Clinical trial NCT03801148
Conditions: Healthy Volunteers
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2019-01-10; Completion date: 2019-04-09
Enrollment: 122 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess the BA of 30 or 60 milligram (mg) dexlansoprazole capsule manufactured at TOB (Takeda GmbH Plant Oranienburg) to the corresponding 30 or 60 mg dexlansoprazole manufactured at TPC (Takeda Pharmaceutical Company Ltd.).

Detailed description:
The drug being tested in this study is called dexlansoprazole. Dexlansoprazole is being tested in healthy participants to compare the BA of dexlansoprazole capsules manufactured by TOB relative to dexlansoprazole capsules manufactured by TPC, under fed conditions. The study consists of two parts: Part 1 participants will receive dexlansoprazole 30 mg capsules manufactured by TOB and TPC in a crossover fashion; Part 2 participants will receive dexlansoprazole 60 mg capsules manufactured by TOB and TPC in a crossover fashion.

The study will enroll approximately 120 participants. Participants will be randomly assigned (by chance, like flipping a coin) to 1 of the 4 treatment sequences as following:

* Part 1: Dexlansoprazole 30 mg (TOB) + Dexlansoprazole 30 mg (TPC)
* Part 1: Dexlansoprazole 30 mg (TPC) + Dexlansoprazole 30 mg (TOB)
* Part 2: Dexlansoprazole 60 mg (TOB) + Dexlansoprazole 60 mg (TPC)
* Part 2: Dexlansoprazole 60 mg (TPC) + Dexlansoprazole 60 mg (TOB)

All participants will be asked to take capsule of assigned dexlansoprazole on Day 1, 30 minutes following the beginning of a high-fat/high calorie breakfast of each treatment period.

This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 86 days. Participants will be contacted by phone call approximately 10 days after the last dose of study drug for a follow-up assessment.

Arms: arm 1: Dexlansoprazole 30 mg, delayed-release capsule manufactured by TOB (Regimen A \[test\]), orally, once, after a high fat/calorie breakfast on Day 1 of Period 1, followed by minimum of 5 day washout period, followed by dexlansoprazole 30 mg, delayed-release capsule manufactured by TPC (Regimen B \[reference\]), orally, once, after a high fat/calorie breakfast on Day 1 of Period 2. arm 2: Dexlansoprazole 30 mg, delayed-release capsule manufactured by TPC (Regimen B \[reference\]), orally, once, after a high fat/calorie breakfast on Day 1 of Period 1, followed by minimum of 5 day washout period, followed by dexlansoprazole 30 mg, delayed-release capsule manufactured by TOB (Regimen A \[test\]), orally, once, after a high fat/calorie breakfast on Day 1 of Period 2. arm 3: Dexlansoprazole 60 mg, delayed-release capsule manufactured by TOB (Regimen C \[test\]), orally, once, after a high fat/calorie breakfast on Day 1 of Period 1, followed by minimum of 5 day washout period, followed by dexlansoprazole 60 mg, delayed-release capsule manufactured by TPC (Regimen D \[reference\]), orally, once, after a high fat/calorie breakfast on Day 1 of Period 2. arm 4: Dexlansoprazole 60 mg, delayed-release capsule manufactured by TPC (Regimen D \[reference\]), orally, once, after a high fat/calorie breakfast on Day 1 of Period 1, followed by minimum of 5 day washout period, followed by dexlansoprazole 60 mg, delayed-release capsule manufactured by TOB (Regimen C \[test\]), orally, once, after a high fat/calorie breakfast on Day 1 of Period 2.
Interventions: intervention 1: 30 mg dexlansoprazole capsules manufactured at TOB intervention 2: 30 mg dexlansoprazole capsules manufactured at TPC intervention 3: 60 mg dexlansoprazole capsules manufactured at TOB intervention 4: 60 mg dexlansoprazole capsules manufactured at TPC
Intervention descriptions: intervention 1: Dexlansoprazole delayed-release capsules. intervention 2: Dexlansoprazole delayed-release capsules. intervention 3: Dexlansoprazole delayed-release capsules. intervention 4: Dexlansoprazole delayed-release capsules.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1, Randomized, Open-Label, Single-Center, Single-Dose, Two-Period, Two-Part 
Crossover Study in Healthy Subjects to Compare the Bioavailability of Dexlansoprazole from 
Dexlansoprazole Delayed-Release Capsules 30 mg and 60 mg Manufactured by Takeda GmbH Plant 
Oranienburg Relative to Dexlansoprazole Delayed-Release Capsules 30 mg and 60 mg Manufactured 
by Takeda Pharmaceutical Company Limited Osaka Plant Following a High-Fat Meal
NCT Number: NCT03801148
Protocol Approve Date: 09 January 2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company confidential 
information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


