An Open-Label, Fixed Sequence, Clinical Drug Interaction Study to Evaluate the Time-Dependent Inhibition Potential of Vonoprazan on a Sensitive CYP3A4 Substrate, Midazolam, in Healthy Volunteers
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: Phathom Pharmaceuticals, Inc.

Protocol Number: VONO-101 
 
Official Title: An Open-Label, Fixed-Sequence, Clinical Drug Interaction Study to Evaluate the Time-
Dependent Inhibition Potential of Vonoprazan on a Sensitive CYP3A4 Substrate, Midazolam, in Healthy 
Volunteers  
 
NCT Number: NCT04545944 
 
Document Date:  04 September 2020 

Title Page 
CLINICAL STUDY PROTOCOL 
IND 079212 
AN OPEN-LABEL, FIXED-SEQUENCE, CLINICAL DRUG 
INTERACTION STUDY TO EVALUATE THE TIME-DEPENDENT 
INHIBITION POTENTIAL OF VONOPRAZAN ON A SENSITIVE CYP3A4 
SUBSTRATE, MIDAZOLAM, IN HEALTHY VOLUNTEERS 
VONO-101 
Sponsor: 
Phathom Pharmaceuticals, Inc. 
2150 E. Lake Cook Road 
Suite 800 
Buffalo Grove, IL 60089 
Sponsor Contact: 
 
 
 
Medical Monitor: 
 
 
 
 
 
 
Version of Protocol: 
Amendment 1, Version 2.0 
Date of Protocol:  
04 September 2020 
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. 
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Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
Page 2 
SIGNATURE PAGE 
PROTOCOL TITLE: 
An Open-Label, Fixed-Sequence, Clinical Drug Interaction 
Study to Evaluate the Time-Dependent Inhibition Potential 
of Vonoprazan on a Sensitive CYP3A4 Substrate, 
Midazolam, in Healthy Volunteers 
PROTOCOL NUMBER: 
VONO-101 
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Phathom Pharmaceuticals, Inc. 
Protocol No. VON0-101 
Vonoprazan 
Clinical Study Protocol Amendment 1 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree to conduct the study as outlined in the protocol titled "An Open-Label, Fixed-Sequence, 
Clinical Drug Interaction Study to Evaluate the Time-Dependent Inhibition Potential of 
Vonoprazan on a Sensitive CYP3A4 Substrate, Midazolam, in Healthy Volunteers" in accordance 
with the guidelines and all applicabl 
overnment regulations, including US Title 21 of the Code 
a e \ ead and understand all sections of the protocol. 

Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
 
Page 4 
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 ................................................................................... 8 
1.3 
RATIONALE FOR DOSE SELECTION................................................................ 9 
2. 
STUDY OBJECTIVES ............................................................................................ 10 
2.1 
PRIMARY OBJECTIVE ....................................................................................... 10 
2.2 
SECONDARY OBJECTIVES .............................................................................. 10 
3. 
STUDY DESIGN ...................................................................................................... 10 
3.1 
SCHEDULE OF EVENTS .................................................................................... 12 
4. 
STUDY POPULATION........................................................................................... 14 
4.1 
INCLUSION CRITERIA ...................................................................................... 14 
4.2 
EXCLUSION CRITERIA ..................................................................................... 14 
4.3 
WITHDRAWAL CRITERIA ................................................................................ 16 
4.4 
SUBJECT REPLACEMENT ................................................................................ 16 
5. 
STUDY TREATMENTS ......................................................................................... 17 
5.1 
TREATMENTS ADMINISTERED ...................................................................... 17 
5.2 
INVESTIGATIONAL PRODUCTS ..................................................................... 17 
5.2.1 
Study Drug Preparation and Storage ................................................................. 17 
5.2.2 
Study Drug Accountability ................................................................................ 18 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS .............. 18 
5.4 
BLINDING ............................................................................................................ 18 
6. 
STUDY PROCEDURES ......................................................................................... 18 
6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS ........................... 18 
6.1.1 
Pharmacokinetic Sample Collection .................................................................. 19 
6.1.2 
Pharmacokinetic Sample Analysis..................................................................... 19 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS ................................................... 19 
6.2.1 
Adverse Events .................................................................................................. 20 
6.2.2 
Clinical Laboratory Assessments ...................................................................... 20 
7. 
STATISTICAL ANALYSIS PLANS ...................................................................... 21 
7.1 
SAMPLE SIZE CALCULATIONS....................................................................... 21 
7.2 
ANALYSIS SETS ................................................................................................. 21 
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Vonoprazan 
Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
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7.3 
STATISTICAL ANALYSES ................................................................................. 22 
7.3.1 
Pharmacokinetic Analyses ................................................................................. 22 
7.3.2 
Safety Analyses ................................................................................................. 23 
7.4 
HANDLING OF MISSING DATA ....................................................................... 23 
7.5 
INTERIM ANALYSES ......................................................................................... 23 
8.
REFERENCE LIST................................................................................................. 24 
9.
APPENDICES .......................................................................................................... 25 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS ....................................................... 25 
9.2 
APPENDIX 2: STANDARD PROCEDURES ...................................................... 27 
9.2.1 
Removal of Subjects From Therapy or Assessment .......................................... 27 
9.2.1.1 
General Criteria for Withdrawal .................................................................... 27 
9.2.1.2 
Handling of Withdrawals ............................................................................... 28 
9.2.2 
Prior and Concomitant Medications and Therapies .......................................... 28 
9.2.2.1 
Prior Medications ........................................................................................... 28 
9.2.2.2 
Concomitant Medications .............................................................................. 28 
9.2.3 
Treatment Compliance....................................................................................... 28 
9.3 
APPENDIX 3: ADVERSE EVENT DEFINITIONS AND REPORTING ........... 29 
9.3.1 
Adverse Event Definitions ................................................................................ 29 
9.3.2 
Eliciting and Documenting Adverse Events ...................................................... 31 
9.3.3 
Reporting Adverse Events and Serious Adverse Events ................................... 32 
9.3.4 
Additional Points to Consider for Pre-Treatment Events and Adverse Events . 33 
9.3.5 
Assessment of Severity ...................................................................................... 36 
9.3.6 
Assessment of Causality .................................................................................... 36 
9.3.6.1 
Relationship to Study Procedures .................................................................. 37 
9.3.6.2 
Start Date ....................................................................................................... 37 
9.3.6.3 
Stop Date ....................................................................................................... 37 
9.3.6.4 
Frequency ...................................................................................................... 37 
9.3.6.5 
Action Concerning Study Drug ..................................................................... 37 
9.3.6.6 
Outcome ......................................................................................................... 38 
9.3.7 
Follow-up of Adverse Events and Serious Adverse Events .............................. 38 
9.3.8 
Pregnancy .......................................................................................................... 39 
9.3.9 
Safety Reporting to Investigators, Institutional Review Boards, Independent 
Ethics Committees, and Regulatory Authorities ............................................... 39 
9.4 
APPENDIX 4: STUDY GOVERNANCE ............................................................ 40 
9.4.1 
Data Quality Assurance ..................................................................................... 40 
9.4.2 
Investigator Obligations .................................................................................... 40 
9.4.2.1 
Confidentiality ............................................................................................... 40 
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Vonoprazan 
Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
 
