Clinical trial NCT03083639
Conditions: Healthy Participants
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2017-03-27; Completion date: 2017-05-13
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine the bioequivalence of esomeprazole 40 milligram (mg) tablets and capsules.

Detailed description:
The drug being tested in this study is called esomeprazole. Esomeprazole is being tested in healthy participants in order to evaluate the bioequivalence between a single oral dose of esomeprazole tablet and capsule. The study will enroll 52 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment sequences:

* Esomeprazole 40 mg capsule + Esomeprazole 40 mg tablet
* Esomeprazole 40 mg tablet + Esomeprazole 40 mg capsule

All participants will be asked to take one capsule or tablet on Day 1 of each Intervention Period based on the treatment sequence to which the participant has been assigned.

This single center trial will be conducted in the United States. The overall duration to participate in this study is 36 days. Participants will visit the clinic on Day -1 and remained confined until Day 1 of Intervention Period 1 and 2. A washout period of minimum 6 days will be maintained between the dose in each Intervention Period.

Arms: arm 1: Esomeprazole 40 mg, capsule, orally, once on Day 1 of Intervention Period 1, followed by 6 days of washout period, followed by esomeprazole 40 mg tablet, orally, once on Day 1 of Intervention Period 2. arm 2: Esomeprazole 40 mg, tablet, orally, once on Day 1 of Intervention Period 1, followed by 6 days of washout period, followed by esomeprazole 40 mg capsule, orally, once on Day 1 of Intervention Period 2.
Interventions: intervention 1: Esomeprazole Capsule intervention 2: Esomeprazole Tablet
Intervention descriptions: intervention 1: Esomeprazole Capsule intervention 2: Esomeprazole Tablet

Protocol documents:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Randomized, Open-label, 2-way Cross-over Study to Evaluate the 
Bioequivalence Between a Single Oral Dose of Esomeprazole 40 mg Capsules and 
Esomeprazole 40 mg Tablets in Healthy Subjects
NCT Number: NCT03083639
Protocol Approve Date: 07 March 2017
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Randomized, Open-label, 2-way Cross-over Study to Evaluate the Bioequivalence 
Between a Single Oral Dose of Esomeprazole 40 mg Capsules and Esomeprazole 40 mg Tablets 
in Healthy Subjects
Esomeprazole Bioequivalence Study
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, Illinois 60015
Study Number:
Esomeprazole-1001
IND Number:
Not applicable
EudraCT Number:
Not applicable
Compound:
Esomeprazole 
Date:
07 March 2017
Version Number:
2
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
TDC sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
should be provided to the site.
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Takeda Pharmacovigilance
Medical Monitor
(medical advice on protocol and study drug)
Responsible Medical Officer (carries overall 
responsibility for the conduct of the study)
PPD


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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and also in accordance with the 
following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures are provided on the last page of this document.
Date
Date
Date
PPD
PPD
PPD


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INVESTIGATOR 
I confirm that I have read and that I understand this protocol, the Prescribing Information for 
esomeprazole capsules and tablets, and any other product information provided by the sponsor. I 
agree to conduct this study in accordance with the requirements of this protocol and also to 
protect the rights, safety, privacy, and well-being of study subjects in accordance with the 
following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
2.0
STUDY SUMMARY ....................................................................................................10
3.0
STUDY REFERENCE INFORMATION ......................................................................12
3.1
Study-Related Responsibilities.................................................................................12
3.2
Principal Investigator...............................................................................................12
3.3
List of Abbreviations ...............................................................................................13
3.4
Corporate Identification...........................................................................................14
4.0
INTRODUCTION.........................................................................................................15
4.1
Background .............................................................................................................15
4.2
Rationale for the Proposed Study.............................................................................15
4.3
Benefit/Risk Profile .................................................................................................16
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................17
5.1
Objectives................................................................................................................17
5.1.1
Primary Objective .......................................................................................17
5.1.2
Additional Objectives..................................................................................17
5.2
Endpoints.................................................................................................................17
5.2.1
Primary Endpoints.......................................................................................17
5.2.2
Additional Endpoints ..................................................................................17
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................18
6.1
Study Design ...........................................................................................................18
6.2
Justification for Study Design, Dose, and Endpoints ................................................19
6.3
Premature Termination or Suspension of Study or Study Site...................................19
6.3.1
Criteria for Premature Termination or Suspension of the Study...................19
6.3.2
Criteria for Premature Termination or Suspension of Study Sites ................20
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s).......................................................................20
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............21
7.1
Inclusion Criteria .....................................................................................................21
7.2
Exclusion Criteria ....................................................................................................21
7.3
Excluded Medications, Supplements, Dietary Products............................................23
7.4
Diet, Fluid, and Activity Control..............................................................................24
7.4.1
Confinement ...............................................................................................24


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7.4.2
Diet and Fluid .............................................................................................24
7.4.3
Activity Control..........................................................................................24
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................25
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................26
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................27
8.1
Study Drug ..............................................................................................................27
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................27
8.1.2
Storage........................................................................................................28
8.1.3
Dose and Regimen ......................................................................................28
8.1.4
Overdose.....................................................................................................29
8.2
Study Drug Assignment and Dispensing Procedures................................................29
8.3
Randomization Code Creation and Storage..............................................................29
8.4
Accountability and Destruction of Sponsor-Supplied Drugs.....................................29
8.5
Reserve Study Medication Samples for Retention....................................................31
9.0
STUDY PLAN ..............................................................................................................32
9.1
Study Procedures.....................................................................................................32
9.1.1
Informed Consent Procedure.......................................................................32
9.1.2
Demographics, Medical History, and Medication History Procedure...........32
9.1.3
Physical Examination Procedure .................................................................32
9.1.4
Weight, Height and BMI.............................................................................33
9.1.5
Vital Sign Procedure ...................................................................................33
9.1.6
Documentation of Concomitant Medications...............................................33
9.1.7
Documentation of Concurrent Medical Conditions......................................33
9.1.8
Procedures for Clinical Laboratory Samples................................................34
9.1.9
Contraception and Pregnancy Avoidance Procedure....................................35
9.1.10
Pregnancy ...................................................................................................37
9.1.11
ECG Procedure ...........................................................................................37
9.1.12
PK Sample Collection.................................................................................38
9.1.13
Pharmacokinetic Parameters........................................................................38
9.1.14
Documentation of Screen Failure ................................................................39
9.1.15
Documentation of Randomization ...............................................................39
9.2
Monitoring Subject Treatment Compliance..............................................................39
9.3
Schedule of Observations and Procedures................................................................40
9.3.1
Screening (Day -28 to Day -2).....................................................................40
9.3.2
Check-in (Day -1 of Periods 1 and 2) ..........................................................40


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9.3.3
Treatment (Day 1 of Periods 1 and 2)..........................................................40
9.3.4
Washout......................................................................................................40
9.3.5
Early Termination .......................................................................................40
9.4
Blood Volume .........................................................................................................40
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................42
10.1
Definitions...............................................................................................................42
10.1.1
PTEs...........................................................................................................42
10.1.2
AEs.............................................................................................................42
10.1.3
Additional Points to Consider for PTEs and AEs.........................................42
10.1.4
SAEs...........................................................................................................44
10.1.5
Intensity of PTEs and AEs ..........................................................................45
10.1.6
Relationship of AEs to Study Drug(s) .........................................................45
10.1.7
Relationship to Study Procedures................................................................45
10.1.8
Start Date....................................................................................................46
10.1.9
Stop Date ....................................................................................................46
10.1.10
Frequency ...................................................................................................46
10.1.11
Action Concerning Study Drug ...................................................................46
10.1.12
Outcome .....................................................................................................46
10.2
Procedures...............................................................................................................47
10.2.1
Collection and Reporting of AEs.................................................................47
10.2.2
Collection and Reporting of SAEs...............................................................48
10.2.3
Reporting of Abnormal Liver Function Tests ..............................................48
10.3
Follow-up of SAEs ..................................................................................................49
10.3.1
Safety Reporting to Investigators, IRBs and Regulatory Authorities............49
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................50
12.0
DATA HANDLING AND RECORDKEEPING............................................................51
12.1
CRFs (Electronic and Paper)....................................................................................51
12.2
Record Retention .....................................................................................................51
13.0
STATISTICAL METHODS..........................................................................................53
13.1
Statistical and Analytical Plans ................................................................................53
13.1.1
Analysis Sets...............................................................................................53
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................53
13.1.3
PK Analysis ................................................................................................53
13.1.4
Safety Analysis ...........................................................................................54
13.2
Interim Analysis and Criteria for Early Termination ................................................54


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13.3
Determination of Sample Size..................................................................................54
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................55
14.1
Study-Site Monitoring Visits ...................................................................................55
14.2
Protocol Deviations..................................................................................................55
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................56
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................57
15.1
IRB and/or IEC Approval ........................................................................................57
15.2
Subject Information, Informed Consent, and Subject Authorization .........................58
15.3
Subject Confidentiality ............................................................................................59
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................59
15.4.1
Publication and Disclosure..........................................................................59
15.4.2
Clinical Trial Registration...........................................................................60
15.4.3
Clinical Trial Results Disclosure .................................................................60
15.5
Insurance and Compensation for Injury....................................................................60
16.0
REFERENCES..............................................................................................................61
LIST OF IN-TEXT TABLES
Table 7.a
Prohibited Medications, Supplements, and Dietary Products ..............................23
Table 8.a
Study Medication – Sponsor Supplied................................................................27
Table 8.b
Dose and Regimen .............................................................................................28
Table 9.a
Clinical Laboratory Tests...................................................................................34
Table 9.b
Collection of Blood Samples for PK Analysis ....................................................38
Table 9.c
Approximate Blood Volume ..............................................................................41
Table 10.a
Takeda Medically Significant AE List................................................................45
Table 14.a
Windows for PK Blood Sample Collection ........................................................56
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................18
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................62
Appendix B
Responsibilities of the Investigator.....................................................................63
Appendix C
Elements of the Subject Informed Consent.........................................................65


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Appendix D
Investigator Consent to Use of Personal Information..........................................68
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples..............................69


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
Esomeprazole
Title of Protocol: A Phase 1, Randomized, Open-label, 2-
way Cross-over Study to Evaluate the Bioequivalence 
between a Single Oral Dose of Esomeprazole 40 mg 
Capsules and Esomeprazole 40 mg Tablets in Healthy 
Subjects
IND No.: not applicable
EudraCT No.:
not applicable 
Study Number: Esomeprazole-1001
Phase: 1
Study Design:
Phase 1, randomized, open-label, 2-way crossover study in healthy adult male and female subjects aged 18 to 55 
years, inclusive, to evaluate the bioequivalence between a single oral dose of esomeprazole 40 mg capsules 
(Nexium) and esomeprazole 40 mg tablets (Nexium).
Primary Objective:
To determine the bioequivalence between esomeprazole 40 mg tablets and capsules.
Subject Population: Healthy adult male and female subjects aged 18 to 55 years, inclusive.
Number of Subjects: Estimated Total: 52 
Number of Sites: 1
Dose Level(s):
Regimen A: A single 40 mg esomeprazole capsule.
Regimen B: A single 40 mg esomeprazole tablet.
Route of Administration:
oral
Duration of Treatment:
Single dose
Period of Evaluation:
36 days
Main Criteria for Inclusion:
Healthy adult male or female subjects aged 18 to 55 years, inclusive, and weighing at least 50 kg with a body mass 
index from 18.5 to 30 kg/m2, inclusive.
Main Criteria for Exclusion:
Subject has a known hypersensitivity to any component of the formulation of esomeprazole capsules or tablets or 
compounds with the same mechanism of action, or related compounds; a history of significant gastrointestinal (GI) 
disorders manifested with persistent, chronic or intermittent nausea, vomiting, diarrhea, or has a current or recent 
(within 6 months) GI disease that would influence the absorption of drugs, or any gastrointestinal-related surgical 
intervention.