E
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Randomized, Open-Label, Single-Center, Single-Dose, Two-Period, Two-Part 
Crossover Study in Healthy Subjects to Compare the Bioavailability of 
Dexlansoprazole from Dexlansoprazole Delayed-Release Capsules 30 mg and 60 mg 
Manufactured by Takeda GmbH Plant Oranienburg Relative to Dexlansoprazole Delayed-Release 
Capsules 30 mg and 60 mg Manufactured by Takeda Pharmaceutical Company Limited Osaka 
Plant Following a High-Fat Meal
Study Identifier:
TAK-390MR-1002
Compound:
Dexlansoprazole Delayed-Release Capsules
Date:
09 January 2019
Version/Amendment 
Number:
Amendment 1
Amendment History:
Date
Amendment Number
Amendment Type
Region
17 December 2018
Initial Version
09 January 2019
01
Not Applicable
United States
Propert
da: For non-commercial use only and subject to the applicable Terms of Use


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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................11
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................12
4.0
INTRODUCTION.........................................................................................................14
Rationale for the Proposed Study .............................................................................14
4.1
Benefit/Risk Profile .................................................................................................15
4.2
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................16
Hypothesis...............................................................................................................16
5.1
Trial Objectives .......................................................................................................16
5.2
5.2.1
Trial Primary Objective......................................................................................16
5.2.2
Trial Secondary Objective..................................................................................16
Endpoints.................................................................................................................16
5.3
5.3.1
Primary Endpoint...............................................................................................16
5.3.2
Additional Endpoints .........................................................................................16
5.3.3
Safety Endpoints................................................................................................17
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................18
Trial Design.............................................................................................................18
6.1
Dose Escalation .......................................................................................................19
6.2
Rationale for Trial Design, Dose, and Endpoints......................................................19
6.3
6.3.1
Rationale of Trial Design ...................................................................................19
6.3.2
Rationale for Dose .............................................................................................20
6.3.3
Rationale for Endpoints......................................................................................20
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures ................20
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
6.4
Parameters...............................................................................................................20
Trial Beginning and End/Completion.......................................................................20
6.5
6.5.1
Definition of Beginning of the Trial ...................................................................20
6.5.2
Definition of End of the Trial .............................................................................20
6.5.3
Definition of Trial Completion...........................................................................20
6.5.4
Definition of Trial Discontinuation ....................................................................21
6.5.5
Criteria for Premature Termination or Suspension of the Trial............................21
6.5.6
Criteria for Premature Termination or Suspension of a Site ................................21
6.5.7
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................21
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ..............22
Inclusion Criteria .....................................................................................................22
7.1
Exclusion Criteria ....................................................................................................22
7.2
Excluded Medications, Supplements, Dietary Products ............................................24
7.3
Diet, Fluid, Activity.................................................................................................25
7.4
7.4.1
Diet and Fluid ....................................................................................................25
7.4.2
Activity..............................................................................................................26
Criteria for Discontinuation or Withdrawal of a Subject ...........................................26
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................27
7.6
Subject Replacement................................................................................................27
7.7
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................28
Clinical Study Drug .................................................................................................28
8.1
8.1.1
Clinical Study Drug Labeling.............................................................................28
8.1.2
Clinical Study Drug Inventory and Storage ........................................................28
8.1.3
Clinical Study Drug Blinding .............................................................................28
8.1.4
Randomization Code Creation and Storage ........................................................29
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................29
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs...............................29
9.0
STUDY PROCEDURES ...............................................................................................31
Administrative Procedures.......................................................................................31
9.1
9.1.1
Informed Consent Procedure..............................................................................31
9.1.2
Inclusion and Exclusion .....................................................................................31
9.1.3
Medical History/Demography ............................................................................31
9.1.4
Concomitant Medications...................................................................................32
Clinical Procedures and Assessments.......................................................................32
9.2
9.2.1