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9.4.2.2 
Institutional Review ....................................................................................... 41 
9.4.2.3 
Subject Consent ............................................................................................. 41 
9.4.2.4 
Study Reporting Requirements ...................................................................... 41 
9.4.2.5 
Financial Disclosure and Obligations ............................................................ 42 
9.4.2.6 
Investigator Documentation ........................................................................... 42 
9.4.2.7 
Study Conduct ............................................................................................... 43 
9.4.2.8 
Case Report Forms and Source Documents .................................................. 43 
9.4.2.9 
Adherence to Protocol ................................................................................... 43 
9.4.2.10 
Reporting Adverse Events ............................................................................. 43 
9.4.2.11 
Investigator’s Final Report ............................................................................ 44 
9.4.2.12 
Records Retention .......................................................................................... 44 
9.4.2.13 
Publications .................................................................................................... 44 
9.4.3 
Study Management ............................................................................................ 44 
9.4.3.1 
Monitoring ..................................................................................................... 44 
9.4.3.2 
Management of Protocol Amendments and Deviations ................................ 45 
9.4.3.3 
Premature Termination or Suspension of the Study or Investigational Site .. 46 
9.4.3.4 
Study Termination .......................................................................................... 47 
9.4.3.5 
Final Report ................................................................................................... 47 
 
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Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
 
Page 7 
1. 
INTRODUCTION 
Vonoprazan fumarate (TAK-438) belongs to a novel class of acid suppressants known as PCABs 
that suppress gastric acid secretion by competitively inhibiting gastric H+, K+-ATPase. 
Vonoprazan was discovered and developed by Takeda Pharmaceutical Company, Japan and is 
being developed by Phathom Pharmaceuticals in the United States, Europe, and Canada for 
healing of all grades of EE and relief of heartburn, maintenance of healing of all grades of EE 
and relief of heartburn, and treatment of Helicobacter pylori infection. Vonoprazan has been 
studied in a number of other acid-related diseases including gastric ulcer/duodenal ulcer healing 
and for the prevention of recurrence of a gastric or duodenal ulcer during nonsteroidal 
anti-inflammatory drugs or aspirin administration. Vonoprazan has received regulatory approval 
in Japan and other countries in Asia and Latin America for these indications. 
1.1 
BACKGROUND 
Gastric H+, K+-ATPase, also known as the proton pump, is responsible for acid secretion from 
parietal cells in the stomach. It is inactive in the cytosol but relocates from the cytosol to the 
secretory membrane of the parietal cells when food is present in the stomach, thereby becoming 
active and pumping H+ ions out of the cells and into the canaliculi in exchange for K+ ions. It 
represents an attractive pharmacological target because it is the final step of the acid secretion 
process. Two classes of pharmaceuticals, with distinct mechanisms of action for inhibiting the 
gastric proton pump, have been developed for clinical application: PPIs and PCABs. As a PCAB, 
vonoprazan has a unique mechanism of action and PK relative to PPIs, as follows: 
x Acid activation and stability: Conventional PPIs are prodrugs that are activated by acid and 
covalently bind H+, K+-ATPase; however, activated PPIs are not stable in acidic conditions. 
In contrast, vonoprazan does not require acid activation, is stable in acidic conditions, and 
does not require enteric-coated formulations; thus they have a more durable effect. 
Furthermore, vonoprazan is rapidly protonated in the parietal cell canaliculi, which 
concentrates the drug proximal to H+, K+-ATPase. 
x Activity against active and inactive proton pumps: Vonoprazan inhibits acid secretion by 
competitively inhibiting the binding of potassium ions to H+, K+-ATPase. Vonoprazan can 
bind to the pump while it is active or inactive; in contrast, PPIs covalently bind 
H+, K+-ATPase only when the pump is active, as an acidic environment is required for the 
activation and accumulation of PPIs in the parietal cell. Pumps are constantly switching 
between the active and inactive states throughout the day; therefore, multiple doses of PPIs 
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Vonoprazan 
Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
 
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are required to control acid compared with a single dose of vonoprazan. Vonoprazan can also 
be dosed in the presence or absence of food, whereas most PPIs require dosing before a meal 
as eating stimulates activation of the pumps. 
x Extended half-life: The plasma half-life of vonoprazan (20 mg) is 6.9 hours after the first 
dose and 8.6 hours after the seventh day of once daily dosing in humans (Jenkins et al 2015). 
This is significantly longer than the half-life of conventional PPIs (<2 hours; Shin and Kim 
2013). 
x Metabolism: Vonoprazan is predominantly metabolized by CYP3A4, which lacks a high 
degree of genetic polymorphism compared with CYP2C19, the primary enzyme responsible 
for the metabolism of PPIs. 
These unique aspects of vonoprazan’s mechanism relative to that of PPIs translate into greater 
magnitude and duration of gastric acid suppression, which are reflected in the pharmacodynamic 
profile. 
In clinical studies, plasma concentrations of TAK-438F (vonoprazan free base) reached a peak by 
approximately 1.0 hour (median) after administration and gradually declined thereafter, with a 
mean apparent t1/2 of 8.9 hours. The exposure and Cmax for TAK-438F increased with increasing 
doses of vonoprazan in a slightly greater than dose-proportional manner. After repeat dosing of 
vonoprazan, steady state was achieved by Day 4 and exhibited time independent PK. No 
clinically relevant effects of food or sex were observed on the PK of vonoprazan. Vonoprazan is 
metabolized mainly by hepatic drug-metabolizing enzyme CYP3A4 and partially by CYP2B6, 
CYP2C19, and CYP2D6. 
Overall, vonoprazan has been well tolerated in healthy volunteers in Phase 1 studies, as well as 
in completed Phase 2 and 3 studies of Japanese, Asian, and Western subjects with acid-related 
diseases. 
Further information on vonoprazan can be found in the investigator’s brochure (Global 
Investigator’s Brochure 10th Edition). 
1.2 
RATIONALE FOR STUDY 
Vonoprazan exhibited time-dependent inhibition of CYP2B6, CYP2C19, and CYP3A4/5 in vitro. 
Evaluation of the CYP inhibition potential with respect to FDA (DHHS 2020), Pharmaceuticals 
and Medical Devices Agency, Japan (Ministry of Health, Labor and Welfare 2014), and 
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Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
 
Page 9 
European Medicines Agency (EMA 2012) drug interaction guidances support the fact that 
reversible inhibition is not expected in the liver but indicate the reversible inhibition of intestinal 
CYP3A4 and time-dependent inhibition of hepatic CYP3A4, CYP2C19, and CYP2B6. 
Vonoprazan had a lower inhibition potential than positive controls. The in vitro data for the 
positive controls translated into a low drug interaction potential in the clinic; the clinical 
relevance of these findings for vonoprazan is expected to be lower. Furthermore, no 
autoinhibition was observed for vonoprazan metabolism with repeat dosing and no clinically 
relevant drug interaction has been observed in clinical studies (Nishihara et al 2019). Therefore, 
the CYP inhibition potential of vonoprazan is considered to be low and it is unlikely to cause any 
significant clinical DDI. 
Midazolam is an ultra–short-acting benzodiazepine used clinically for brief sedation and is 
commonly used as a sensitive CYP3A4 substrate in clinical drug interaction studies. After oral 
administration, midazolam is almost completely absorbed from the gastrointestinal tract. The 
mean t1/2 of midazolam and 1-hydroxymidazolam, its major metabolite (mediated by CYP3A4), 
is approximately 3 hours in humans. The Cmax is reached at about 1 hour after oral 
administration. Midazolam is contraindicated in patients with a known hypersensitivity to the 
drug or allergies to cherries or formulation excipients. Potential AEs are summarized in the 
midazolam prescribing information (Midazolam hydrochloride 2012). 
This study is designed in accordance with the US FDA Guidance for Industry, Clinical Drug 
Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions 
(DHHS 2020) to assess the effects of vonoprazan on the PK, safety, and tolerability of 
midazolam. 
This study will improve understanding of the interaction and resulting changes in exposure (if 
any) when a sensitive CYP3A4 substrate (midazolam) is given in combination with vonoprazan. 
1.3 
RATIONALE FOR DOSE SELECTION 
The vonoprazan 20 mg BID dose was selected because this is the highest dose being evaluated in 
clinical studies and approved for use, thus maximizing the possibility of identifying a DDI, in 
line with regulatory guidance. 
A single dose of 2 mg of midazolam was chosen because this is one of the most common dosing 
strategies for CYP3A drug interaction studies and is expected to provide adequate plasma 
concentrations to assess a drug interaction. Furthermore, this dose is anticipated to reduce the 
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Phathom Pharmaceuticals, Inc. 
Vonoprazan 
Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
 