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Main Criteria for Evaluation and Analyses:
The concentrations of esomeprazole in plasma following tablet and capsule administration will be measured at 0 
(predose), and at 0.33, 0.66, 1, 1.33, 1.66, 2, 2.33, 2.66, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, and 10 hours postdose. The 
primary endpoints for this study are the pharmacokinetic parameters derived from the plasma concentrations of 
esomeprazole 40 mg administered via capsule and tablet after a single dose including: area under the concentration-
time curve from time 0 to infinity, calculated using the observed value of the last quantifiable concentration 
(AUC∞); area under the concentration-time curve from time 0 to time t (AUCt) and maximum observed 
concentration (Cmax).
Statistical Considerations:
Descriptive statistics (arithmetic mean, SD, percent coefficient of variation (%CV), median, minimum and 
maximum) will be used to summarize the plasma concentrations and plasma pharmacokinetics parameters for 
esomeprazole. In addition, geometric mean and %CV will be computed for Cmax, AUC∞, and AUCt.
Natural-logarithmically transformed Cmax and AUCs will be analyzed using analysis of variance with fixed factors 
for period, sequence, and regimen, and subject within sequence as a random effect. Bioequivalence will be assessed 
via point estimates and 90% CI for the ratio of Cmax, and AUCs central values for esomeprazole tablet (Regimen B –
test) versus esomeprazole capsule (Regimen A - reference). Bioequivalence between tablet and capsule will be 
claimed if the 90% CI for the ratio is within the bioequivalence criteria of 0.80 to 1.25.
Sample Size Justification: The sample size for this study is estimated at 52, which provides an allowance for 4 
dropouts. The sample size was estimated based on variability data from a previous study, using a %CV of 28% as 
the intrasubject variation for the natural logarithm of Cmax and the assumed true ratio of 0.95 for tablet over capsule. 
Given the above information, a sample size of 52 subjects provides at least 90% power for concluding 
bioequivalence for Cmax and the power for AUCs is greater than 90%.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator
PPD


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3.3
List of Abbreviations
%CV
percent coefficient of variation
λz
terminal disposition rate constant
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUCt
area under the concentration-time curve from time 0 to time t
AUC∞
area under the concentration-time curve from time 0 to infinity
bpm
beats per minute
BMI
body mass index
CHMP
Committee for Medicinal Products for Human Use
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed concentration
CRO
contract research organization
CS
clinically significant
CYP
cytochrome P-450
ECG
electrocardiogram
eCRF
case report form electronic or paper
EMA
European Medicines Agency
DU
duodenal ulcer
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase
GERD
gastroesophageal reflux disease
GI
gastrointestinal
GU
gastric ulcer
H. pylori
helicobacter pylori
HBsAg
hepatitis B virus surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IEC
independent ethics committee
ICH
International Conference on Harmonisation
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
NCS
not clinically significant


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PK
pharmacokinetic
PPIs
proton pump inhibitors
PTE
pretreatment event
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
tlag
lag time to first quantifiable concentration
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal disposition phase
after extravascular administration
3.4
Corporate Identification 
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
Acid-related diseases including peptic ulcer and gastroesophageal reflux disease (GERD) are one 
of the most common gastrointestinal (GI) diseases. The proton pump inhibitors (PPIs), such as 
esomeprazole magnesium, represent the drugs of first choice for acid-related disorders, and are 
being widely used all over the world. The PPIs inhibit the H+, K+-ATPase enzyme (proton pump) 
which represents the final step in acid secretion by the parietal cells in the gastric mucosa, and 
produce potent anti-secretory efficacy for acid-related disorders. 
However, even with these potent acid-inhibitory effects, the PPIs are not without their limitations 
and have not necessarily produced adequate improvements in extent and speed of symptom 
relief [1]. Indeed, the PPIs appear to leave room for improvement, the reasons being that: 
1. Being less resistant to acid exposure and provided as enteric-coated drugs, the PPIs vary in 
time for onset of their action; 
2. About 3 to 5 days are required to obtain maximum acid-inhibitory effects with the PPIs; 
3. Acid-inhibitory effects with the PPIs appear to be satisfactory during daytime, but not 
adequate to inhibit acid regurgitations from the stomach to the esophagus occurring during 
nighttime, leading to nocturnal acid breakthroughs in some individuals; 
4. Metabolized by cytochrome P-450 (CYP)2C19 associated with polymorphisms, the PPIs are 
associated with varying serum concentrations, thus producing disparate acid-inhibitory 
effects in extensive metabolizers versus poor metabolizers. 
The development of new drug treatments for acid-related diseases such as GERD needs to 
include clinical trials with an active comparator considered an accepted standard of care, ie, PPIs 
(namely esomeprazole).
TAK-438 (vonoprazan fumarate), a potassium-competitive acid blocker, was developed to 
overcome some of the limitations of PPIs. It is approved and marketed for the treatment of acid-
related diseases in Japan including the indications of: erosive esophagitis healing and 
maintenance; healing of gastric ulcer (GU) and duodenal ulcer (DU); the prevention of 
recurrence of GU or DU associated with administration of low-dose aspirin or nonsteroidal anti-
inflammatory; and for the eradication of helicobacter pylori (H. pylori) infection as a component 
of triple therapy (co-administered with 2 antibiotics). Vonoprazan is currently undergoing further 
global development with studies ongoing in Asia and the European Union, and more studies 
planned globally, where esomeprazole is likely to be used as active comparator.
4.2
Rationale for the Proposed Study
Esomeprazole is available in several pharmaceutical forms including different formulations 
across regions for the same indications, namely tablets in the European Union and capsules in the 
United States. To ensure the global applicability of clinical study results utilizing esomeprazole 
as a comparator, this phase 1, randomized, open-label, 2-way crossover study in healthy adult 


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male and female subjects is being conducted to evaluate the bioequivalence of a single oral dose 
of esomeprazole 40 mg capsules and esomeprazole 40 mg tablets. The design is based on 
previously conducted esomeprazole bioequivalence studies [2-4], and is consistent with 
regulatory guidance [5,6]. 
4.3
Benefit/Risk Profile 
Given that this study is being conducted in healthy subjects with the aim of establishing 
bioequivalence of single doses of esomeprazole, this study is not expected to provide benefit to 
the subjects taking part. In this study it is planned that subjects will receive 2 doses of 
esomeprazole separated by at least a 6-day washout. Esomeprazole was first approved in 2001 
and since this time has been widely used in the treatment of acid-related disorders. Esomeprazole 
is well characterized in terms of efficacy and safety, and there are no anticipated risks associated 
with administering esomeprazole in the context of this phase 1 study to this healthy subject 
population. Finally, although this study requires that blood is withdrawn for the purposes of 
analyzing clinical laboratory markers, and the bioequivalence of esomeprazole tablets and 
capsules, the approximate total volume of blood for the study is 356 mL over the course of the 
study.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
To determine the bioequivalence of esomeprazole 40 mg tablets and capsules.
5.1.2
Additional Objectives
To determine pharmacokinetic (PK) parameters for each formulation.
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints for this study are the PK parameters derived from the plasma 
concentrations of esomeprazole 40 mg administered via capsule and tablet after a single dose 
including: area under the concentration-time curve from time 0 to infinity (AUC∞), area under 
the concentration-time curve from time 0 to time t (AUCt), and maximum observed 
concentration (Cmax).
5.2.2
Additional Endpoints
Additional endpoints for this study are the PK parameters derived from the plasma 
concentrations of esomeprazole 40 mg administered via capsule and tablet after a single dose 
including: time of first occurrence of Cmax (tmax); terminal disposition phase half-life (t1/2z); 
apparent clearance after extravascular administration, calculated using the observed value of the 
last quantifiable concentration (CL/F); apparent volume of distribution during the terminal 
disposition phase after extravascular administration, calculated using the observed value of the 
last quantifiable concentration (Vz/F); terminal disposition phase rate constant (λz), and lag time 
to first quantifiable concentration (tlag).


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 1, randomized, open-label, 2-way cross-over study in healthy adult male and 
female subjects aged 18 to 55 years, inclusive, to evaluate the bioequivalence of a single oral 
dose of esomeprazole 40 mg capsules (reference [A]) and esomeprazole 40 mg tablets (test [B]). 
It is estimated that 52 subjects will be needed to ensure that 48 subjects complete both periods. 
Screening for potential subjects will occur between 28 and 2 days prior to Day 1. On Day -1, 
subjects’ eligibility will be reconfirmed and eligible subjects will be randomized in a 1:1 ratio to 
1 of 2 sequences, which defines the order in which they will receive esomeprazole regimens in 
Periods 1 and 2. In both periods, subjects will fast for 10 hours prior to study drug administration 
and refrain from eating until 4 hours after drug administration. Each period will be separated by 
a minimum 6-day washout period. Blood samples for PK analysis will be drawn up to 10 hours 
after study drug administration on Day 1 in each period. Subjects will be confined to the phase 1 
unit from Day -1 until the end of all assessments on Day 1 of each period.
Given that esomeprazole is a marketed product with a well-characterized safety profile, this 
study does not include a follow-up evaluation period. In total, the period of evaluation is 
expected to be a maximum of 36 days (assuming a washout period of 6 days), including the 
Screening Period.
A schematic of the study design is shown in Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Figure 6.a
Schematic of Study Design
Pretreatment Period
Period 1 (a)
Period 2 (a)
Screening (b)
Check-in
Single 
Dose and 
PK (c)
Checkout
Washout 
(d)
Check-in
Single Dose 
and PK (c)
Checkout
Days -28 to -
2
Day -1
Day 1
Day 1
Day 2-6
Day -1
Day 1
Day 1
Confinement 
Confinement
(a) Subjects will be admitted to the clinic on Day -1 of each period. On Day 1, subjects will be randomized to 1 of 2 
sequences of esomeprazole tablet and capsule. Subjects will be discharged from the clinic on Day 1 after dosing and 
the completion of all scheduled procedures.
(b) For clinical laboratory tests that are required to be taken under fasting conditions, the subject will be asked to 
return to the unit at a later date under fasting conditions.
(c) PK samples at 0 (predose), and at 0.33, 0.66, 1, 1.33, 1.66, 2, 2.33, 2.66, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, and 10 hours 
postdose.
(d) Minimum 6-day washout between doses. Day -1 of Period 2 could be the sixth day of washout.