Full Physical Exam ............................................................................................32
9.2.2
Height and Weight .............................................................................................33
9.2.3
BMI ...................................................................................................................33
9.2.4
Vital Signs .........................................................................................................33
9.2.5
12-Lead ECG.....................................................................................................33
9.2.6
Study Drug Administration ................................................................................33
9.2.7
AE Monitoring...................................................................................................34
9.2.8
Laboratory Procedures and Assessments ............................................................34
Biomarker, PK, PD, and PGx, Samples....................................................................36
9.3
9.3.1
PK Measurements..............................................................................................36
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9.3.2
Biomarker Measurements...................................................................................38
9.3.3
PGx Measurements ............................................................................................38
9.3.4
Confinement ......................................................................................................38
10.0
ADVERSE EVENTS ....................................................................................................39
Definitions and Elements of AEs .............................................................................39
10.1
10.1.1 SAEs..................................................................................................................41
10.1.2 Special Interest AEs...........................................................................................42
AE Procedures.........................................................................................................42
10.2
10.2.1 Assigning Severity/Intensity of AEs...................................................................42
10.2.2 Assigning Causality of AEs................................................................................42
10.2.3 Start Date...........................................................................................................42
10.2.4 End Date............................................................................................................43
10.2.5 Pattern of Adverse Event (Frequency)................................................................43
10.2.6 Action Taken With Study Treatment ..................................................................43
10.2.7 Outcome ............................................................................................................43
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................44
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....46
11.0
STATISTICAL METHODS..........................................................................................47
Statistical and Analytical Plans ................................................................................47
11.1
11.1.1 Analysis Sets......................................................................................................47
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................47
11.1.3 PK Analysis .......................................................................................................47
11.1.4 PD Analysis .......................................................................................................48
11.1.5 Safety Analysis ..................................................................................................48
Interim Analysis and Criteria for Early Termination ................................................48
11.2
Determination of Sample Size..................................................................................48
11.3
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................50
Study-Site Monitoring Visits ...................................................................................50
12.1
Protocol Deviations..................................................................................................50
12.2
Quality Assurance Audits and Regulatory Agency Inspections ................................50
12.3
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................51
IRB and/or IEC Approval ........................................................................................51
13.1
Subject Information, Informed Consent, and Subject Authorization .........................52
13.2
Subject Confidentiality ............................................................................................53
13.3
Publication, Disclosure, and Clinical Trial Registration Policy.................................53
13.4
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13.4.1 Publication and Disclosure.................................................................................53
13.4.2 Clinical Trial Registration..................................................................................54
13.4.3 Clinical Trial Results Disclosure ........................................................................54
Insurance and Compensation for Injury....................................................................54
13.5
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................55
Administrative Information......................................................................................55
14.1
14.1.1 Study Contact Information .................................................................................55
14.1.2 INVESTIGATOR AGREEMENT......................................................................56
14.1.3 Study-Related Responsibilities...........................................................................57
14.1.4 Protocol Amendment 01 Summary of Changes ..................................................57
14.1.5 List of Abbreviations .........................................................................................57
15.0
DATA HANDLING AND RECORD KEEPING...........................................................59
CRFs .......................................................................................................................59
15.1
Record Retention .....................................................................................................59
15.2
16.0
REFERENCES..............................................................................................................61
17.0
APPENDICES...............................................................................................................62
LIST OF IN-TEXT TABLES
Table 6.a
Part 1 Sequences ................................................................................................18