Page 10 
chance of excessive sedation in the presence of an interaction that could cause increased levels of 
midazolam. 
2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to determine the time-dependent inhibition potential of 
repeated doses of oral vonoprazan on the PK of a single oral dose of midazolam, a sensitive 
CYP3A4 substrate, in healthy subjects. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives are as follows: 
x To assess the safety and tolerability of a single oral dose of midazolam alone or when 
coadministered with multiple oral doses of vonoprazan in healthy subjects 
x To evaluate the plasma PK of the metabolite 1-hydroxymidazolam in the presence of 
vonoprazan in healthy subjects 
3. 
STUDY DESIGN 
This is a Phase 1, open-label, fixed-sequence, clinical drug interaction study designed to assess 
the effect of vonoprazan on the PK of midazolam in healthy subjects. 
The study will consist of a screening period, check-in, a treatment period, an EOS visit, and a 
follow-up telephone call. The treatment period will include administration of single oral doses of 
2 mg of midazolam syrup on Day 1 and Day 9 and BID doses of 20 mg vonoprazan oral tablets 
on Days 2 through 10. 
Subjects will fast overnight (nothing to eat or drink except water) for at least 8 hours before the 
morning dose administration. On Day 9, midazolam will be administered 1 hour after the 
vonoprazan morning dose administration. Subjects will continue fasting for 4 hours after dosing 
on Days 1 and 9. On vonoprazan-only days, food will be allowed 1 hour after the vonoprazan 
dose has been administered. Evening vonoprazan dosing should occur more than 1 hour before 
or after a meal. 
Pharmacokinetic and safety endpoints will be evaluated in the study. 
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Vonoprazan 
Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
 
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Subjects will be confined to the clinical unit from Day –1 until discharge on Day 11 (EOS visit). 
A follow-up telephone call will occur on Day 25 (±2 days). The duration of the study, excluding 
Screening and including the follow-up telephone call, is approximately 27 days. 
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Vonoprazan 
Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
 
Page 12 
3.1 
SCHEDULE OF EVENTS 
Phase Screening Check-in 
Treatment Period 
EOS/ET 
Follow-up 
Procedure(a) 
Day –28 to –2 
–1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
25 (±2 days) 
Admission to clinic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from clinic(b) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Telephone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology(c) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 screening 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Serum FSH(d) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight, and BMI(e) 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical examination(f) 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital sign measurements(g) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG(h) 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Clinical laboratory testing(i) 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
 
Urine drug/alcohol/cotinine screen(j) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test(k) 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Guidance on avoidance of pregnancy 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Midazolam administration(l) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Vonoprazan administration (BID) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Midazolam PK sample collection(m) 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
Vonoprazan PK sample collection(n) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fasting/nonfasting periods(o) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PTEs(p) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AEs(q) 
 
 
X 
Prior/concomitant medications 
X 
Notes: 
(a) When procedures overlap or occur at the same time point, all blood draws should follow vital signs or ECGs, and PK sampling should be timed to occur 
last and as close to the scheduled time window as possible. 
(b) Discharge following last study assessment. 
(c) Serology testing will include hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus type 1 and 2 antibodies. 
(d) Females with at least 12 months of amenorrhea should have a serum FSH test performed at Screening to confirm postmenopausal status. 
(e) Height and weight will be measured and BMI will be calculated at Screening. Only weight will be measured at Check-in and Day 11. 
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Vonoprazan 
Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
 
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(f) A full physical examination will be performed at Screening (at minimum, assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, heart, 
cardiovascular system, abdomen, lymph nodes, and musculoskeletal system/extremities). A brief physical examination will be performed at Check-in 
and Day 11 (at minimum, assessment of skin, lungs, cardiovascular system, and abdomen [liver and spleen]). Interim physical examinations may be 
performed at the discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. 
(g) Vital signs will be measured after the subject has been in the seated position for at least 5 minutes at Screening and Check-in; on Days 1 and 9 within 
60 minutes prior to midazolam dosing and at 0.5, 1, 2, 4, 8, 12, and 24 hours following midazolam dosing; on Days 3 through 8 before the morning dose 
of vonoprazan; and on Day 11. Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and tympanic temperature. 
(h) Single 12-lead ECG recordings will be made after the subject has been in the supine position for at least 5 minutes at Screening and Check-in, on 
Days 1 and 9 within 30 minutes before midazolam dosing, and on Day 11. 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 (if abnormal, whether clinically significant or not clinically significant); 
rhythm; the presence of arrhythmia or conduction defects; morphology; any evidence of myocardial infarction; and ST-segment, T-wave, and U-wave 
abnormalities. 
(i) Clinical laboratory testing will occur at Screening, Check-in, before morning dosing on Days 6 and 8, and on Day 11. Testing includes liver function 
tests: ALT, AST, and total and direct bilirubin. A complete list of assessments is provided in Section 6.2.2. Blood and urine samples will be collected 
under fasting conditions and prepared per the clinic’s standard procedures. 
(j) Urine drug/alcohol/cotinine screen will occur at Screening and Check-in per the clinic’s standard procedures. 
(k) All females will have a pregnancy test performed at Screening, Check-in, and Day 11. 
(l) The time of midazolam dosing will be called “0” hour. Doses of midazolam and 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. On Day 9, midazolam will be administered 
1 hour after the vonoprazan morning dose administration. 
(m) Blood samples for PK analysis of midazolam and 1-hydroxymidazolam in plasma will be collected within 30 minutes prior to midazolam dosing and at 
0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours following midazolam dosing on Day 1 and within 30 minutes prior to midazolam dosing 
and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours following midazolam dosing on Day 9. 
(n) Blood samples for PK analysis of vonoprazan in plasma will be collected within 30 minutes prior to the morning administration of vonoprazan on 
Days 2 through 10 and on Day 11 for the assessment of steady state. The Day 11 sample should be collected at approximately the same time of day as 
the samples collected on Days 2 through 10.  
(o) During fasting periods, subjects should have nothing to eat or drink except water from 8 hours prior to study drug dosing. On Days 1 and 9, subjects 
will continue to fast until 4 hours after dosing. Water is permitted as desired except for the period 1 hour before and 1 hour after administration of study 
drug (other than as permitted for study drug dosing). During non-fasting periods, subjects should receive standardized meals per the clinic’s standard 
procedures. 
(p) Collection of PTEs will start after the subject has signed the ICF. 
(q) Adverse events will be assessed from the time of midazolam dosing until the follow-up visit and should be followed until they are resolved, stable, or 
judged by the investigator to be not clinically significant. 
 