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6.2
Justification for Study Design, Dose, and Endpoints
Study design
This phase 1, randomized, open-label, single-dose, 2-way crossover relative bioequivalence 
study is designed in accordance with the draft Food and Drug Administration (FDA) guidance 
[6], and European Medicines Agency (EMA) guidance [5].
A single-dose study under fasting conditions for assessing the relative bioequivalence between 
formulations is recommended in FDA and Committee for Medicinal Products for Human Use
(CHMP) guidance and will be used for comparison of the 2 different formulations. The crossover 
design is appropriate for the objectives of this study because each subject receives both regimens 
and serves as his or her own control.
The sample size for this study is estimated as 52 which allows for 4 dropouts (see Section 13.3
for further details of sample size calculation).
In humans, esomeprazole has a mean PK t1/2z of approximately 1 hour, and a mean 
pharmacodynamic t1/2z of approximately 50 hours for sulphenamide complex. The pH levels 
have been shown to return to Baseline ~48 hours after the previous dose. Therefore, a minimum 
6-day washout interval between the doses is sufficient to ensure that there is no drug carryover 
effect, and collection of PK blood samples for 10 hours postdose is appropriate to characterize 
the PK of esomeprazole. The primary PK endpoints, AUC∞, Cmax and AUCt are standard 
parameters to assess bioequivalence.
Dose selection
This study is testing the bioequivalence between esomeprazole capsules and tablets at the highest 
dose strength, 40 mg, consistent with the published data [2]. Administered as a single-dose with 
a minimum 6-day washout between doses, this dose is expected to be generally well tolerated in 
healthy subjects. 
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the esomeprazole, such that the risk is 
no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
–
Two or more subjects experience any of the Takeda Medically Significant List events (as 
outlined in Table 10.a).*


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–
Two or more subjects experience alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) elevations >5 × upper limit of normal (ULN) in the absence of a 
concomitant bilirubin increase [see below].*
–
One or more subjects experience ALT and/or AST elevations >3 ×ULN in the presence 
of a total bilirubin increase >2 ×ULN or an international normalized ratio (INR) >1.5 
without findings of cholestasis or other alternate etiology to explain the elevations (ie, 
“Hy’s Law cases”).
–
Two or more subjects experience ALT and/or AST elevations >3 ×ULN with the 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash and/or eosinophilia (>5%).*
* Please note that the study may be terminated early prior to full attainment of these 
criteria (eg, if just 1 subject experiences 1 of these events) if warranted by safety data 
from the other subjects dosed in the study to date.
6.3.2
Criteria for Premature Termination or Suspension of Study 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, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, an institutional review board (IRB)/ independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of a 
study site, a study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable study sites during the course of 
termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to first dose.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study:
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and 
dates a written, informed consent form and any required privacy authorization prior to the 
initiation of any study procedures including requesting that a subject fast for any laboratory 
evaluations. [Note: this is not a contradiction of Criterion 1. A subject may understand and be able to comply 
with the protocol but physically unable to sign (eg, blind / broken hand).]
3. The subject is a healthy adult male or female subject.
4. The subject is aged 18 to 55 years, inclusive, at the time of informed consent and first study 
medication dose.
5. The subject weighs at least 50 kg and has a body mass index (BMI) from 18.5 to 30 kg/m2, 
inclusive at Screening and Day -1.
6. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use a highly effective method of contraception* from signing of informed 
consent throughout the duration of the study and for 31 days after the last dose of the study
drug.
* Definitions and highly effective methods of contraception are defined in 
Section 9.1.9 and reporting responsibilities are defined in Section 9.1.10.
7. The subject is willing to abstain from caffeine from 72 hours before Day -1 and alcohol from 
7 days before Day -1 and throughout the duration of the study. 
8. The subject is willing to abstain from strenuous exercise from 72 hours before first dose 
(Day 1) in Period 1 and throughout the duration of the study. 
9. Subject has clinical chemistry, hematology, and complete urinalysis at Screening and Check-
in (Day -1 of Period 1) results within the reference range for the testing laboratory unless the 
out-of-range results are deemed not clinically significant by the investigator. 
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received any investigational compound within 30 days prior to first dose 
2. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(eg, spouse, parent, child, sibling) or may consent under duress.


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3. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality, which 
may impact the ability of the subject to participate or potentially confound the study results. 
It is the responsibility of the investigator to assess the clinical significance; however, 
consultation with the Takeda Medical Monitor may be warranted.
4. The subject has a history of significant GI disorders manifested with persistent, chronic or 
intermittent nausea, vomiting, diarrhea, or has a current or recent (within 6 months) GI 
disease that would influence the absorption of drugs (eg, a history of malabsorption, severe 
esophageal reflux, peptic ulcer disease or erosive esophagitis), or any gastrointestinal-related 
surgical intervention.
5. Subject has a known hypersensitivity to any component of the formulation of esomeprazole 
capsules or tablets or compounds with the same mechanism of action (dexlansoprazole, 
lansoprazole, omeprazole, rabeprazole, pantoprazole), or related compounds.
6. The subject has a positive urine/blood drug result for drugs of abuse, (defined as any illicit 
drug use) or alcohol at Screening or Check-in (Day -1).
7. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse (defined as regular consumption of 4 or more units per day) within 1 year prior to the 
Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the 
study. One unit is equivalent to a half-pint of beer or 1 measure of spirits or 1 glass of wine.
8. Subject has taken any excluded medication, supplements, or food products during the time 
periods listed in the Excluded Medications and Dietary Products table (listed in Section 7.3).
9. If female, the subject is pregnant or lactating or intending to become pregnant before
participating in this study, and during the study and within 31 days after last dose of the study
drug; or intending to donate ova during such time period. 
10. Subject has evidence of current cardiovascular, central nervous system, hepatic, 
hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious 
allergy, asthma, hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding 
in the subject’s medical history, physical examination, or safety laboratory tests giving 
reasonable suspicion of a disease that would contraindicate taking esomeprazole, or a similar 
drug in the same class, or that might interfere with the conduct of the study. This includes, 
but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias.
11. Subject has a history of cancer, except basal cell carcinoma which has been in remission for 
at least 5 years prior to Day 1 of Period 1.
12. Subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, or human immunodeficiency virus (HIV) antibody at Screening. 
13. Subject has used nicotine-containing products (including but not limited to cigarettes, pipes, 
cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in on 
Day -1 of Period 1 and throughout the study. Cotinine test is positive at Screening and
Check-in (Day -1).


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14. The subject has poor peripheral venous access.
15. The subject has donated or lost 450 mL or more of his or her blood volume (including 
plasmapheresis), or had a transfusion of any blood product within 30 days prior to Day 1 of 
Period 1.
16. Subject has a Screening or Check-in (Day -1) abnormal (clinically significant) 
electrocardiogram (ECG). 
7.3
Excluded Medications, Supplements, Dietary Products
Use of the agents in Table 7.a is prohibited from the time points specified until completion of all 
study activities on Period 2, Day 1 Checkout. 
Table 7.a
Prohibited Medications, Supplements, and Dietary Products
28 Days Prior to Check-in 
(Day -1)
7 Days Prior to Check-in 
(Day -1)
72 Hours Prior to Check-in 
(Day -1)
Prescription medications
Any other investigational drugs(a)
OTC medications (b)
Products containing caffeine or 
xanthine
Neutraceuticals (eg, St. John’s wort, 
ginseng, kava kava, ginkgo biloba, 
Chinese herbs, and melatonin)
Vitamin supplements
poppy seeds
Immunization/Vaccines
Foods or beverages containing 
grapefruit or Seville-type (sour) 
oranges and marmalade, apple, 
orange, or pineapple juices, vegetables 
from the mustard green family (eg, 
kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts, 
mustard), and charbroiled meats
Nicotine-containing products
Alcohol (including alcohol-based 
mouthwash)
Intake of inhibitors/inducers of CYPs 
3A4/5, 2C9, 2C19, 2D6, 1A2, 2B6, 2E1, 
and 2A6
OTC=over-the-counter. 
(a) Subjects are excluded from receiving any other investigational compound within 30 days prior to first dose.
(b) Occasional use of acetaminophen/paracetamol (1 g/day) or other medication as approved by Takeda on a case-
by-case basis is allowed. 
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator.


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7.4
Diet, Fluid, and Activity Control 
7.4.1
Confinement
Subjects enrolled in this study will be confined in the clinical research unit for 1 night in each 
period, beginning at Check-in (Day -1) to the completion of all assessments on Day 1. There will 
be a minimum 6-day washout interval between the dose in the first period and the dose in the 
second period. Subjects will be released from the clinic during the washout interval.
7.4.2
Diet and Fluid
During each day of the confinement period, subjects will receive standardized meals and an 
evening snack, each of which contains approximately 30% fat (caloric value). The clinical 
research site will ensure the same meals are served to all subjects on Day 1 of both study periods. 
All subjects may consume water ad libitum except for 1 hour before and 1 hour after drug 
administration. The study menu should be recorded and submitted to the study file with a copy 
provided to the sponsor prior to the start of the study.
During confinement, foods and beverages listed in Table 7.a will be prohibited, and all subjects 
will be limited to only standardized meals and snacks provided by the site.
Subjects will fast for a minimum of 10 hours prior to dosing on Day 1 of each period and will 
continue to fast for a further 4 hours after dosing. On Day 1 of each period, breakfast will not be 
served. Lunch will be served approximately 4 hours postdose. Dinner/snack will be served 
approximately 10 hours postdose. No additional meals will be served on Day 1 of each period. 
The start and stop times of meals on Day 1 of each period, along with whether the meal was 
completely consumed, will be recorded in the source documentation and on the electronic case 
report form (eCRF). 
If a blood draw or any study procedure coincides with a meal, the blood draw will take 
precedence followed by the study procedure and then the meal. 
7.4.3
Activity Control
Subjects will remain upright (seated, standing, semirecumbent, or ambulatory) for 2 hours 
following the dose administration, except as necessitated by the occurrence of an adverse event
(AE) /or study procedures (eg, obtaining 12-lead ECG). Subjects will refrain from strenuous 
exercise 72 hours before first dose in Period 1 and for the duration of their participation in the 
study.


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7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug
should be recorded in the eCRF using the following categories. For screen failure subjects, refer 
to Section 9.1.14.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires 
early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE.

Liver Function Test (LFT) Abnormalities
In multidose studies study drug should be discontinued immediately with appropriate 
clinical follow-up (including repeat laboratory tests, until a subject’s laboratory profile 
has returned to normal/baseline status, see Section 9.1.8), if the following circumstances 
occur at any time during study drug treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or INR 
>1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
2. Significant protocol deviation. The discovery after the first dose of study drug that the
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s 
source documentation.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to 
an AE should not be recorded in the “voluntary withdrawal” category.
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.


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7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit. Discontinued or withdrawn subjects will 
not be replaced.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medication provided directly by the sponsor, 
and/or sourced by other means, that are required by the study protocol, including important 
sections describing the management of clinical trial material.
8.1
Study Drug
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to esomeprazole 40 mg capsules manufactured 
for the US market and esomeprazole 40 mg tablets manufactured for the EU market, both 
sourced by the Sponsor as defined below. 
Commercially available esomeprazole magnesium (Nexium), 40 mg hard capsules, delayed 
release (bottle of 30 capsules) 
Commercially available esomeprazole magnesium (Nexium), 40 mg gastro-resistant tablets (2 
blisters of 14 tablets in a carton)
Each bottle and each carton will bear a single panel open computer- generated label containing 
the required information, including the Federal caution statement: “CAUTION: New Drug-
Limited by Federal (or United States) Law to Investigational Use.
The sponsor will supply a site with study drug as shown in Table 8.a.
Table 8.a
Study Medication – Sponsor Supplied 
Formulation
Investigational Product
Dosage
Manufacturer and Location
A (test)
Esomeprazole capsule
40 mg 
AstraZeneca, France
B (reference)
Esomeprazole tablet
40 mg 
AstraZeneca, UK
UK=United Kingdom. 
8.1.1.1
Investigational Drug
Esomeprazole capsules, 40 mg are manufactured and packaged in bottles by AstraZeneca with 
single-panel Takeda clinical study label applied on the bottle. The label includes study 
information along with the caution statement. Each bottle contains 30 tablets.
Esomeprazole tablets, 40 mg are manufactured and packaged in a carton by AstraZeneca with 
single-panel Takeda clinical study label on the carton. The label includes study information 
along with the caution statement. Each carton contains 28 tablets.
8.1.1.2
Sponsor-Supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol include the following: 
esomeprazole capsule, 40 mg and esomeprazole tablet, 40 mg.


