:1 ratio to 
ensure stability of vonoprazan in the milk sample. Aliquots from each of these interval collections will be stored and analyzed for vonoprazan concentrations. 
(n) Subjects will have access to a lactation consultant throughout the study to provide lactation support as needed. 
(o) At Screening and Baseline, subjects will be encouraged to have stored breast milk available for feeding their infants for the duration of approximately 9 days 
(from Day 1 till 5 days after the last dose). Subjects will be asked about their intentions for continuing breastfeeding after Day 9 and information will be obtained 
regarding their current breastfeeding practices (eg, frequency, duration of feeds, use of formula supplementation). At the safety follow-up telephone call, subjects 
will be asked whether reinitiation of breastfeeding was established for subjects who planned to continue breastfeeding after Day 9. Breastfeeding practices will be 
reassessed, along with a description of any challenges the subject experienced and any need for a lactation consultant. 
(p) Collection of PTEs will start after the subject has signed the ICF. 
(q) Adverse events will be assessed from the time of the first study drug dosing until EOS and should be followed until they are resolved, stable, or judged by the 
investigator to be not clinically significant.
 
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Statistical Analysis Plan (SAP) Client Approval Form 
Document Number: FORM-02894 v8.0 
Page 1 of 1 
Effective Date: 22 Nov 2021 
Printed on: 30 August 2024 
Client: 
Phathom Pharmaceuticals, Inc. 
Protocol Number: 
VONO-401 
Document Description: 
Final Statistical Analysis Plan 
SAP Title: 
A Phase 1, Open-Label Study to Evaluate Vonoprazan 
Concentrations in Breast Milk of Healthy Lactating 
Women Receiving Vonoprazan 20 mg Once Daily or 
Vonoprazan 20 mg Twice Daily 
SAP Version Number: 
Final Version 1.0 
Effective Date: 
30 August 2024 
Author(s): 
For 
 
, Biostatistician 
Approved by: 
Biostatistics and Programming, 
Phathom Pharmaceuticals, Inc. 
Date (DD-MMM-YYYY) 
Clinical Ph
Phathom Pharmaceuticals, Inc. 
Date (DD-MMM-YYYY) 
30-Aug-2024
30-Aug-2024
Page 23