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Protocol No. VONO-101 
Clinical Study Protocol Amendment 1 
 
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4. 
STUDY POPULATION 
Approximately 20 healthy male and female subjects will be enrolled at a single center in the 
United States to achieve at least 16 evaluable subjects. 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. The subject is male or female 18 to 45 years of age, inclusive, at Screening. 
2. The subject has a BMI 18 to 30 kg/m2, inclusive, and body weight >50 kg at Screening. 
3. The subject is considered by the investigator to be in good general health as determined 
by medical history, clinical laboratory test results, vital sign measurements, 12-lead ECG 
results, and physical examination findings at Screening. 
4. Female subjects of childbearing potential who may be sexually active with a 
non-sterilized male partner must use an acceptable method of birth control (ie, diaphragm 
with spermicide, intrauterine device, condom with foam or vaginal spermicide, oral 
contraceptives, or abstinence) from the signing of informed consent until 4 weeks after 
the last dose of study drug or be surgically sterile (ie, hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or postmenopausal (defined as amenorrhea for 
12 consecutive months and documented plasma FSH level >40 IU/mL). 
5. Female subjects must have a negative pregnancy test at Screening and Check-in. 
6. The subject agrees to comply with all protocol requirements. 
7. The subject is able to provide written informed consent. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. The subject has a history of any clinically significant neurological, cardiovascular, 
pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, hematological, or 
endocrine disease or other abnormality that may affect the ability of the subject to 
participate in the study. 
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2. The subject has a positive test result for COVID-19, hepatitis B surface antigen, 
hepatitis C virus antibody, or human immunodeficiency virus type 1 or 2 antibodies at 
Screening. 
3. The subject has ALT or AST >2 × ULN or total bilirubin >1.5 × ULN (with the exception 
of Gilbert’s syndrome) at Screening or Check-in. 
4. The subject has serum creatinine >1.2 mg/dL or blood urea nitrogen >20 mg/dL at 
Screening or Check-in. 
5. The subject has any acute laboratory abnormality at Screening that precludes 
participation in the study, in the opinion of the investigator. 
6. The subject has a current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert’s syndrome and asymptomatic gallstones). 
7. The subject has used any prescription (excluding hormonal birth control) or 
over-the-counter medications (including CYP3A4 inducers) except paracetamol (up to 
2 g per day), including herbal or nutritional supplements, within 14 days (or 5 half-lives) 
before the first dose of study drug or throughout the study. 
8. The subject has consumed grapefruit or grapefruit juice, Seville orange or Seville 
orange-containing products (eg, marmalade), or other food products that may be 
CYP3A4 inhibitors (eg, vegetables from the mustard green family [kale, broccoli, 
watercress, collard greens, kohlrabi, Brussels sprouts, mustard] and charbroiled meats) 
within 7 days (or 5 half-lives) before the first dose of study drug or throughout the study. 
9. The subject has consumed caffeine- or xanthine-containing products within 48 hours (or 
5 half-lives) before the first dose of study drug or throughout the study. 
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 addiction within the last year, 
excessive alcohol consumption (regular alcohol intake >21 units per week for male 
subjects and >14 units of alcohol per week for female subjects; 1 unit is equal to 
approximately 1/2 pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure 
[25 mL] of spirits), or use of alcohol 48 hours before the first dose of study drug or 
throughout the study. 
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12. The subject has a positive test result for drugs of abuse, alcohol, or cotinine (indicating 
active current smoking) at Screening or Check-in. 
13. The subject is involved in strenuous activity or contact sports within 24 hours before the 
first dose of study drug or throughout the study. 
14. The subject has donated blood or blood products >450 mL within 30 days before the first 
dose of study drug. 
15. The subject has a history of relevant drug and/or food allergies (ie, allergy to midazolam, 
vonoprazan, or their excipients [including cherries] or any significant food allergy that 
could preclude a standard diet in the clinical unit). 
16. The subject has received study drug in another investigational study within 30 days of 
dosing. 
17. Female subject is pregnant or lactating, intends to become pregnant before, during, or 
within 4 weeks after participating in this study, or intends to donate ova during this time 
period. 
18. The subject has a history of acute narrow-angle glaucoma. 
19. 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 
Subjects may be re-screened at the discretion of the investigator and the sponsor, after 
consultation with the medical monitor. 
At the discretion of the investigator and sponsor, and after consultation with the medical 
monitor, any subject who withdraws before completing the study may be replaced to achieve 
the target of 16 evaluable subjects. 
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5. 
STUDY TREATMENTS 
5.1 
TREATMENTS ADMINISTERED 
All subjects will receive the study treatments as described in Section 3 and according to the 
SOE (Section 3.1). Additional instructions for dosing, fasting periods, and non-fasting 
periods can be found in the SOE. 
5.2 
INVESTIGATIONAL PRODUCTS 
The study drugs that will be used are as follows: 
Product 
Dose Administered 
Supplied Formulation 
Vonoprazan  
20 mg 
20 mg tablet 
Midazolam 
2 mg 
2 mg/mL syrup 
 
Vonoprazan tablets contains the following inactive excipients: D-mannitol, microcrystalline 
cellulose, hydroxypropyl cellulose, fumaric acid, croscarmellose sodium, magnesium 
stearate, hypromellose, macrogol 6000, titanium oxide, red ferric oxide, and printing ink gray 
F1. Further information on vonoprazan can be found in the investigator’s brochure (Global 
Investigator’s Brochure 10th Edition). 
Midazolam syrup will be sourced by the clinical unit. Details regarding midazolam can be 
found in the package insert (Midazolam hydrochloride 2012). 
5.2.1 
Study Drug Preparation and Storage 
Phathom Pharmaceuticals, Inc. will provide the investigator and clinical unit with adequate 
quantities of vonoprazan tablets. The tablets will be packaged in 50-count high-density 
polyethylene bottles. Midazolam will be supplied by the clinical unit. The clinical unit 
pharmacy will prepare the study treatments for each subject according to the SOE 
(Section 3.1). 
All study drugs must be stored according to the labeled instructions in a secure cabinet or 
room with access restricted to necessary clinic personnel. The site will be required to keep a 
temperature log to establish a record of compliance with storage conditions. 
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5.2.2 
Study Drug Accountability 
The investigator will maintain accurate records of receipt of all study drugs, including dates 
of receipt. Accurate records will be kept regarding when and how much study drug is 
dispensed and used by each subject in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, and to satisfy 
regulatory requirements regarding drug accountability, all study drugs will be reconciled and 
retained or destroyed according to applicable regulations. 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT 
GROUPS 
This is a non-randomized study. Subjects who meet all inclusion criteria and none of the 
exclusion criteria will receive all study treatments according to the SOE (Section 3.1). 
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. 
6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS 
The following PK parameters for midazolam and 1-hydroxymidazolam will be calculated as 
endpoints using standard noncompartmental methods: AUC0-t, AUC0-inf, Cmax, Tmax, Kel, t1/2 
for both for midazolam and 1-hydroxymidazolam, and CL/F and Vd/F for midazolam only. 
Metabolite to parent ratios for Cmax and AUC0-inf will also be reported. To assess attainment 
of steady state, Ctrough concentrations will be reported for vonoprazan. 
The primary endpoints will be AUC0-t, AUC0-inf, and Cmax of midazolam with and without 
vonoprazan. 
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The timing and frequency of PK sample collection is listed in the SOE (Section 3.1). 
Definitions of the PK parameters can be found in the list of abbreviations, Appendix 1. 
6.1.1 
Pharmacokinetic Sample Collection 
Details for the collection, processing, storage, and shipping of PK samples will be provided 
to the clinical unit separately. 
6.1.2 
Pharmacokinetic Sample Analysis 
Pharmacokinetic samples will be analyzed using a validated liquid chromatography coupled 
with tandem mass spectrometry assay for midazolam, 1-hydroxymidazolam, and vonoprazan 
in human plasma. 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 are 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), vital sign 
measurements, 12-lead ECG results, and physical examination findings. 
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 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: 
 