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8.1.2
Storage
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. Investigational drug, must be stored under 
the conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day.
Drug supplies must be stored at 25°C (77°F) with excursions permitted to 15°C to 30°C (59°F to 
86°F) in a secure location until dispensed to study subjects or returned to Takeda. Temperature 
excursions must be reported to the sponsor. In order to protect drug supply from moisture, the 
container should be kept tightly closed (bottle) or stored in the original package (blister). Do not 
take a tablet out of the blister foil until the subject is ready to take it.
8.1.3
Dose and Regimen
Subjects will fast for a minimum of 10 hours prior to dosing in Periods 1 and 2. On Day 1 at 
approximately 0800 hours, subjects will be instructed to swallow the intact capsule/tablet with 
240 mL of water. All subjects may consume water ad libitum, except for 1 hour prior to and 1 
hour post drug administration. Subjects must drink all of the water provided with the dose. 
Subjects will continue to fast for 4 hours after dose administration in both periods.
Following the administration of the study drug, hand and mouth checks will be performed to 
ensure the dose was swallowed. Although the timing of events requires that each subject will be 
consistently administered the appropriate dose at specific times, the exact dose time of 
consecutive subjects may be staggered to obviate the need to have all subjects on precisely the 
same study schedule.
On each dosing day (Day 1 of Periods 1 and 2) subjects will be administered dosing regimens 
according to the sequence group to which they are assigned (Table 8.b).
The 2 dosing regimens are:
Regimen A: A single 40 mg esomeprazole capsule.
Regimen B: A single 40 mg esomeprazole tablet.
Following the completion of all assessments on Day 1 of Period 1, subjects will be discharged 
from the study site for a minimum washout interval of 6 days between the dose in the first period 
and the dose in the second period. 
Table 8.b
Dose and Regimen
Treatment Sequence
Number of Subjects
Period 1
Regimen
Period 2
Regimen
1
26
A
B
2
26
B
A
Regimen A: A single 40 mg esomeprazole capsule administered orally on Day 1 following a 10-hour fast.
Regimen B: A single 40 mg esomeprazole tablet administered orally on Day 1 following a 10-hour fast.
No additional preparation is necessary.


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8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be documented on AE CRF(s) according to Section 10.0.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Study Drug Assignment and Dispensing Procedures
Qualified subjects will be assigned, in the order in which they are randomized into the study, to 
receive study drug according to the randomization schedule allocated to the site. Subjects who 
qualify for this study will be assigned to receive a 4-digit randomization number. The number 
will be assigned by the clinic site personnel in sequential order beginning with 1001 and ending 
with 1052. This 4-digit number will be entered into the eCRF and used by the clinical site to 
facilitate the prelabeling of PK samples, and will be the only subject identifier used on all PK 
sample collections. It should also be contained on the PK transport vials shipped to the 
bioanalytical laboratory, and will be used by the laboratory to report the subject data results. This 
4-digit number should only be used for the purposes described in this section. It does not replace 
the 3-digit subject number which is assigned at the time the informed consent is obtained and 
which is used for all other procedures to identify the subjects throughout the study. 
8.3
Randomization Code Creation and Storage
The randomization schedule will be generated by the Quantitative Science Department at Takeda 
Development Center, Inc. (TDC Americas) unless delegated to the CRO prior to the start of the 
study. The randomization schedule will be provided to the site pharmacist prior to the start of 
this study. All randomization information will be stored in a secured area, accessible only by 
authorized personnel.
8.4
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee, or destroyed.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug, the investigator or designee must maintain records of
all sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each 
subject, and return to the sponsor or designee.


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Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment by signing bottom half of the packing 
list and faxing per instructions provided on the form. If there are any discrepancies between the 
packing list versus the actual product received, Takeda must be contacted to resolve the issue. 
The packing list should be filed in the investigator’s essential document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot number used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. Note that expiry date monitoring will not be required as the drug provided will 
have more than 2 years before expiry.
The investigator or designee must record the current inventory of all sponsor-supplied 
esomeprazole on a sponsor-approved drug accountability log. The following information will be 
recorded at a minimum: protocol number and title, name of investigator, site identifier and 
number, description of sponsor-supplied drugs, expiry date and amount dispensed, including 
initials, seal, or signature of the person dispensing the drug, and the date and amount returned to 
the site by the subject, including the initials, seal, or signature of the person receiving the 
sponsor-supplied drug. The log should include all required information as a separate entry for 
each subject to whom sponsor-supplied drug is dispensed.
All study drug not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, 
and/or destruction, and originals will be sent to the sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction.


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8.5
Reserve Study Medication Samples for Retention
The investigator will retain a reserve sample (5 times the amount required for full analytical 
release testing) of esomeprazole in accordance with FDA regulations. The investigator or the 
investigator’s designee will select the appropriate number of containers of study drug for 
retention, as specified in the bioretention letter to be provided by Takeda Clinical Supplies. 
Reserve samples will be stored under conditions consistent with the product’s labeling and in a 
segregated area with access limited to authorized personnel. Each reserve sample will be retained 
for a period of at least 5 years following the date the application or supplemental application is 
approved by the FDA. If the application is not approved, regulations specify that these samples 
must be stored for at least 5 years following the date of completion of this bioequivalence study. 
The clinical site should not dispose of the reserve samples without written authorization from 
Takeda. If at any time the investigator is unable to comply with these requirements, the 
investigator should immediately notify Takeda regarding arrangements for storing reserve 
samples and associated study records on the investigator’s behalf.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed, including requesting that a subject fast for 
laboratory evaluations.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race 
as described by the subject, height, weight, caffeine consumption, xanthine consumption, alcohol 
use, reproductive status (including last menstrual period) and smoking status of the subject at 
Screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.7).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 28 days prior to signing of informed consent.
9.1.3
Physical Examination Procedure
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; 
(6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 
(10) lymph nodes; and (11) other.
Any abnormal finding on a pretreatment physical examination assessment must be assessed as 
not clinically significant (NCS) or clinically significant (CS) by the investigator and recorded in 
the source document and eCRF. All CS findings/changes will be recorded as a PTE or concurrent 
medical condition in the source document and on the appropriate eCRF described in Section 10.0
or Section 9.1.7. 
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately prior to the start of the study drug (Day 1) must be assessed as 


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NCS or CS by the investigator and recorded in the source document and eCRF. Any CS change 
or new diagnosis as a result of a CS change, as determined by the investigator, will be recorded 
as an AE in source documentation and on the PTE/AE eCRF described in Section 10.0. 
9.1.4
Weight, Height and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated, using metric units with the formula provided below. The Takeda 
standard for collecting height is centimeters without decimal places and for weight it is 
kilograms (kg) with 1 decimal place. BMI should be derived as:
Metric:
BMI = weight (kg)/height (m)2
Note that although height is reported in centimeters, the formula uses meters for height; meters 
can be determined from centimeters by dividing by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2
.
The values should be reported to 1 decimal place by rounding. Thus, in the above example BMI 
would be reported as 25.6 kg/m2. However, if the BMI is used as entry criteria based on the 
range 18.5-30 kg/m2 cut-off point, then this determination must be made after rounding.
9.1.5
Vital Sign Procedure
Vital signs will include oral body temperature, respiratory rate, sitting blood pressure (resting in 
a sitting or supine position for at least 5 minutes), and pulse (beats per minute [bpm]).
Vital signs may be repeated once. All measurements will be recorded on the source documents 
and in the eCRF. 
9.1.6
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by the sponsor. At each study visit, subjects will be asked whether they have taken 
any medication other than the study drug (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. Documentation will 
include generic medication name, dose, unit, frequency, route of administration, start and end 
dates, and reason for use. 
9.1.7
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at baseline examination, according the judgment of the 
investigator. The condition (ie, diagnosis) should be described.


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9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Laboratory 
samples will be taken following a minimum 8 hour overnight fast on the days stipulated in the 
Schedule of Study Procedures (Appendix A).
Table 9.a lists the tests that will be obtained for each laboratory specimen.
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBC
WBC (with differential)
Hemoglobin
Hematocrit
Platelets
MCHC
MCV
RDW
Reticulocyte count
PT/INR
aPTT
Alanine aminotransferase
Albumin
Alkaline phosphatase
Aspartate aminotransferase
Glucose (a)
Gamma-glutamyl transferase 
Total bilirubin
Total protein
Serum creatinine
Blood urea nitrogen
Phosphorous
Potassium
Chloride
Bicarbonate or carbon dioxide
Sodium
pH
Specific gravity
Protein
Ketones
Glucose 
Bilirubin
Blood 
Nitrites
Leukocyte esterase
Microscopic Analysis 
(only of positive dipstick 
result):
RBC/high power field
WBC/high power field
Epithelial cells, casts
Diagnostic Screening:
Serum
Urine
HIV test
Hepatitis panel, including HBsAg and anti-HCV Ab
Drug screen, including alcohol, amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine, 
opiates, and cotinine
Female subjects:
Human chorionic gonadotropin (for pregnancy)
Female subjects of child-bearing potential only when 
menopause is suspected:
Follicle-stimulating hormone
anti-HCV Ab=anti-hepatitis C virus antibody, aPTT=activated partial thromboplastin time, MCH=mean corpuscular 
hemoglobin, MCHC=mean corpuscular hemoglobin concentration, MCV=mean corpuscular volume, 
PT=prothrombin time, RBC=red blood cell, RDW=red cell distribution width, WBC=white blood cell.
(a) Conducted under fasting conditions. 
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible 
for reviewing and filing these results.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, γ-glutamyl transferase [GGT], and INR) should 
be performed within a maximum of 7 days and preferably within 48-72 hours after the 


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abnormality was noted. (Refer to Section 7.5 and Section 10.2.3 for the appropriate guidance on 
reporting abnormal liver function tests.)
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions, the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study drug, discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 for reporting requirements).
All laboratory safety data will be transferred electronically to Takeda or designee in the format
requested by Takeda. If the laboratory is unable to electronically transfer data, the study site
coordinator or designee is responsible for transcribing laboratory results to the eCRF. The 
investigator will maintain a copy of the laboratory accreditation and the reference ranges for the 
laboratory used.
Laboratory reports must be signed and dated by the principal investigator or subinvestigator 
indicating that the report has been reviewed and any abnormalities have been assessed for 
clinical significance. Any abnormalities identified prior to first dose will require clear and 
complete documentation in the source documents as to the investigator’s assessment of not 
clinically significant before proceeding with enrollment/randomization.
All clinically significant laboratory abnormalities must be recorded as a PTE/AE in the subject’s 
source documents and on the appropriate eCRF. A clinically significant laboratory abnormality 
that has been verified by retesting will be followed until the abnormality returns to an acceptable 
level or a satisfactory explanation has been obtained.
9.1.9
Contraception and Pregnancy Avoidance Procedure
9.1.9.1
Male Subjects and Their Female Partners
Male subjects are not required to use barrier contraception.
9.1.9.2
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 31 days after last 
dose of study drug, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use a highly effective method of contraception (from the list 
below).
In addition they must be advised not to donate ova during this period.
9.1.9.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential (WOCBP), that is, fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, or bilateral oophorectomy. A postmenopausal state is defined as 


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no menses for 12 months without an alternative medical cause. A high follicle-stimulating 
hormone (FSH) level in the postmenopausal range (FSH >40 IU/L) may be used to confirm a 
post-menopausal state in younger women (eg, those <45 years old) or women who are not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that 
they have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, 
that result in a low failure rate (ie, less than 1% failure rate per year when used consistently 
and correctly). In this study, where medications and devices containing hormones are 
included, the only acceptable methods of contraception are:

Non-hormonal Methods: 
–
Intrauterine device (IUD).

Hormonal Methods:
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if 
for shorter duration until she has been on contraceptive for 3 months;

Oral.

Intravaginal (eg, ring).

Transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months prior to the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has 
been on contraceptive for 3 months;

Oral.

Injectable.

Implantable.
2. Subjects will be provided with information on highly effective methods of contraception as 
part of the subject informed consent process and will be asked to sign a consent form stating 
that they understand the requirements for avoidance of pregnancy, donation of ova, during 
the course of the study.