Table 6.b
Part 2 Sequences ................................................................................................18
Table 7.a
Prohibited Medications, Supplements, and Dietary Products ..............................25
Table 8.a
Study Medication – Sponsor Supplied................................................................28
Table 9.a
Dose and Regimen .............................................................................................34
Table 9.b
Primary Specimen Collections ...........................................................................36
Table 9.c
Collection of Blood Samples for PK Analysis ....................................................37
Table 9.d
Windows for PK Sample Collection...................................................................37
Table 10.a
Takeda Medically Significant AE List................................................................41
LIST OF IN-TEXT FIGURES
Figure 2.a
Schematic of Study Design ................................................................................11
Figure 2.b
Schematic of Crossover Design..........................................................................11
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LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................62
Appendix B
Elements of the Subject Informed Consent.........................................................64
Appendix C
Investigator Consent to the Use of Personal Information ....................................67
Appendix D
Pregnancy and Contraception.............................................................................68
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples..............................72
Appendix F
Detailed Description of Amendments to Text.....................................................75
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceuticals
Takeda Development Center Americas, Inc.
One Takeda Parkway, Deerfield, IL 60015
Compound:
Dexlansoprazole Delayed-Release Capsules
(TAK-390)
Study Identifier: TAK-390MR-1002 (CA24021)
Phase: 1
Protocol Title: A Phase 1, Randomized, Open-Label, Single-Dose, Two-Period Crossover Study to Compare the 
Bioavailability of Dexlansoprazole Capsules Manufactured by Takeda GmbH Relative to Dexlansoprazole Capsules 
Manufactured by Takeda Osaka Following a High-Fat Meal
Trial Design:
This is a phase 1, randomized, open-label, single-center, single-dose, 2-part, 2-way crossover bioavailability (BA) 
study to compare the BA of 30 or 60 mg dexlansoprazole capsules manufactured at Takeda GmbH Plant Oranienburg 
(TOB) to the corresponding 30 and or 60 mg dexlansoprazole capsules manufactured at Takeda Pharmaceutical 
Company Ltd. (TPC) plant in Osaka, Japan under fed conditions. The study will be conducted in 2 parts. In Part 1, 
60 healthy subjects will receive dexlansoprazole 30 mg capsules manufactured by TOB and TPC in a crossover 
fashion. In Part 2, an additional 60 healthy subjects will receive dexlansoprazole 60 mg capsules manufactured by 
TOB and TPC in a crossover fashion. Due to the difference between the Granules-L used in the 30 mg (Granules-LL) 
and 60 mg (Granules-LS) capsules, the relative BA of both dosage strengths will be assessed. 
Subjects who satisfy the Screening evaluation and selection criteria may be enrolled in the study. For each part, 
eligible subjects will be randomized on Day 1 of Period 1 in a 1:1 ratio to 1 of 2 sequences, which defines the order in 
which they will receive dexlansoprazole regimens in Periods 1 and 2. The dosing between periods will be separated by 
a minimum 5-day washout interval. During Periods 1 and 2, blood samples will be collected predose and over 24 hours 
postdose to measure dexlansoprazole plasma concentrations. The treatment sequences are outlined in the following 
tables for Part 1 and for Part 2.
Part 1 Sequences
Sequence
Number of Subjects
Period 1
Period 2
1
30
A
B
2
30
B
A
Regimen A (test): A single dexlansoprazole 30 mg capsule manufactured at TOB administered orally on Day 1, 30 
minutes following the beginning of a high-fat/high calorie breakfast.
Regimen B (reference): A single dexlansoprazole 30 mg capsule manufactured at TPC administered orally on Day 1,
30 minutes following the beginning of a high-fat/high calorie breakfast.
Part 2 Sequences
Sequence
Number of Subjects
Period 1
Period 2
3
30
C
D
4
30
D
C
Regimen C (test): A single dexlansoprazole 60 mg capsule manufactured at TOB administered orally on Day 1, 30 
minutes following the beginning of a high-fat/high calorie breakfast.
Regimen D (reference): A single dexlansoprazole 60 mg capsule manufactured at TPC administered orally on Day 1,
30 minutes following the beginning of a high-fat/high calorie breakfast.
In each period of each part, subjects will be confined from Check-in Day -1 until all study procedures have been 
completed on Day 2. Study drug will be administered in the morning of Day 1 of each period 30 minutes following the 
beginning of a high-fat/high calorie breakfast. The entire standardized breakfast is to be consumed within 25 minutes. 
Dosing may be staggered to help facilitate logistics at the site. Subjects will be instructed to swallow the intact capsule 
with 240 mL of water. During Periods 1 and 2 of each part, blood samples will be collected predose and over 24 hours 
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postdose to measure dexlansoprazole plasma concentrations.
Subjects will be discharged from the study site on Day 2 of each period (subjects will exit the study on Day 2 of 
Period 2 within each part), and the dosing between periods within each part will be separated by a minimum 5-day 
washout interval.
A follow-up phone call will be made 10 (±2) days post last dose of study drug to inquire for any ongoing adverse 
events (AEs) or serious adverse events (SAEs), as well as new AEs or SAEs, and concomitant medications taken since 
final dose. Subjects who received at least one dose of study drug and terminate from the study early will still be 
contacted for a safety follow-up call. The contact will only be recorded in their source documents and the case report 
forms (CRFs), according to data protection regulations.
Primary completion date will be based on the final data collection for the primary endpoint, Day 2 of Period 2. End of 
trial (study completion date) will be based on the final data collection date for the entire study, which is the follow-up 
phone call.
A schematic of the study design is shown below.
Schematic of Study Design
Treatment Periods 1 and 2
Screening 
Period
Check-in
(Periods 1 
and 2)
Dexlansoprazole 30 
and 60 mg capsule 
Single Dose PK
Discharge
(Period 1)
Study Exit 
(Period 2)
Follow-up
Phone Call
Days -28 to -2
Day -1
Day 1
Day 2 Period 1
Day 2
Day 10 (±2 days)
Confinement 
PK=Pharmacokinetic.
Note: There is a minimum 5-day washout period between the dose in Period 1 and the dose in Period 2. A follow-up 
phone call will be made for collection of AEs, SAEs, and concomitant medications taken since the final dose.
Trial Primary Objective:

To assess the BA of dexlansoprazole from a 30 mg capsule manufactured at TOB relative to that of 
dexlansoprazole from a 30 mg capsule manufactured at TPC.

To assess the BA of dexlansoprazole from a 60 mg capsule manufactured at TOB relative to that of 
dexlansoprazole from a 60 mg capsule manufactured at TPC.
Secondary Objectives:
To evaluate the safety and tolerability of dexlansoprazole following oral administration of a single dexlansoprazole 30 
or 60 mg capsule.
Trial Subject Population: Healthy subjects aged 18 to 55 years, inclusive, who have a body mass index between 18 
and 30 kg/m2.
Planned Number of Subjects:
Per dose level: 60
Estimated Total: 120
Planned Number of Sites:
Estimated total: 1 in the United States
Dose Levels:
Part 1: 30 mg dexlansoprazole
Part 2: 60 mg dexlansoprazole
Route of Administration:
Oral
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Duration of Treatment:
Part 1:
Dexlansoprazole 30 mg capsule (manufactured at TOB 
or TPC) administered on Day 1 of Periods 1 and 2.
Part 2:
Dexlansoprazole 60 mg capsule (manufactured at TOB 
or TPC) administered on Day 1 of Periods 1 and 2.
Total number of dosing days: 2 per part.
Planned Trial Duration:
Screening: 27 days.
Check-in (Day -1) for each Period: 2 days total.
Treatment Period (Days 1 to 2) for each Period: 4 days total.
Washout between dosing: at least 5 days.
Follow-up phone call: 10 days (±2) after last dose.
Total Study Duration including Screening: Approximately 
43 days per part. 
Main Criteria for Inclusion:
Healthy men and women aged 18 to 55 years old, inclusive, with a body mass index between 18 and 30 kg/m2, 
inclusive, who are capable of understanding and complying with protocol requirements. Subjects must be in good 
health as determined by a physician based upon medical history, vital signs, electrocardiogram (ECG), and physical 
examination. Subjects must have clinical chemistry, hematology, and complete urinalysis (after fasting for at least 
12 hours) 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. Subjects must sign a written 
informed consent form (ICF) prior to initiation of study procedures.
Main Criteria for Exclusion: 
The subject has 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 (eg, a history of malabsorption, severe esophageal reflux, peptic ulcer disease or erosive 
esophagitis (EE) with frequent [more than once per week] occurrence of heartburn); or has consumed medications,
certain foods, and supplements, including prescription and over-the-counter medications, within the 
protocol-specified time periods prior to Check-in (Day -1 of Period 1), or is unwilling to agree to abstain from these 
products. The subject must not have received dexlansoprazole in a previous clinical study or as a therapeutic agent 
within 6 months of Screening, or have a known hypersensitivity to any component of the formulation of 
dexlansoprazole capsules or other drugs with the same mechanism of action (including lansoprazole, omeprazole, 
rabeprazole, pantoprazole, or esomeprazole), or related compounds; or any significant results from physical 
examination or clinical laboratory results that make the subject unsuitable for the study.
Main Criteria for Evaluation and Analyses:
The primary endpoints of the study are the following plasma PK parameters of dexlansoprazole derived on Day 1 of 
each period:

Maximum observed concentration (Cmax).

Area under the concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast).

Area under the concentration-time curve from time 0 to infinity (AUC∞).
Additional Endpoints
In addition, the following plasma PK parameters for dexlansoprazole will be calculated: 

time to first occurrence of Cmax (tmax), 

terminal disposition phase half-life (t1/2z), 

terminal disposition phase rate constant (λz), 

apparent clearance after extravascular administration (CL/F), 

apparent volume of distribution during the terminal disposition phase after extravascular administration (Vz/F).
Safety Endpoints
Safety will be assessed by summarizing the incidence of AEs, clinical laboratory values, physical examinations, 
ECGs, and vital signs
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Statistical Considerations:
For each regimen of each part, dexlansoprazole plasma concentrations and PK parameter estimates will be tabulated 
and descriptive statistics computed.
For each part, analysis of variance (ANOVA) will be performed on natural logarithms of dexlansoprazole Cmax and 
area under the plasma concentration-time curve (AUC) with factors for sequence, subject nested within sequence, 
period, and regimen. The factor of the subject nested within sequence will be the error term for testing the sequence 
effect. Other factors will be tested with the residual as the error term. For the relative BA determination, pairwise 
comparisons will be performed to assess the relative BA of dexlansoprazole via point estimates and 90% confidence 
intervals (CI) for the ratio of Cmax and AUC central values of the dexlansoprazole 30 or 60 mg capsules manufactured 
at TOB compared to the respective 30 or 60 mg capsules manufactured at TPC. A conclusion of BE in the PK of 
dexlansoprazole between test regimen (dexlansoprazole capsule - TOB) and the reference regimen (dexlansoprazole 
capsule - TPC) will be reached if the 90% CIs for Cmax and AUC are within the (0.80–1.25) interval.
Statistical analyses of other plasma PK parameters will be performed, if appropriate.
Sample Size Justification:
For each part, a sample size of 60 (30 per sequence) will be used in this study. This sample size will allow for up to 
6 dropouts (10% dropout rate) and provide 90% probability of concluding equivalence on dexlansoprazole Cmax
between the 2 regimens if the true difference between dexlansoprazole Cmax central values from 2 regimens is no more 
than 5%. The power for concluding equivalence on dexlansoprazole AUC between 2 regimens would be over 95%. 
This sample size was based on the intrasubject variance of 0.0884 for log(Cmax) and 0.0365 for log(AUC) from Part 1 
(30 mg) of the TAK-390MR-1001 study. Part 1 was used because the intrasubject variance of log(Cmax) was higher 
than in Part 2 (60 mg).
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2.0
STUDY SCHEMATIC
Figure 2.a
Schematic of Study Design
Screening 
Period
Check-in
(Periods 1 
and 2)
Treatment Periods 1 and 2
Study Exit 
(Period 2)
Follow-up
Phone Call
Dexlansoprazole 30 
and 60 mg capsule 
Single Dose PK
Discharge
(Period 1)
Days -28 to -2
Day -1
Day 1
Day 2 Period 1
Day 2
Day 10 (±2 days)
Confinement 
Note: There is a minimum 5-day washout period between the dose in Period 1 and the dose in Period 2. A follow-up 
phone call will be made for collection of AEs, SAEs, and concomitant medications taken since the final dose.
Figure 2.b
Schematic of Crossover Design
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CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES
Study Day: 
Pretreatment Period
Treatment Periods 1 and 2 (a)
Study Exit (Day 2 of 
Period 2)/ 
Early Termination
(c)
Follow-up 
Phone Call (d)
Days -28 to -2
(screening) (b)
Day -1 
(Check-in)
Day 1 
Day 2 (Period 1)
Confinement
X
X
X (e)
X (c)
Informed consent
X
Inclusion/exclusion criteria
X
X (f)
Demographics and medical history
X
Medication history
X
Physical examination
X
X
X
Height, Weight, and BMI (g)
X
Vital signs (h)