 
 
 
 
6.2.2 
Clinical Laboratory Assessments 
The following clinical laboratory assessments will be performed: 
Hematology 
Hematocrit, hemoglobin, red blood cell count, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, mean 
corpuscular volume, red blood cell distribution width, leukocytes 
and leukocyte differential (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), and platelet count 
Serum Chemistry 
ALT, albumin, alkaline phosphatase, AST, bilirubin (total and 
direct), blood urea nitrogen, calcium, carbon dioxide, chloride, 
cholesterol (total, high-density lipoprotein, and calculated 
low-density lipoprotein), creatine kinase, creatinine, 
gamma-glutamyltransferase, globulin, glucose (fasting), lactate 
dehydrogenase, magnesium, phosphorus, potassium, sodium, total 
protein, triglycerides (fasting), 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; includes bacteria, casts, crystals, 
epithelial cells, red blood cells, and white blood cells), nitrites, 
occult blood, pH, protein, specific gravity, turbidity, and 
urobilinogen 
Serology 
Hepatitis B surface antigen, hepatitis C virus antibody, and human 
immunodeficiency virus type 1 and 2 antibodies (Screening only) 
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Other analyses 
x All subjects: urine drug screen (alcohol, amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine 
metabolites, cotinine, methamphetamines, 
methylenedioxymethamphetamine, and opiates [including 
heroin, codeine, and oxycodone]) 
x All subjects: COVID-19 screening 
x All female subjects: pregnancy test (human chorionic 
gonadotropin [serum or urine, per site practice]) 
x Female subjects with at least 12 months of amenorrhea: FSH 
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. 
7. 
STATISTICAL ANALYSIS PLANS 
7.1 
SAMPLE SIZE CALCULATIONS 
The sample size for this study is based on consideration of the precision of the estimate of 
GMRs of PK parameters of midazolam with and without vonoprazan. To evaluate the effect 
of vonoprazan on the PK of midazolam, with 16 evaluable subjects, there is an 80% 
probability that the 90% CI will be within 81.4% and 122.9% of the point estimate of the 
GMR of midazolam PK parameters with and without vonoprazan. This calculation assumes 
that midazolam PK parameters are log-normally distributed with an intrasubject CV no 
greater than 30% (Mueller et al 2017). 
Approximately 20 healthy male and female subjects will be enrolled at a single center in the 
United States to achieve at least 16 evaluable subjects. 
7.2 
ANALYSIS SETS 
The analysis populations are as follows: 
x The PK population will include subjects who receive at least 1 dose of study drug and 
have sufficient concentration data to support accurate estimation of at least 1 PK 
parameter. Subjects who experience vomiting within 2 times the median Tmax after 
midazolam dosing will be excluded from the PK analysis. 
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x 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, 
SD, minimum, and maximum). 
Baseline demographic and background variables will be summarized overall for all subjects. 
The number of subjects who enroll in the study and the number and percentage of subjects 
who complete the study will be presented. The frequency and percentage of subjects who 
withdraw or discontinue from the study and the reason for withdrawal or discontinuation will 
also be summarized. 
7.3.1 
Pharmacokinetic Analyses 
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be summarized by time point for each treatment (midazolam 
alone, vonoprazan alone, midazolam + vonoprazan) using the following descriptive statistics: 
number of subjects, arithmetic mean, SD, CV, geometric mean, geometric CV, median, 
minimum, and maximum. Individual and mean plasma concentration versus scheduled time 
profiles will be presented in figures on both linear and semilogarithmic scales. 
The PK parameters of midazolam and 1-hydroxymidazoam will be analyzed based on the 
actual sampling times. All parameters will be calculated using the latest versions of Phoenix® 
WinNonlin® (Certara USA Inc., Princeton, New Jersey) or SAS (SAS Institute Inc., Cary, 
North Carolina). The individual PK parameters will be presented in data listings and 
summarized by treatment using the following descriptive statistics: number of subjects, 
mean, SD, CV, median, minimum, and maximum. Geometric means will be included for 
AUC0-t, AUC0-inf, and Cmax. 
A linear mixed model with treatment as a fixed effect and subject as a random effect will be 
performed on the natural log-transformed values of AUC0-t, AUC0-inf, and Cmax to assess the 
effect of vonoprazan on the PK of midazolam. A 90% CI for the ratio (midazolam + 
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vonoprazan versus midazolam alone) will be constructed as the antilog of the confidence 
limits of the mean difference. No adjustment will be made for multiplicity. 
Non-parametric methods will be used to examine median differences in Tmax for midazolam 
and 1-hydroxymidazolam. 
7.3.2 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities. All AE data will be presented in 
a data listing. Treatment-emergent AEs will be summarized by treatment and overall, as well 
as by severity and relationship to study drug. Serious AEs and AEs leading to discontinuation 
of study drug will also be presented in the data listings and summarized by treatment and 
overall. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized at each time point using 
descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum). 
Shift tables will be generated for clinical laboratory test results. Physical examination 
findings will be presented in a data listing. 
7.4 
HANDLING OF MISSING DATA 
Plasma concentrations that are BLQ will be treated as zero for descriptive statistics. Mean 
BLQ concentrations will be presented as BLQ, and the SD and CV will be reported as not 
applicable. Missing concentrations will be excluded from the calculations. 
For the PK analysis, BLQ values will be treated as zero with the exception that a BLQ value 
between 2 quantifiable concentrations will be set as missing. Missing concentrations will be 
treated as missing from the PK parameter calculations. If consecutive BLQ concentrations 
are followed by quantifiable concentrations in the terminal phase, those concentrations after 
BLQ concentrations will be treated as missing. 
7.5 
INTERIM ANALYSES 
No formal interim analyses will be performed in this study. 
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8. 
REFERENCE LIST 
Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (US). Guidance for Industry: Clinical drug interaction 
studies - cytochrome P450 enzyme- and transporter-mediated drug interactions. January 2020 
[cited 2020 July 31] [27 screens]. Available from: 
https://www.fda.gov/media/134581/download. 
European Medicines Agency (EMA), Committee for Human Medicinal Products (CHMP). 
Guideline on the investigation of drug interactions. London, 21 June 2012. Publication 
No. CPMP/EWP/560/95/Rev. 1 Corr. 2 [cited 2020 Jul 31] [59 screens]. Available from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-drug-
interactions-revision-1_en.pdf. 
Jenkins H, Sakurai Y, Nishimura A, et al. Randomised clinical trial: safety, tolerability, 
pharmacokinetics and pharmacodynamics of repeated doses of TAK-438 (vonoprazan), a 
novel potassium-competitive acid blocker, in healthy male subjects. Aliment Pharmacol Ther 
2015;41(7):636-48. 
Midazolam hydrochloride (midazolam hydrochloride syrup) [prescribing information]. 
Roxane Laboratories, Inc. Columbus (OH); 2012. 22 p. 
Ministry of Health, Labor and Welfare. Drug interaction guideline for drug development and 
labeling recommendations. Draft Guidance. Tokyo, January 2014. 
Mueller SC, Majcher-Peszynska J, Wacke R, et al. Within and between subject variability of 