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3. During the course of the study, serum human chorionic gonadotropin (hCG) pregnancy tests 
will be performed in all women and all female subjects will receive continued guidance with 
respect to the avoidance of pregnancy as part of the study procedures. Such guidance should 
include a reminder of the following:
a) contraceptive requirements of the study
b) assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)?
iv. Is there a chance you could be pregnant?
4. In addition to a negative serum hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative serum hCG pregnancy test at Day -1 of either period. 
9.1.10 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-
supplied drug (esomeprazole) should be immediately discontinued.
If the pregnancy occurs during administration of active study drug, eg, after Day -1 of Period 1
until check out in Period 2 the pregnancy should be reported immediately, using a pregnancy 
notification form, to the contact listed in Section 1.0.
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the female subject was participating in a clinical study at 
the time she became pregnant and provide details of the study drug the subject received.
All reported pregnancies, 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.
9.1.11 ECG Procedure
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the study 
site) will interpret the ECG using 1 of the following categories: within normal limits, abnormal 
but not clinically significant, or abnormal and clinically significant. A copy of the ECG trace 
should be kept with the subject’s notes.


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9.1.12 PK Sample Collection
9.1.12.1 Collection of Blood for PK Sampling
Blood samples (one 6 mL sample per scheduled time) for PK analysis of esomeprazole will be 
collected into chilled vacutainers containing anticoagulant potassium EDTA according to the 
schedule in Appendix A. Instructions for sample processing and shipment are provided in 
Appendix E.
Serial blood samples for determination of esomeprazole will be collected according to Table 9.b.
Table 9.b
Collection of Blood Samples for PK Analysis
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
Esomeprazole
Plasma
1
Predose, 0.33, 0.66, 1, 1.33, 1.66, 2, 2.33, 2.66, 3, 3.5, 4, 4.5, 
5, 6, 7, 8, 9, and 10 hours
The actual time of sample collection will be recorded on the source document and eCRF. The PK 
sample should not be collected on early termination if a PK collection is not scheduled.
9.1.12.2 Bioanalytical Methods
Plasma concentrations of esomeprazole will be measured by high-performance liquid
chromatography with tandem mass spectrometry.
9.1.13 Pharmacokinetic Parameters 
The PK parameters of esomeprazole will be determined from the concentration-time profiles for 
all evaluable subjects. Actual sampling times, rather than scheduled sampling times, will be used 
in all computations involving sampling times. The following PK parameters will be calculated 
for plasma concentration values of esomeprazole.
Symbol/Term
Definition
Plasma
AUCt
Area under the concentration-time curve from time 0 to time t 
AUC∞
Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration.
Cmax
Maximum observed concentration.
CL/F
Apparent clearance after extravascular administration, calculated using the observed value of 
the last quantifiable concentration.
λz
Terminal disposition phase rate constant.
t1/2z
Terminal disposition phase half-life.
tlag
Lag time to first quantifiable concentration.
tmax
Time of first occurrence of Cmax.
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration.


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Subjects who have experienced vomiting, diarrhea, or have predose concentrations >5% Cmax or 
a mean exposure <5% of the population mean may be excluded from the analysis of PK 
parameters. Samples may also be excluded prior to bioanalysis if their validity is of concern.
9.1.14 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If a subject is withdrawn 
at the Screening Visit, the investigator should complete the eCRF screen failure form. The 
primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria <specify reason>.

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal <specify reason>.

Study termination.
Subject identification numbers assigned to subjects who fail screening should not be reused. If a 
subject fails screening, a subject may be rescreened at the investigator’s discretion. If a subject is 
later successfully rescreened, the data for the subject will be entered as if these were 2 separate 
subjects. Therefore the data should be entered as follows:
1. The screen failure data should be entered as a screen failure subject.
2. Rescreened subjects should be assigned a new subject number and treated as a stand-alone 
subject.
9.1.15 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
Study medication will be administered while subjects are under observation in the clinical 
research unit. Following administration of the study drug, appropriate mouth and/or hand checks 
will be performed to ensure that the dose is swallowed and noted in the source document. The 
date and time of each dose will be recorded in the source documents and on the eCRFs. An 
inventory of the study drug supplies dispensed will be performed by the site pharmacist or 
authorized study designee and recorded onto the Drug Accountability Log in the subject’s source 
document records or equivalent. The exact dose time of consecutive subjects may be staggered to 
facilitate logistics at the site.


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9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening (Day -28 to Day -2)
Subjects will be screened in accordance with predefined inclusion and exclusion criteria as 
described in Section 7.0. See Section 9.1.14 for procedures for documenting screening failures.
Procedures to be carried out at Screening are described in Appendix A.
9.3.2
Check-in (Day -1 of Periods 1 and 2)
On Day -1 of Period 1, eligibility will be confirmed. If the subject has satisfied all of the 
inclusion criteria and none of the exclusion criteria for randomization, the subject should be
admitted to the Unit overnight. The procedure for documenting screening failures is provided in 
Section 9.1.14. Procedures to be carried out on Day -1 of each period are described in 
Appendix A.
9.3.3
Treatment (Day 1 of Periods 1 and 2)
On Day 1 of Period 1, subjects will be randomized as described in Section 8.2. On Day 1 of each 
period, subjects will be administered study drug in the unit under the supervision of the 
investigator or designee, as described in Section 8.2. Procedures to be carried out on Day 1 of 
each period are described in Appendix A. Subjects will be discharged from the unit following the 
completion of all scheduled procedures on Day 1 of Periods 1 and 2.
9.3.4
Washout 
Subjects will undergo a minimum 6-day washout period between doses in Period 1 and Period 2.
Day -1 of Period 2 could be the sixth day of washout.
9.3.5
Early Termination
The reason for discontinuation must be documented in the source document and eCRF. The PK 
sample should not be collected on early termination if a PK collection is not scheduled.
Procedures to be carried out on early termination in either period are described in Appendix A. 
For all subjects receiving study drug, the investigator must complete the End of Study eCRF 
page.
9.4
Blood Volume
Total blood sampling volume for an individual subject is shown in Table 9.c


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Table 9.c
Approximate Blood Volume
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Sample Type
Screening 
Period 1
Period 2
Day -1
Day 1
Day -1
Day 1
Biochemistry, FSH and 
hCG for pregnancy tests (a)
8.5
1
1
1
1
1
42.5
Hematology
4.0 
1
1
1
1
1
20.0
Hepatitis Panel
8.5
1
0
0
0
0
8.5
PK blood collection
6.0
NA
0
19
0
19
228
Total Approximate Blood Sampling Volume
299
NA=not applicable.
(a) FSH test will be conducted at the Screening visit only. 
The maximum volume of blood at any single day is approximately 126.5 mL, and the
approximate total volume of blood for the study is 299 mL. 
Direct venipuncture is the preferred method of blood collection. A catheter with a normal saline 
flush may be used; however, the 299 mL total blood volume does not include discarded blood 
from predraws (assuming minimally the catheter dead volume plus 1.5 mL of blood is discarded 
each time a sample is collected from a catheter). Should a catheter be used, the total blood 
volume taken during the study is not expected to exceed 356 mL.


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study drug; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or 
AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be 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 vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG 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 


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laboratory or ECG retest and/or continued monitoring of an abnormal value or finding is not 
considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

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, ECG, X-rays 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(worsening or complication occurs before start of study drug) or an 
AE (worsening or complication occurs after start of study drug). Investigators should ensure 
that the event term recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) 
any occurrence of an episode should only be captured as a PTE/AE if the condition becomes
more frequent, serious or severe in nature. Investigators should ensure that the AE term 
recorded captures the change in the condition from Baseline (eg “worsening of…”).

If a subject has a pre-existing degenerative concurrent medical condition (eg, cataracts, 
rheumatoid arthritis), worsening of the condition should only be recorded as a PTE/AE if 
occurring to a greater extent to that which would be expected. Investigators should ensure 
that the AE term recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that 
the AE term recorded captures the change in the condition (eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in intensity of AEs /Serious PTEs:

If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded.
Preplanned surgeries or procedures:

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 


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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:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
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. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by 
a medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered 
as “Important Medical Events” satisfying SAE reporting requirements.
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Intensity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6 Relationship of AEs to Study Drug(s)
The relationship (causality) of each AE to study drug(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 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 drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant medications and concurrent treatments.
10.1.7 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.


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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.
10.1.8 Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator.
10.1.9 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died.
10.1.10Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.11Action Concerning Study Drug 

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been 
taken.

Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped 
before the onset of the AE.

Dose Reduced – the dose was reduced due to the particular AE.

Dose Increased – the dose was increased due to the particular AE.

Dose Interrupted – the dose was interrupted due to the particular AE.
10.1.12Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has 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”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 


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anomaly; the subject died from another cause with the particular AE/PTE state remaining 
“Not recovered/not resolved”.

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.

Fatal – the AEs/PTEs which are considered as the cause of death.

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study drug (Day 1, 
Period 1) 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 commence from the time that the subject is first administered study drug 
(Day 1, Period 1). Routine collection of AEs will continue until check-out following the 
completion of all assessments on Day 1 of Period 2.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes 
in laboratory values have returned to Baseline or there is a satisfactory explanation for the 
change. Non-serious 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. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date.
3. Frequency.


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4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of 
study drug(s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately 
or within 24 hours of first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0.
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be 
completed providing additional information on relevant recent history, risk factors, clinical signs 
and symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 


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tests as described in Section 9.1.8 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it within 24 hours of receipt. Copies of any relevant data from the hospital notes (eg, ECGs, 
laboratory tests, discharge summary, postmortem results) should be sent to the addressee, 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.
10.3.1 Safety Reporting to Investigators, IRBs and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs, as 
applicable, in accordance with national regulations in the countries where the study is conducted.
Relative to the first awareness of the event by/or further provision to the sponsor or sponsor’s 
designee, SUSARs will be submitted to the regulatory authorities as expedited report within 7 
days for fatal and life-threatening events and 15 days for other serious events, unless otherwise 
required by national regulations. The sponsor will also prepare an expedited report for other 
safety issues where these might materially alter the current benefit-risk assessment of the 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 his or her IRB in accordance with local
regulations.


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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent medical conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization Drug Dictionary.
12.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply study sites with eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the 
reason for change. Reasons for significant corrections should additionally be included.
The principal investigator must review the eCRFs for completeness and accuracy and must e-
sign the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the study database, any change of, modification of or addition to the data on the 
eCRFs should be made by the investigator with use of change and modification records of the 
eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign, and date. 
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by the sponsor or its designee. The sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. 
The completed eCRFs are the sole property of the sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 


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enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for 
a time specified in the study site agreement between the investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
13.1.1 Analysis Sets
PK Set
The PK set will consist of all subjects who are in Safety Set and have at least 1 measurable 
plasma concentration for esomeprazole. If any subjects are found to be with incomplete data, a 
decision will be made on a case-by-case basis as to their inclusion in the analysis, but will be 
presented in the subject listings. 
Safety Set
The Safety Analysis Set will consist of all subjects who are enrolled and receive study drug.
Subjects in this analysis set will be used for demographic, baseline characteristics, and safety
summaries.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for all enrolled subjects by
sequence, and overall. Summary statistics (eg, number of subjects, mean, median, standard
deviation and range) will be generated for continuous variables (eg, age and weight) and the
number and percentage of subjects within each category will be presented for categorical 
variables (eg, gender, ethnicity, race, smoking status).
13.1.3 PK Analysis
The concentration of esomeprazole in plasma will be summarized by formulation over each 
scheduled sampling time point using descriptive statistics (arithmetic mean, SD, percent 
coefficient of variation [%CV], median, minimum and maximum). Individual plasma/ 
concentration data versus time will be presented in a data listing.
Descriptive statistics will also be used to summarize the plasma pharmacokinetics parameters for 
esomeprazole. In addition, geometric mean and coefficient of variation will be computed for 
Cmax and AUCs (AUC∞and AUCt).
Natural-logarithmically transformed Cmax and AUCs will be analyzed using analysis of variance
with fixed factors for period, sequence, and regimen, and subject within sequence as a random 
effect. The bioequivalence will be assessed via point estimates and 90% CI for the ratio of Cmax
and AUCs central values for esomeprazole tablet (Regimen B – test) versus esomeprazole 
capsule (Regimen A - reference). Bioequivalence between tablet and capsule will be claimed if 
the 90% CI for the ratio is within the bioequivalence criteria of 0.80 to 1.25 [5,6].


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A more detailed analysis will be presented in the SAP.
13.1.4 Safety Analysis
AEs will be summarized using the safety analysis set. No statistical testing or inferential 
statistics will be generated. All AEs will be coded using MedDRA. Data will be summarized 
using preferred term and primary system organ class.
For safety laboratory tests, vital signs, and ECG, data will be listed and summarized, as 
appropriate. 
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
The sample size for this study is estimated at 52, which provides an allowance for 4 dropouts. 
The sample size was estimated based on variability data from a previous study[2], using a %CV 
of 28% as the intrasubject variation for the natural logarithm of Cmax and the assumed true ratio 
of 0.95 for tablet over capsule. Given the above information, a sample size of 52 subjects 
provides at least 90% power for concluding bioequivalence for Cmax and the power for AUCs is 
greater than 90%.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent forms), and review of eCRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the 
sponsor or designee for any significant deviation from the protocol. 
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. Table 14.a
defines the windows allowed for sample collections. 
However, blood samples not collected within the interval specified for the scheduled sample time 
should be reported to Takeda/ CRO using the Protocol Deviation Form. Protocol Deviation 
Forms are to be completed for PK samples collected outside of the following intervals:


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Table 14.a
Windows for PK Blood Sample Collection
Minutes
Nominal Sampling Time
no more than 30 minutes predose
0 hour
±5
immediately postdose to ≤6 hours
±10
>6 hours to 10 hours postdose
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of 
Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor should 
be notified immediately. The investigator and study site guarantee access for quality assurance 
auditors to all study documents as described in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix 
B. The principles of Helsinki are addressed through the protocol and through appendices 
containing requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those Americas sites unwilling to provide names 
and titles of all members due to privacy and conflict of interest concerns should instead provide a 
Federal Wide Assurance Number or comparable number assigned by the Department of Health 
and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, Prescribing Information, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol 
and subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug once the sponsor has confirmed 
the adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the study. Until the site receives drug no protocol 
activities, including screening may occur.
Study sites must adhere to all requirements stipulated by their respective IRB or IEC. This may 
include notification to the IRB or IEC regarding protocol amendments, updates to the informed 
consent form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals 
specified by the respective IRB, and submission of the investigator’s final status report to IRB or 
IEC. All IRB or IEC approvals and relevant documentation for these items must be provided to 
the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form and the subject information sheet 
(if applicable) further explain the nature of the study, its objectives, and potential risks and
benefits, as well as the date informed consent is given. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable)
must be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB or IEC. In the event the subject is not 
capable of rendering adequate written informed consent, then the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable laws and 
regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and subject authorization (if applicable) at the time of consent and 
prior to subject entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit the monitor or the sponsor’s designee, representatives 
from any regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the
appropriate IRBs and/or IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the study site agreement. In the event of any discrepancy 
between the protocol and the study site agreement, the study site agreement will prevail.


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15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda policy/standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide 
the sponsor with a written notice requesting that their information not be listed on the registry 
site. 
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda policy/standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to study 
subjects. Refer to the study site agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee.


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16.0
REFERENCES
1. Fass R, Shapiro M, Dekel R, Sewell J. Systematic review: proton-pump inhibitor failure in 
gastro-oesophageal reflux disease--where next? Aliment Pharmacol Ther 2005;22(2):79-94.
2. Bladh N, Blychert E, Johansson K, Backlund A, Lundin C, Niazi M, et al. A new 
esomeprazole packet (sachet) formulation for suspension: in vitro characteristics and 
comparative pharmacokinetics versus intact capsules/tablets in healthy volunteers. Clin Ther 
2007;29(4):640-9.
3. Food and Drug Administration, Center for Drug Evaluation and Research. Approval Package 
for Nexium (esomeprazole magnesium) delayed-release oral suspension. Application 21-957 
S005: Clinical Review for Short-term GERD Symptoms in 0-11 Month Olds, Inclusive. 
AstraZeneca: 18 June 2009.
4. Food and Drug Administration, Center for Drug Evaluation and Research. Approval Package 
for Nexium (esomeprazole magnesium) delayed-release capsules. Application NDA 
21153/S-008. AstraZeneca LP: 01 September 2004.
5. Guideline on the Investigation of Bioequivalence. European Medicines Agency, Committee 
for Medicinal Products for Human Use. 20 January 2010. Publication No. 
CPMP/EWP/QWP/1401/98 Rev. 1.
6. Guidance for Industry: Bioavailability and Bioequivalance Studies Submitted in NDAs or 
INDs - General Considerations. US Dept of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER). March 2014.


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Appendix A
Schedule of Study Procedures
Pretreatment Period
Treatment Periods 
1 and 2
Washout (a)
Study Exit / 
Early Termination
Study Day:
Days
-28 to -2
Day -1 
(Check-in)
Day 1
Days 2-6
Day 1 of Periods 1 and 
2 (prior to Checkout)
Confinement
X
X
X
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical 
history
X
Medication history
X
X
Physical examination
X
X (b)
X
Vital signs (c)
X
X
X
X
Height, weight and BMI 
(d)
X
X
Concomitant medications
X
X
X
X
12-lead ECG
X
X
X
Clinical laboratory tests (e)
X
X
X
Urine drug, alcohol, and 
cotinine screen
X
X
Pregnancy test (hCG)
X
X
X
Serum FSH (f)
X
HIV test
X
Hepatitis panel
X
Randomization
X
Administration of study 
drug (g)
X
PK blood collection (h)
X
Adverse Event assessment 
(i)
X
X
X
X
X
(a) There will be a minimum 6-day washout period between doses. Day -1 of Period 2 could be the sixth day of 
washout.
(b) Can be conducted up to 24 hours prior to dosing.
(c) Vital signs: oral body temperature, sitting blood pressure (after resting 5 minutes), respiratory rate, and pulse 
(beats per minute) at Screening. Only blood pressure and pulse will be collected on Check-in (Day -1) through Day 
1 of each period, or if the subject early terminated from study. On Day 1 of each period, vital signs will be taken at 
predose.
(d) Height only measured at Screening.
(e) Hematology, serum chemistries, and urinalysis tests.
(f) For women where menopause is suspected.
(g) Study drug administered beginning at approximately 0800 hours.
(h) Blood samples for PK obtained predose (within 15 minutes prior to dose), and at 0.33, 0.66, 1, 1.33, 1.66, 2, 
2.33, 2.66, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, and 10 hours postdose on Day 1 of each period. The PK sample should not be 
collected on Early Termination if a PK collection is not scheduled.
(i) Pretreatment adverse events will be captured immediately following the signing of the informed consent at 
Screening until dosing on Day 1 of Period 1. The routine collection of AEs will continue after dosing through to 
check out on Period 2, Day 1.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with 
the study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), 
IRB/IEC, and the monitor may inspect the records. By signing a written informed consent 
form, the subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if injury 
occurs and, if so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a research-
related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the subject otherwise is entitled, and that the subject or the 


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subject’s legally acceptable representative may discontinue participation at any time without 
penalty or loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be
informed in a timely manner if information becomes available that may be relevant to the 
subject’s willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. A written subject authorization (either contained within the informed consent form or 
provided as a separate document) describing to the subject the contemplated and permissible 
uses and disclosures of the subject’s personal information (including personal health 
information) for purposes of conducting the study. The subject authorization must contain the 
following statements regarding the uses and disclosures of the subject’s personal 
information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients,
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
24. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from Screening and throughout the duration of the study, and for 31 days after last 


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dose of study drug. Regular pregnancy tests will be performed throughout the study for all
female subjects. If a subject is found to be pregnant during study, study drug will be 
discontinued and the investigator will offer the subject the choice to receive unblinded 
treatment information. 
25. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov. 


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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s 
own country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples
Instructions for Processing of Plasma Samples for Pharmacokinetic Analysis of 
Esomeprazole
1. Collect 6 mL of venous blood for the plasma into a chilled Becton-Dickinson Vacutainer. All 
esomeprazole blood samples should be collected into vacutainers containing K2EDTA.
2. Gently invert the vacutainer several times to mix the additive with the collected blood prior 
to centrifugation and place immediately on ice.
3. Centrifuge the vacutainers for 10 minutes at approximately 1100 to 1300 (relative centrifugal 
force [RCF]) at 4°C. Note: if using a collection device other than Becton-Dickinson, refer to 
manufacturer’s instruction for proper centrifugation force and time.
4. Immediately following centrifugation, gently remove plasma from the packed cells. To 
ensure a more homogeneous sample, all plasma should first be transferred into 1 aliquot. 
From there, split the plasma evenly between the 2 aliquots. A minimum of approximately
1 mL needs to be obtained for each sample. Labeling or manifest to the bioanalytical 
laboratory should include protocol number (Esomeprazole_1001), sample matrix (ie, plasma) 
enrollment number, period, profile day (optional) and nominal time, and either “SET 1” (for 
original sample) or “SET 2” (for duplicate sample).
5. Cap the labeled storage tubes and freeze the plasma samples immediately at approximately 
-20°C or lower until shipment to (vendor name, city, state/country). No more than 45 to 60
minutes will elapse between blood collection and freezing the plasma sample.
Shipping of Plasma Samples 
The following instructions are recommended unless they differ from the site’s SOPs for labeling, 
packaging, or shipping of pharmacokinetic samples.
1. Biological samples (ie, plasma) should be shipped on dry ice to prevent thawing during 
transit. Samples should be shipped only on Monday, Tuesday, or Wednesday, and at least 2 
days prior to a national holiday, in order to minimize the possibility of samples in transit over 
a weekend or holiday. If duplicate samples are to be shipped, send SET 1 samples and await 
confirmation of arrival before shipping the duplicate SET 2 samples.
2. Before shipping, make sure the sample tubes are tightly sealed. Separate each subject’s 
samples as follows:
3. Separate the duplicate SET 2 samples from the SET 1 samples.
4. Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc) containing additional 
absorbent material.
5. Using a permanent marker, write the 4-digit {randomization sequence/enrollment} number, 
sample matrix (ie, plasma), number of samples, and “SET 1” on each self-sealing bag.
6. Place the bags of individual subject’s samples into a larger plastic bag so that samples are 
double bagged. Duplicate SET 2 samples should be returned to the freezer for storage. 