oral midazolam pharmacokinetic parameters as surrogate for global CYP3A function in 
female and male volunteers [abstract] Clin Ther. 2017;39(8 Suppl):e29. 
Nishihara M, Yamasaki H, Czerniak R, Jenkins H. In vitro assessment of potential for 
CYP-inhibition-based drug-drug interaction between vonoprazan and clopidogrel. Eur J Drug 
Metab Pharmacokinet. 2019;44(2):217-27. 
Takeda Pharmaceutical Company, Ltd. Vonoprazan fumarate (TAK-438). Global 
Investigator’s Brochure, 10th ed. 2020. 340 p. 
Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. 
J Neurogastroenterol Motil. 2013;19(1):25-35. 
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9. 
APPENDICES 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-inf 
area under the plasma concentration versus time curve from time 0 
extrapolated to infinity 
AUC0-t 
area under the plasma concentration versus time curve from time 0 
to the last quantifiable concentration 
BID 
twice daily 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
apparent total body clearance 
Cmax 
maximum observed plasma concentration 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
Ctrough 
trough concentration 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EE 
erosive esophagitis 
EOS 
end of study 
ET 
early termination 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMR 
geometric mean ratio 
H+, K+-ATPase 
hydrogen, potassium–adenosine triphosphatase 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
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Abbreviation 
Term 
INR 
international normalized ratio 
IRB 
institutional review board 
Kel 
apparent terminal elimination rate constant 
PCAB 
potassium-competitive acid blocker 
PK 
pharmacokinetic(s) 
PPI 
proton pump inhibitor 
PTE 
pre-treatment 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 
t1/2 
terminal phase half-life 
Tmax 
time to maximum observed plasma concentration 
ULN 
upper limit of normal 
Vd/F 
apparent volume of distribution 
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9.2 
APPENDIX 2: STANDARD PROCEDURES 
9.2.1 
Removal of Subjects From Therapy or Assessment 
9.2.1.1 
General Criteria for Withdrawal 
Subjects can withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment. 
The investigator may withdraw a subject from the study if the subject meets any of the 
following criteria: 
1. Is non-compliant with the protocol. 
2. Experiences an SAE or intolerable PTE/AE(s) that, in the investigator’s opinion, requires 
withdrawal from the study. 
3. Has laboratory safety assessments that reveal clinically significant hematological or 
biochemical changes from baseline values (if a subject’s ALT or AST or total bilirubin is 
>3 × ULN at any time during study medication treatment, the study medication should be 
discontinued immediately with appropriate clinical follow-up, including repeat laboratory 
tests, until the subject’s laboratory profile has returned to normal/baseline status). 
4. Develops symptoms or conditions that are listed in the exclusion criteria during the 
course of the study. 
5. Requires a medication prohibited by the protocol. 
6. Requests early discontinuation for any reason. 
7. Becomes pregnant. 
The investigator can also withdraw a subject upon the request of the sponsor, or if the 
sponsor terminates the study. If withdrawal is considered because of an SAE or intolerable 
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 EOS assessments. Any subject who 
fails to return for final assessments will be contacted by the site in a reasonable attempt to 
have them comply with the protocol. The status of subjects who fail to complete final 
assessments will be documented in the eCRF. 
9.2.2 
Prior and Concomitant Medications and Therapies 
Restrictions for prior and concomitant medications and therapies are provided in Section 4.2. 
Prior and concomitant medications and therapies will be coded using the latest version of the 
World Health Organization Drug Dictionary. 
9.2.2.1 
Prior Medications 
Information regarding prior medications taken by the subject within the 30 days before 
signing the ICF will be recorded in the subject’s eCRF. 
9.2.2.2 
Concomitant Medications 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be administered at the discretion of the investigator. If a concomitant medication 
is taken, except for those specified in the protocol, a joint decision will be made by the 
investigator and the sponsor to continue or discontinue the subject based on the time the 
medication was administered, its pharmacology and PK, and whether the use of the 
medication will compromise the safety of the subject or the interpretation of the data. The 
investigator is responsible for ensuring that details regarding the medication are adequately 
recorded in the eCRF. 
9.2.3 
Treatment Compliance 
All doses of study drug will be administered in the clinical unit under direct observation of 
clinic personnel and will be recorded in the eCRF. Clinic personnel will confirm that the 
subject has received the entire dose of study drug. 
The date and time of study drug dosing will be recorded on the appropriate page of the eCRF. 
If a subject is not administered study drug, the reason for the missed dose will be recorded. 
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9.3 
APPENDIX 3: ADVERSE EVENT DEFINITIONS AND 
REPORTING 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF 
and reported to the sponsor, regardless of their relationship to study drug or clinical 
significance. If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported. 
9.3.1 
Adverse Event Definitions 
A PTE is defined as any untoward medical occurrence that has occurred prior to 
administration of any study drug in a clinical investigation subject who has signed informed 
consent to participate in a study; it does not necessarily have to have a causal relationship 
with study participation. 
An AE is defined as any untoward medical occurrence in a subject enrolled in this study 
regardless of its causal relationship to study drug. An AE can therefore be an unfavorable 
sign or symptom or a disease temporally associated with the use of study drug. 
A treatment-emergent AE is defined as any event that occurs after the first dose of study drug 
or any event at baseline that worsens in either intensity or frequency after the first dose of 
study drug. 
An SAE is defined as any untoward medical occurrence at any dose that meets one of the 
following criteria: 
1. Results in death. 
2. Is life-threatening. The term “life-threatening” refers to an event in which the subject was 
at risk of death at the time of the event; it does not refer to an event that hypothetically 
might have caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. 
4. Results in persistent or significant disability/incapacity. 
5. Is a congenital anomaly/birth defect. 
6. Is an important medical event that satisfies any of the following: 
x May require intervention to prevent items 1 through 5 above 
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x May include any event or symptoms described in the medically significant AE list 
(Table 9-1) 
x Exposes the subject to danger, even though the event is not immediately 
life-threatening or fatal or does not result in hospitalization 
Table 9-1 
Medically Significant Adverse Event List 
Term 
Acute respiratory failure/acute respiratory distress syndrome 
Torsade de pointes/ventricular fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizures 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/Stevens-Johnson syndrome 
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis 
Confirmed or suspected endotoxin shock 
Confirmed or suspected transmission of infectious agent by a medicinal product 
Neuroleptic malignant syndrome/malignant hyperthermia 
Spontaneous abortion/stillbirth and fetal death 
COVID-19 pneumonia 
COVID-19–related disease 
 