Esomeprazole
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Repeat steps 3 through 6 above when preparing duplicate samples for shipment, except self-
sealing bags should be marked “SET 2.”
7. An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study drug (esomeprazole), protocol number (Esomeprazole-
1001), investigator’s name, sample type (ie, plasma), subject randomization/enrollment 
number, period, nominal collection day and time, and intended sample storage conditions. 
When duplicate SET 2 samples are being shipped, make a copy of the original SET 1 sample 
inventory and mark as “SET 2.” Place the inventory paperwork into a large self-sealing bag. 
SET 1 samples will be shipped first on dry ice, followed by shipment of duplicate SET 2 
samples after SET 1 samples have been received by the analytical laboratory.
8. For sample packing, utilize dry ice generously (eg, 20-25 pounds per day of transit) to 
safeguard against longer than expected shipping times and delays. Use newspaper or other 
material to insulate the double-bagged samples from direct contact with the dry ice. Place the 
sample bundles into a Styrofoam container (or other suitable container) and fill the excess 
space with dry ice slabs or ice pellets (preferably the latter). Make a note of the estimated 
weight of the dry ice used per shipping container.
9. Place the inventory paperwork (in a large self-sealing bag) on top of the dry ice in the 
Styrofoam container. Place the lid on the Styrofoam container and seal completely with 
strapping tape. Place the Styrofoam container in a cardboard shipping carton and seal 
securely with strapping tape.
10. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
11. Affix an address label to each shipping carton. Complete the address label with the following 
information:
Plasma Samples for Esomeprazole
12. Affix a carbon dioxide label on each carton, specifically:
Carbon Dioxide Solid UN-1845
Class 9 PKG GR III
Quantity _____________________
(fill in weight to nearest lb/kg and specify unit of measure used)
13. Affix 2 dry ice symbol labels on opposite sides of the carton. Mark KEEP FROZEN on 
each carton. Specify a return address and contact person on the carton.
14. Obtain the airway bill number and a receipt of shipment from the carrier.
PPD


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15. After shipping of the esomeprazole samples, please contact
via e-mail:
to notify of next day delivery. Please provide the following 
information:
Name of courier or transport company
Time and date the shipment left the clinical site
Airway bill number
PPD
PPD


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SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Randomized, Open-label, 2-way Cross-over Study to Evaluate the
Bioequivalence Between a Single Oral Dose of Esomeprazole 40 mg Capsules and
Esomeprazole 40 mg Tablets in Healthy Subjects
NCT Number: NCT03083639
SAP Approve Date: 01 June 2017
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Esomeprazol-1001
A Phase 1, Randomized, Open-label, 2-way Cross-over Study to Evaluate the Bioequivalence
Between a Single Oral Dose of Esomeprazole 40 mg Capsules and Esomeprazole 40 mg Tablets
in Healthy Subjects
Esomeprazole Bioequivalence Study
PHASE 1
Version: Final
Date: 1 June 2017
Prepared by:
Based on:
Protocol Version: 2 
Protocol Date: 07 March 2017
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


Esomeprazole-1001
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Statistical Analysis Plan Final
01 June 2017
CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


Esomeprazole-1001
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Statistical Analysis Plan Final
01 June 2017
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................6
4.1
Primary Objectives ....................................................................................................6
4.2
Secondary Objectives.................................................................................................6
4.3
Additional Objectives ................................................................................................6
4.4
Study Design .............................................................................................................6
5.0
ANALYSIS ENDPOINTS...............................................................................................8
5.1
Primary Endpoints .....................................................................................................8
5.2
Secondary Endpoints .................................................................................................8
5.3
Additional Endpoints .................................................................................................8
6.0
DETERMINATION OF SAMPLE SIZE.........................................................................9
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................10
7.1
General Principles....................................................................................................10
7.1.1
Study Definitions ...............................................................................................10
7.1.2
Definition of Study Days....................................................................................10
7.1.3
Definition of Study Visit Windows ....................................................................10
7.1.4
Conventions for Missing Adverse Event Dates...................................................10
7.1.5
Conventions for Missing Concomitant Medication Dates...................................10
7.1.6
Conventions for Missing Data............................................................................11
7.2
Analysis Sets ...........................................................................................................11
7.3
Disposition of Subjects ............................................................................................11
7.4
Demographic and Other Baseline Characteristics.....................................................12
7.5
Medical History and Concurrent Medical Conditions...............................................12
7.6
Medication History and Concomitant Medications...................................................12
7.7
Study Drug Exposure and Compliance.....................................................................12
7.8
Efficacy Analysis.....................................................................................................12
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................13
7.9.1
Pharmacokinetic Analysis ..................................................................................13
7.9.2
Pharmacodynamic Analysis ...............................................................................14
7.10
Other Outcomes.......................................................................................................14
7.11
Safety Analysis........................................................................................................14


Esomeprazole-1001
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Statistical Analysis Plan Final
01 June 2017
CONFIDENTIAL
7.11.1 Adverse Events ..................................................................................................14
7.11.2 Clinical Laboratory Evaluations .........................................................................15
7.11.3 Vital Signs .........................................................................................................16
7.11.4 12-Lead ECGs ...................................................................................................16
7.11.5 Other Observations Related to Safety.................................................................17
7.12
Interim Analysis ......................................................................................................17
7.13
Changes in the Statistical Analysis Plan...................................................................17
8.0
REFERENCES..............................................................................................................18
LIST OF IN-TEXT TABLES
Table 7.a
Collection of Blood Samples for Pharmacokinetic Analysis ...............................13
Table 7.b
Plasma PK Parameters .......................................................................................13
Table 7.c
Clinical Laboratory Tests...................................................................................16
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ..................................................................................7
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................19
Appendix B
Criteria for Identification of Markedly Abnormal Laboratory Values .................20
Appendix C
Criteria for Abnormal Changes from Baseline of Vital Signs..............................22
Appendix D
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters..........23


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3.0
LIST OF ABBREVIATIONS
%CV
percent coefficient of variation
λz
terminal dispostion rate constant
AE
adverse event
ANOVA
analysis of variance
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUCt
area under the plasma concentration-time curve from time 0 to the time of last 
quantifiable concentration
BMI
body mass index
Cmax
maximum observed plasma concentration
CI
confidence interval
CL/F
apparent clearance after extravascular administration
ECG
electrocardiogram
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Drug Regulatory Activities
PK
pharmacokinetic(s)
PT
preferred term
PTE
pretreatment event
SD
standard deviation
SAE
serious adverse event
SI
International System of Units
SOC
system organ class
t1/2z
terminal elimination half-life
tmax
time to reach Cmax
TEAE
treatment-emergent adverse event
WHODrug
World Health Organization Drug Dictionary


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4.0
OBJECTIVES
4.1
Primary Objectives
To determine the bioequivalence of esomeprazole 40 mg tablets and capsules.
4.2
Secondary Objectives
Not applicable.
4.3
Additional Objectives
To determine pharmacokinetic (PK) parameters for each formulation.
4.4
Study Design
This is a phase 1, randomized, open-label, 2-way cross-over study in healthy adult male and
female subjects aged 18 to 55 years, inclusive, to evaluate the bioequivalence of a single oral
dose of esomeprazole 40 mg capsules (reference [A]) and esomeprazole 40 mg tablets (test [B]).
It is estimated that 52 subjects will be needed to ensure that 48 subjects complete both periods.
Screening for potential subjects will occur between 28 and 2 days prior to Day 1. On Day -1,
subjects’ eligibility will be reconfirmed and eligible subjects will be randomized in a 1:1 ratio to
1 of 2 sequences (AB or BA), which defines the order in which they will receive esomeprazole 
regimens in Periods 1 and 2. In both periods, subjects will fast for 10 hours prior to study drug 
administration and refrain from eating until 4 hours after drug administration. Each period will 
be separated by a minimum 6-day washout period. Blood samples for PK analysis will be drawn 
up to 10 hours after study drug administration on Day 1 in each period. Subjects will be 
confined to the phase 1 unit from Day -1 until the end of all assessments on Day 1 of each 
period.
Given that esomeprazole is a marketed product with a well-characterized safety profile, this
study does not include a follow-up evaluation period. In total, the period of evaluation is
expected to be a maximum of 36 days (assuming a washout period of 6 days), including the
Screening Period.
A schematic of the study design is shown in Figure 4.a. A schedule of assessments is listed in
Appendix A.


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Figure 4.a
Schematic of Study Design
Pretreatment Period
Period 1 (a)
Period 2 (a)
Screening (b)
Check-in
Single 
Dose and 
PK (c)
Checkout
Washout 
(d)
Check-in
Single Dose 
and PK (c)
Checkout
Days -28 to -
2
Day -1
Day 1
Day 1
Day 2-6
Day -1
Day 1
Day 1
Confinement 
Confinement
(a) Subjects will be admitted to the clinic on Day -1 of each period. On Day 1, subjects will be randomized to 1 of 2 
sequences of esomeprazole tablet and capsule. Subjects will be discharged from the clinic on Day 1 after dosing and 
the completion of all scheduled procedures.
(b) For clinical laboratory tests that are required to be taken under fasting conditions, the subject will be asked to 
return to the unit at a later date under fasting conditions. 
(c) PK samples at 0 (predose), and at 0.33, 0.66, 1, 1.33, 1.66, 2, 2.33, 2.66, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, and 10 hours 
postdose.
(d) Minimum 6-day washout between doses. Day -1 of Period 2 could be the sixth day of washout.


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoints for this study are the PK parameters derived from the plasma
concentrations of esomeprazole 40 mg administered via capsule and tablet after a single dose, 
which include: 

area under the concentration-time curve from time 0 to infinity (AUC∞)

area under the concentration-time curve from time 0 to time t (AUCt)

maximum observed concentration (Cmax)
5.2
Secondary Endpoints
Not applicable.
5.3
Additional Endpoints
Additional endpoints for this study are the PK parameters derived from the plasma
concentrations of esomeprazole 40 mg administered via capsule and tablet after a single dose, 
which include: 

time of first occurrence of Cmax (tmax) 

terminal disposition phase half-life (t1/2z)

apparent clearance after extravascular administration, calculated using the observed value of 
the last quantifiable concentration (CL/F) 

apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration 
(Vz/F)

terminal disposition phase rate constant (λz)

lag time to first quantifiable concentration (tlag)


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6.0
DETERMINATION OF SAMPLE SIZE
The sample size for this study is estimated at 52, which provides an allowance for 4 dropouts.
The sample size was estimated based on variability data from a previous study, using a percent 
coefficient of variation (%CV) of 28% as the intrasubject variation for the natural logarithm of 
Cmax and the assumed true ratio of 0.95 for tablet over capsule. Given the above information, a 
sample size of 52 subjects provides at least 90% power for concluding bioequivalence for Cmax
and the power for AUCs is greater than 90%.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Continuous data will be summarized using descriptive statistics, including the number of 
subjects, mean, standard deviation (SD), median, minimum, and maximum. The coefficient of 
variation (%CV) and geometric mean will be included in the summary of continuous data where 
indicated. Categorical data will be summarized as the number and percentage of subjects in each 
category.
Arithmetic means, geometric means, and medians will be presented to 1 more decimal place than 
the recorded data, and SDs will be presented to 2 more decimal places than the recorded data, 
where appropriate. Where applicable, confidence intervals about a parameter estimate will be 
presented using the same number of decimal places as the parameter estimate and p-values will 
be rounded to 3 decimal places prior to assessment of statistical significance.
All study-related raw data for enrolled subjects, including derived data, will be presented in data 
listings. In addition, the actual day relative to the first dose will be presented, where applicable.
All statistical analyses will be performed using the SAS System® Version 9.4.
7.1.1
Study Definitions
There are no study-specific definitions.
7.1.2
Definition of Study Days
Study Day 1 is defined as the date of the first dose of study drug, as recorded on the electronic 
case report form (eCRF) dosing page. Other study days are defined relative to Study Day 1, with 
Day 1 being Study Day 1 and Day -1 being the day prior to Study Day 1. Study days prior to the 
first dose of study drug will be calculated as: {date of assessment/event – date of first dose of 
study drug}. Study days on or after the first dose of study drug will be calculated as: {date of 
assessment/event – date of first dose of study drug + 1}.
All protocol-specified study visit dates are defined relative to Study Day 1.
7.1.3
Definition of Study Visit Windows
There will be no visit windowing.
7.1.4
Conventions for Missing Adverse Event Dates
There will be no imputation of incomplete or missing adverse event dates.
7.1.5
Conventions for Missing Concomitant Medication Dates
There will be no imputation of incomplete or missing concomitant medication dates.


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7.1.6
Conventions for Missing Data
There will be no imputation of incomplete or missing data. 
Plasma concentrations that are below the lower limit of quantification (< LLOQ) will be treated 
as zero in the summarization of concentration values and derivation of PK parameters.
7.2
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data:

Randomized Set: The randomized set will consist of all subjects who are randomized.

Safety Analysis Set: The safety analysis set will consist of all subjects who are randomized
and received at least 1 dose of study drug. Subjects in this analysis set will be used for 
demographic, baseline characteristics, and safety summaries.