The PTEs that fulfill one or more of the serious criteria above are also considered SAEs and 
should be reported and followed up in the same manner. 
A special interest AE (serious or nonserious) is one of scientific and medical concern specific 
to the compound or program for which ongoing monitoring and rapid communication by the 
investigator to Phathom Pharmaceuticals may be appropriate. Such events may require 
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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 Pharmaceuticals. There are no special interest AEs for this study. 
Reporting of Abnormal Liver Function Tests: 
If a subject is noted to have an ALT or AST value >3 × ULN and a total bilirubin value 
>2 × ULN during the treatment or follow-up period for which an alternative etiology has not 
been identified, the event should be reported as an SAE. The investigator must contact the 
medical monitor for discussion of the relevant subject details and possible alternative 
etiologies, such as acute viral hepatitis A or B, other acute liver disease, medical history, or 
concurrent medical conditions. Study drug should be discontinued immediately as per 
Section 9.2.1.1. Laboratory tests should be followed-up as described in Section 6.2.2. In 
addition, a Liver Function Test Increase eCRF must be completed and transmitted with the 
SAE form. 
If subjects with normal baseline ALT or AST levels experience ALT or AST >3 × ULN and a 
2-fold increase above baseline, follow-up laboratory tests (at a minimum, serum alkaline 
phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase, and INR) should be 
repeated within a maximum of 7 days and preferably within 48 to 72 hours after the 
abnormality was 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, γ-glutamyl transferase, and INR) should be repeated within a maximum of 
48 hours after the abnormality is found. 
9.3.2 
Eliciting and Documenting Adverse Events 
Collection of PTEs will commence at the time the subject signs the informed consent to 
participate in the study and will continue until the subject is first administered study drug or 
until screen failure. For subjects who discontinue prior to study drug administration, PTEs 
are collected until the subject discontinues study participation. Collection of AEs will 
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commence from the time that the subject is first administered study drug (Day 1). Routine 
collection will continue until the follow-up visit or withdrawal from the study. 
On each study day, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing 
a serious PTE must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline or there is a satisfactory explanation 
for the change. Nonserious PTEs, related or unrelated to the study procedure, need not 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 and Serious 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 it deteriorates at any time 
during the study, it should be recorded as an AE. Section 9.3.4 provides additional details. 
The Medical Dictionary of Regulatory Activities will be used to code all AEs. 
Any AE that is considered serious by the investigator or that meets SAE criteria 
(Section 9.3.1) must be reported to the sponsor within 24 hours (after the investigator has 
confirmed the occurrence of the SAE). The investigator will assess whether there is a 
reasonable possibility that the study drug(s) caused the SAE. The sponsor will be responsible 
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for notifying the relevant regulatory authorities of any SAE as outlined in US Title 21 CFR 
Parts 312 and 320. The investigator is responsible for notifying the 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/she 
considers the event to be reasonably related to the study drug or study participation, the 
investigator must promptly notify the sponsor. Reporting of serious PTEs will follow the 
same procedure as SAE reporting. 
9.3.4 
Additional Points to Consider for Pre-Treatment Events and 
Adverse Events 
An untoward finding generally may involve the following: 
x Indicates a new diagnosis or unexpected worsening of a pre-existing condition 
(pre-existing conditions or underlying disease should not be considered PTEs or AEs) 
x Necessitates therapeutic intervention 
x Requires an invasive diagnostic procedure 
x Requires discontinuation or a change in dose of study drug or a concomitant medication 
x Is considered unfavorable by the investigator for any reason 
PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as 
a PTE/AE. 
Diagnoses versus signs and symptoms: 
x Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, signs or symptoms should be 
recorded appropriately as PTEs or as AEs. 
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Laboratory values and ECG findings: 
x Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if 
they are judged to be clinically significant (ie, if some action or intervention is required 
or if the investigator judges the change to be beyond the range of normal physiologic 
fluctuation). A laboratory or ECG retest or continued monitoring of an abnormal value or 
finding is not considered an intervention. In addition, repeated or additional noninvasive 
testing for verification, evaluation, or monitoring of an abnormality is not considered an 
intervention. 
x If abnormal laboratory values or ECG findings are the result of pathology for which there 
is an overall diagnosis (eg, increased creatinine in renal failure), only the diagnosis 
should be reported as a PTE or an AE. 
Pre-existing conditions: 
x Pre-existing conditions (present at the time of signing of informed consent) are 
considered concurrent medical conditions and should NOT be recorded as PTEs or AEs. 
Baseline evaluations (eg, laboratory tests, ECGs, etc) should NOT be recorded as PTEs 
unless related to study procedures. However, if the subject experiences a worsening or 
complication of such a concurrent medical condition, the worsening or complication 
should be recorded appropriately as a PTE (if the worsening or complication occurs 
before administration of study drug) or an AE (if the worsening or complication occurs 
after administration of study drug). Investigators should ensure that the recorded event 
term captures the change in the condition (eg, “worsening of…”). 
x If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, 
epilepsy), any occurrence of an episode should be captured as a PTE/AE only if the 
condition becomes more frequent, serious, or severe in nature. Investigators should 
ensure that the recorded AE term captures the change in the condition from baseline (eg, 
“worsening of…”). 
x If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE/AE if it occurs to 
a greater extent than would be expected. Investigators should ensure that the recorded AE 
term captures the change in the condition (eg, “worsening of…”). 
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Worsening of PTEs or AEs: 
x If the subject experiences a worsening or complication of a PTE after the start of study 
drug, the worsening or complication should be recorded as an AE. Investigators should 
ensure that the recorded AE term captures the change in the PTE (eg, “worsening of…”). 
x If the subject experiences a worsening or complication of an AE after any change in 
study drug, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the recorded AE term captures the change in the condition 
(eg, “worsening of…”). 
Changes in intensity of AEs /serious PTEs: 
x If the subject experiences changes in the intensity of an AE/serious PTE, the event should 
be captured once with the maximum intensity recorded. 
Preplanned procedures (surgeries or interventions): 
x Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, 
the worsening of the condition should be recorded as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
x Elective procedures performed when there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
x Insufficient clinical response, efficacy, or pharmacologic action should NOT be recorded 
as an AE. The investigator must make the distinction between exacerbation of 
pre-existing illness and lack of therapeutic efficacy. 
Overdose: 
x 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 
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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: 
x Mild: The event is transient and easily tolerated by the subject. 
x Moderate: The event causes the subject discomfort and interrupts the subject’s usual 
activities. 
x Severe: The event causes considerable interference with the subject’s usual activities. 
Changes in the severity of an AE should be documented to allow the duration of the event at 
each level of intensity to be assessed. An AE characterized as intermittent does not require 
documentation of the onset and duration of each episode. 
9.3.6 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process but is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The investigator will assess causality (ie, whether there is a reasonable possibility that the 
study drug caused the event) for all AEs and SAEs. The relationship will be classified as 
follows: 
x Not related: An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant drugs, and concurrent treatments. 
x Related: An AE that follows a reasonable temporal sequence from administration of 
study drug (including the course after withdrawal of the drug) or for which possible 
involvement of the drug cannot be ruled out, although factors other than the study drug, 
such as underlying diseases, complications, concomitant drugs, and concurrent 
treatments, may also be responsible. 
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9.3.6.1 
Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as not related. 
9.3.6.2 
Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the 
subject or investigator. 
9.3.6.3 
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved 
with sequelae, or the subject died. 
9.3.6.4 
Frequency 
Episodic AEs/PTE (eg, vomiting) or those that occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous. 
9.3.6.5 
Action Concerning Study Drug 
x Drug withdrawn: a study drug is stopped due to the particular AE. 
x Dose not changed: the particular AE did not require stopping study drug. 
x Unknown: only to be used if it cannot be determined what action was taken. 
x Not applicable: study drug was stopped for a reason other than the particular AE; eg, the 
study was terminated, the subject died, or dosing with study drug was already stopped 
before the onset of the AE. 
x Dose reduced: the dose was reduced due to the particular AE. 