Pharmacokinetic Set: The PK set will consist of all subjects who received at least 1 dose of 
study drug and have at least 1 measurable plasma concentration.
If any subjects are found to be noncompliant in dosing schedule or with incomplete data, a 
decision will be made on a case-by-case basis as to their inclusion in the analysis but will be 
presented in the subject listings.
Number of subjects in each analysis set will be tabulated by randomization sequence and overall. 
7.3
Disposition of Subjects
Study Information, including date of first subject signing Informed Consent Form (ICF), date of 
first/last study drug, date of last subject’s last visit/contact, date of last subject’s last procedure 
for collection of data for primary endpoint, Medical Dictionary for Drug Regulatory Activities 
(MedDRA) Version, World Health Organization Drug Dictionary (WHODrug) Version, and 
SAS Version, will be tabulated.
The eligibility of subjects will be summarized, along with the primary reasons of screen failure 
as recorded in eCRF.
Number of subjects randomized will be tabulated by randomization sequence (ie AB or BA) and 
overall. 
Disposition of all enrolled subjects will be tabulated. Categories will include:

Subjects who were randomized but not treated

Subjects who completed the study

Subjects who prematurely discontinued study
Primary reasons for discontinuing study, as entered on the eCRF will be tabulated. 


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7.4
Demographic and Other Baseline Characteristics
Demographic and study baseline characteristics, including age at informed consent, gender, 
ethnicity, race, height (cm), weight (kg), body mass index (kg/m2), smoking status, alcohol use, 
caffeine/xanthine consumption, and female reproductive status, will be summarized by sequence 
and overall. 
There will be no inferential analysis of demographic and baseline characteristics.
7.5
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases that resolved at or prior to the 
time of informed consent. Concurrent medical conditions are defined as significant conditions or 
diseases that are present at signing of informed consent.
Medical history and concurrent medical conditions will be coded using the MedDRA coding 
system.
Medical history and concurrent medical conditions will be listed by site and subject number.
There will be no summary or inferential analysis of medical history and concurrent medical 
conditions.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped at 
or within 28 days prior to signing of informed consent. Concomitant medication is any drug 
given in addition to the study drug, taken at any time from signing of informed consent through 
the end of study.
Medication history and concomitant medications will be coded using the WHODrug.
Listings for medication history and concomitant medications will be produced by site and subject 
number. 
There will be no summary or inferential analysis of medication history and concomitant 
medications.
7.7
Study Drug Exposure and Compliance
All doses of study medication will be administered during confinement. Dosing data, including 
dosing time will be provided by subject and visit in the listings.
7.8
Efficacy Analysis
Not applicable.


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7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
The schedule for blood samples for PK analysis of Esomeprazole is listed in Table 7.a.
The concentration of esomeprazole in plasma will be summarized by formulation over each
scheduled sampling time point using descriptive statistics (arithmetic mean, SD, CV%, median,
minimum and maximum). Individual plasma concentration data versus time will be presented in 
a data listing.
In addition, the figures for mean plasma concentrations of esomeprazole versus time (linear and 
semi-log scale) will be generated. 
Descriptive statistics (N, mean, SD, CV%, median, minimum and maximum) will be used to 
summarize the PK parameters for Esomeprazole by formulation. In addition, geometric mean 
will be computed for PK parameters. The PK parameters of Esomeprazole are listed in Table 7.b.
Table 7.a
Collection of Blood Samples for Pharmacokinetic Analysis
Table 7.b
Plasma PK Parameters


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Box plots for Cmax and AUC∞will be generated by formulation. 
The bioequivalence between Esomeprazole capsules (Reference - Regimen A) and Esomeprazole 
tablets (Test - Regimen B ) will be assessed for the natural logarithms of AUCt, AUC∞, and 
Cmax using analysis of variance (ANOVA) models. The models will include regimen, period, 
and sequence as fixed effects and subject nested within sequence as a random effect. Within the 
ANOVA framework, point estimates and their 90% CIs for the ratio of AUCs and Cmax central 
values between Esomeprazole capsules and tablets will be presented. Bioequivalence between 
tablet and capsule will be claimed if the 90% CI for the ratio is within the bioequivalence criteria 
of 0.80 to 1.25.
All pharmacokinetic parameters calculated will be provided in a listing.
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
Daily meals during confinement in each period will be reported in the data listing.
7.11
Safety Analysis
Safety analyses include adverse events (AEs), clinical laboratory parameters, vital sign 
parameters, and 12-lead electrocardiogram (ECG) results.
All summaries of safety data are based on subjects in the Safety Analysis Set. 
7.11.1 Adverse Events
A treatment -emergent adverse event (TEAE) will be defined as an AE or serious adverse event 
(SAE) that started or worsened after first study drug administration and within 30 days of last 
dose of study drug (onset date – date of last dose + 1 ≤30). A TEAE will be attributed to a 
regimen if the TEAE occurs after administration of the study drug in a period and up to just prior 
to study drug administration in the next period. A TEAE that occurs after administration of the 
study drug in the last period and up to 30 days after the last study drug dose is attributed to the 
regimen received in the last period. All AE verbatim terms will be coded by system organ class
(SOC) and preferred term using (PT) the MedDRA coding system.
TEAEs will be summarized by regimen and overall. The tables will include the number and 
percentage (N [%]) of subjects reporting any event for that term. The following TEAE tables will 
be summarized. 
–
Overview of TEAEs.
–
TEAEs by SOC and PT at subject and event level.
–
Subject Mappings for TEAEs.
–
TEAEs by PT.


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–
Most Frequent TEAEs by PT term
–
Most Frequent Non-Serious TEAEs by PT term at subject and event level
–
Relationship of TEAEs to Study Drug by SOC and PT.
–
Drug-Related TEAEs by SOC and PT.
–
Severity of TEAEs by SOC and PT.
–
Severity of Drug-Related TEAEs by SOC and PT.
In addition, pretreatment events (PTEs) will be summarized overall by SOC and PT.
For each regimen and overall, subjects reporting more than one occurrence for a term (SOC or 
PT) being summarized will be counted only once using the most extreme incident (most severe 
for the severity tables and related for the relationship to study drug tables).
Most frequent TEAEs are those events occurred in at least ≥5% (before any rounding) of 
subjects in a regimen.
Data listings will be provided for all TEAEs, PTEs, TEAEs that led to study discontinuation, 
TEAEs that led to abnormal liver functions, SAEs, AEs that resulted in death, and AEs occurring 
more than 30 days after the last dose of study medication.
7.11.2 Clinical Laboratory Evaluations
Clinical safety laboratory tests include hematology, chemistry, urinalysis, and diagnostic 
screening. Refer to Appendix A for scheduled clinical laboratory test measurements and to 
Table 7.c for the list of all clinical laboratory tests.
Individual results for hematology and chemistry laboratory tests that meet the Takeda predefined 
laboratory markedly abnormal value (MAV) criteria in Appendix B will be presented in a data 
listing. If a subject has a MAV for a particular laboratory test, all visits for that subject for that 
parameter will be listed. 
All clinical laboratory data will be presented in both SI and conventional units in the data 
listings. Laboratory data outside of the normal reference range will be listed. Out of normal 
range values and MAVs will be flagged in data listings.


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Table 7.c
Clinical Laboratory Tests
7.11.3 Vital Signs
Refer to Appendix A for scheduled vital signs measurement visits.
Individual results for vital sign measurements that meet the Takeda predefined vital signs MAV 
criteria in Appendix C will be presented in a data listing. If a subject has a MAV for a particular 
vital sign parameter, all visits for that subject for that parameter will be listed. 
All vital sign data will be presented in the listings. Vital sign MAVs will be flagged in the 
listings.
7.11.4 12-Lead ECGs
The scheduled 12-lead ECG data will be collected according to Appendix A. The ECG 
parameters include heart rate, RR interval, PR interval, QRS interval, QT interval, and QTc 
interval (Fredericia’s and Bazett’s corrections).


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Individual results for 12-lead ECG measurements that meet the Takeda predefined 12-lead ECG 
MAV criteria in Appendix D will be presented in a data listing. If a subject has a MAV for a 
particular ECG parameter, all visits for that subject for that parameter will be listed. 
All ECG data will be presented in the listings. ECG MAVs will be flagged in the listings.
7.11.5 Other Observations Related to Safety
Physical examination findings will be presented in the listings. No summary tables will be 
provided.
All cases of overdose will be listed.
7.12
Interim Analysis
Not applicable.
7.13
Changes in the Statistical Analysis Plan 
None.


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8.0
REFERENCES
1. A Phase 1, Randomized, Open-label, 2-way Cross-over Study to Evaluate the Bioequivalence 
Between a Single Oral Dose of Esomeprazole 40 mg Capsules and Esomeprazole 40 mg 
Tablets in Healthy Subjects, Takeda Development Center Europe, Ltd., Protocol No. 
Esomeprazole-1001, dated 07 March, 2017.


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Appendix A
Schedule of Study Procedures
(a) There will be a minimum 6-day washout period between doses. Day -1 of Period 2 could be the sixth day of
washout.
(b) Can be conducted up to 24 hours prior to dosing.
(c) Vital signs: oral body temperature, sitting blood pressure (after resting 5 minutes), respiratory rate, and pulse
(beats per minute) at Screening. Only blood pressure and pulse will be collected on Check-in (Day -1) through Day
1 of each period, or if the subject early terminated from study. On Day 1 of each period, vital signs will be taken at
predose.
(d) Height only measured at Screening.
(e) Hematology, serum chemistries, and urinalysis tests.
(f) For women where menopause is suspected.
(g) Study drug administered beginning at approximately 0800 hours.
(h) Blood samples for PK obtained predose (within 15 minutes prior to dose), and at 0.33, 0.66, 1, 1.33, 1.66, 2, 2.33, 
2.66, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, and 10 hours postdose on Day 1 of each period. The PK sample should not be
collected on Early Termination if a PK collection is not scheduled.
(i) Pretreatment adverse events will be captured immediately following the signing of the informed consent at
Screening until dosing on Day 1 of Period 1. The routine collection of AEs will continue after dosing through to
check out on Period 2, Day 1.


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Appendix B
Criteria for Identification of Markedly Abnormal Laboratory Values 
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
< 0.8 × LLN
> 1.2 × ULN
Hematocrit
Both
< 0.8 × LLN
> 1.2 × ULN
RBC count 
Both
< 0.8 × LLN 
> 1.2 × ULN
WBC count 
Both 
<0.5 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/L
>600 x 103/L
SI
<75 x 109/L
>600 x 109/L
MCV
Both 
<70 fL
>110 fL
Prothrombin 
time/international 
normalized ratio
Both
--
>1.5 × ULN
Activated partial 
thromboplastin time
Both
--
>1.5 × ULN
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
>177 mol/L
Blood urea nitrogen
Conventional 
>30 mg/dL
SI
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L


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Parameter
Unit 
Low Abnormal
High Abnormal
Glucose
Conventional
< 50 mg/dL
>350 mg/dL
SI
< 2.8 mmol/L
>19.4 mmol/L
Chloride
Conventional
< 75 mEq/L
>126 mmol/L
SI
< 75 mmol/L
>126 mmol/L
Bicarbonate
Conventional 
< 8.0 mEq/L
SI
< 8.0 mmol/L
Phosphorous 
Conventional 
< 1.6 mg/dL
>6.2 mg/dL
SI 
< 0.52 mmol/L
>2.000 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.


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Appendix C
Criteria for Abnormal Changes from Baseline of Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85
>180 
Diastolic blood pressure
mm Hg
<50
>110
Body temperature
oC
< 35.6
>37.7


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Appendix D
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters
Parameter
Lower Criteria
Upper Criteria
Heart rate
<50 beats per minute
>120 beats per minute
PR
≤80 milliseconds
≥200 milliseconds
QT Interval
≤300 milliseconds
≥460 milliseconds
QTcB Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and 
≥450 milliseconds
QTcF Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and
≥450 milliseconds
QRS
≤80 milliseconds
≥180 milliseconds


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