x Dose increased: the dose was increased due to the particular AE. 
x Drug interrupted: the dose was interrupted due to the particular AE. 
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9.3.6.6 
Outcome 
x Recovered/resolved: the subject returned to first assessment status with respect to the 
AE/PTE. 
x Recovering/resolving: the intensity is decreased by 1 or more stages, the diagnosis or 
signs/symptoms have almost disappeared, the abnormal laboratory value improved but 
has not returned to the normal range or to baseline, the subject died from a cause other 
than the particular AE/PTE with the condition remaining “recovering/resolving”. 
x Not recovered/not resolved: there is no change in the diagnosis, signs, or symptoms; the 
intensity of the diagnosis, signs/symptoms, or laboratory value on the last day of the 
observed study period is worse than when it started; the condition is an irreversible 
congenital anomaly; the subject died from another cause while the particular AE/PTE 
state was “not recovered/not resolved”. 
x Resolved with sequelae: the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis). 
x Fatal: AEs/PTEs that are considered the cause of death. 
x Unknown: the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
9.3.7 
Follow-up of Adverse Events and Serious Adverse Events 
All AEs must be reported in detail on the appropriate page of the eCRF and followed until 
they are resolved, stable, or judged by the investigator to be not clinically significant. 
For SAEs, if information not available at the time of the first report becomes available at a 
later date, the investigator should update the SAE eCRF form and transmit it immediately 
within 24 hours of receipt. Copies of any relevant data from the hospital notes (eg, ECG 
results, laboratory test results, discharge summary, postmortem results) should be provided, if 
requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
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9.3.8 
Pregnancy 
During the course of the study, human chorionic gonadotropin pregnancy tests will be 
performed for women, and subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures (Section 3.1). 
If any subject is found to be pregnant during the study, she should be withdrawn and any 
study drug should be immediately discontinued. If the pregnancy occurs during 
administration of active study drug or within 4 weeks of the last dose of active study drug, 
the pregnancy should be reported immediately, using a pregnancy notification form, to the 
contact listed in Section 6.2.1. If the female subject agrees that the primary care physician 
can be informed, the investigator should notify the primary care physician that the subject 
was participating in a clinical study at the time she became pregnant and provide details of 
the treatment the subject received. All pregnancies in subjects receiving study drug will be 
followed up to final outcome, using the pregnancy form. The outcome, including any 
premature termination, must be reported to the sponsor. An evaluation after the birth of the 
child will also be conducted. 
9.3.9 
Safety Reporting to Investigators, Institutional Review 
Boards, Independent Ethics Committees, and Regulatory 
Authorities 
The sponsor is responsible for reporting all SUSARs and any other applicable SAEs to 
regulatory authorities, investigators and IRBs or IECs, as applicable, in accordance with 
national regulations in the countries where the study is conducted. The SUSARs will be 
submitted to the regulatory authorities as an expedited report within 7 days for fatal and 
life-threatening events and 15 days for other serious events, relative to the first awareness of 
the event by/or further provision to the sponsor or sponsor’s designee, unless otherwise 
required by national regulations. The sponsor also will prepare an expedited report for other 
safety issues that might materially alter the current benefit-risk assessment of a study 
drug/sponsor-supplied drug or that would be sufficient to consider changes in the study 
drug/sponsor-supplied drug administration or in the overall conduct of the trial. The study 
site also will forward a copy of all expedited reports to their IRB or IEC in accordance with 
local regulations. 
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9.4 
APPENDIX 4: STUDY GOVERNANCE 
9.4.1 
Data Quality Assurance 
This study will be conducted using the quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and 
will comply with current ICH guidance on quality and risk management. All aspects of the 
study will be monitored for compliance with applicable government regulatory requirements, 
current 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 
Section 10.2 of the clinical study report. 
9.4.2 
Investigator Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study and may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB 
but will not result in protocol amendments. 
9.4.2.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject (or the subject’s legal guardian), 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 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any confidential information to other parties. 
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9.4.2.2 
Institutional Review 
Federal regulations and ICH guidelines require that approval be obtained from an IRB before 
participation of human subjects in research studies. Before study onset, the protocol, ICF, 
advertisements to be used for the recruitment of study subjects, and any other written 
information regarding this study that is to be provided to the subject or the subject’s legal 
guardian must be approved by the IRB. Documentation of all IRB approvals and of IRB 
compliance with 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 he or she enters the study or before performing any unusual or nonroutine 
procedure that involves risk to the subject. If any institution-specific modifications to 
study-related procedures are proposed or made by the site, the consent should be reviewed by 
the sponsor or its designee or both before IRB submission. Once reviewed, the investigator 
will submit the ICF to the IRB for review and approval before the start of the study. If the 
ICF is revised during the course of the study, all active participating subjects must sign the 
revised form. 
Before recruitment and enrollment, each prospective subject or his/her legal guardian 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/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give his or her consent 
to participate in the study by signing the ICF. A copy of the ICF will be provided to the 
subject/legal guardian. 
9.4.2.4 
Study Reporting Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB as appropriate. 
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9.4.2.5 
Financial Disclosure and Obligations 
The investigator is required to provide financial disclosure information to allow the sponsor 
to submit the complete and accurate certification or disclosure statements required under US 
Title 21 CFR Part 54. In addition, the investigator must provide to the sponsor a commitment 
to promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor PPD 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 PPD is financially responsible for 
further treatment of the disease under study. 
9.4.2.6 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH 
E6(R2) Section 8.2 and US Title 21 of the CFR by providing essential documents, including 
but not limited to, the following: 
x IRB approval 
x An original investigator-signed investigator agreement page of the protocol, 
x Form FDA 1572, fully executed, and all updates on a new fully executed 
Form FDA 1572 
x Curriculum vitae for the principal investigator and each subinvestigator listed on Form 
FDA 1572. Current licensure must be noted on the curriculum vitae. Curriculum vitae 
will be signed and dated by the principal investigators and subinvestigators at study 
start-up, indicating that they are accurate and current. 
x An IRB-approved ICF, samples of site advertisements for recruitment for this study, and 
any other written information about this study that is to be provided to the subject or legal 
guardians 
x Laboratory certifications and reference ranges for any local laboratories used by the site, 
in accordance with US Title 42 CFR Part 493 
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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. 
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 
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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. 
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 
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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. 
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. 
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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 of deviations in writing by the monitor. 
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 ET of the study are met: 
x New information or other evaluation regarding the safety or efficacy of the study 
medication that indicates a change in the known risk/benefit profile for the compound, 
such that the risk/benefit is no longer acceptable for subjects participating in the study. 
x Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety. 
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, protocol, or contractual agreement or is 
unable to ensure adequate performance of the study or as otherwise permitted by the 
contractual agreement. 
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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 ET 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 is defined as the date on which the last subject completes the last visit 
(including the EOS visit and any additional long-term follow-up). Any additional long-term 
follow-up that is required for monitoring of the resolution of an AE or finding may be 
appended to the clinical study report. 
9.4.3.5 
Final Report 
Regardless of whether the study is completed or prematurely terminated, the sponsor will 
ensure that clinical study reports are prepared and provided to regulatory agency(ies) as 
required by the applicable regulatory requirement(s). The sponsor will also ensure that 
clinical study reports in marketing applications meet the standards of 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. 
Upon completion of the clinical study report, the investigator(s) will be provided with the 
final approved clinical study report, as appropriate. 
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