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
Clinical laboratory tests (i)
X
X
X
X
HIV and Hepatitis panel
X
Pregnancy test (hCG) (j)
X
X
X
FSH (k)
X
Urine drug and alcohol screen
X
X
Urine cotinine test 
X
X
ECG (l)
X
X
X
X
Administration of study drug (m) 
X
PK blood collection (n)
X
X
X (o)
AE assessment (p)
X
X
X
X
X
X
Footnotes are on following page.
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CONFIDENTIAL
(a) There will be at least 5 days between the dose in 1 period and the dose in a subsequent period.
(b) Screening procedures must be performed within 28 days prior to first administration of investigational product.
(c) Following study procedure completion on Day 2 of Period 1, subjects will be discharged from the clinic for the washout period.
(d) Follow-up phone call will be made 10±2 days after last dose of study drug (including any subject who received at least one dose of study drug and terminated from the study early) 
to inquire about any TEAE or SAEs, as well as new AEs or SAEs, and concomitant medications taken since final dose. Any TEAE/SAE spontaneously reported within 30 days 
postdose will be included within the database as a TEAE/SAE.
(e) Following study procedure completion on Day 2 of Period 2, subjects will be discharged from the clinic. Early termination procedures are explained in Section7.5.
(f) Assessment of inclusion and exclusion criteria will be done on Day -1, Period 1 only. 
(g) The BMI is calculated using metric units as follows: Metric: BMI = weight (kg)/[height (m)]2.
(h) 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 in each period on Check-in (Day -1), prior to dosing and at 8 hours postdose on Day 1, and prior to discharge from the clinic on Day 2, or if the subject terminates early 
from the study. When vital signs are scheduled at the same time as blood draws, the blood draw will take priority and vital signs will be obtained within 30 minutes before or after the 
scheduled blood draw.
(i) Hematology, serum chemistries, and urinalysis tests. Clinical laboratory samples will be collected after a minimum of an 12 hour fast on Screening, Check-in (Day -1) of Periods 
1 and 2; Day 2 of Period 1, and Study Exit (Day 2 of Period 2)/Early termination. If a 12-hour fast is not possible at Early Termination or due to re-checks, laboratory samples will still 
be collected.
(j) A serum pregnancy test will be done on all female subjects at Screening and Day -1 of each period, Study Exit (Day 2 of Period 2), or if a subject prematurely terminates from the 
study.
(k) For women where menopause is suspected (see Appendix D).
(l) ECG will be performed at Screening, Check-in (Day -1 of Period 1), and Study Day 2 of each period or if a subject terminates early from the study. 
(m) Study drug will be administered in the morning of Day 1 of each period 30 minutes following the beginning of a high-fat/high-calorie breakfast. Dosing may be staggered to help 
facilitate logistics at the site.
(n) Blood samples for PK obtained predose (within 1 hour prior to dose), and at 1, 2, 3, 4, 5, 6, 6.5, 7, 8, 10, 12, 14, 16, and 24 hours post Day 1 dosing in each period.
(o) The PK sample should not be collected at Early Termination if a PK collection is not scheduled at that time
(p) Pretreatment AEs 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 the follow-up phone call.
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4.0
INTRODUCTION
Dexlansoprazole is a proton-pump inhibitor (PPI) with prolonged elevation of intragastric pH. 
PPIs inhibit the secretion of H+ ions in the stomach by inhibiting the (H+, K+)-ATPase enzyme 
(proton pump) at the secretory surface of the gastric parietal cell [1]. Dexlansoprazole is the 
R-enantiomer of the racemate lansoprazole. Lansoprazole, initially approved in France in 1990, is 
currently marketed in over 90 countries and has a well-established safety profile. 
Takeda Development Center Americas, Inc. (TDC Americas) developed dexlansoprazole 
delayed-release capsules (also referred to as dexlansoprazole modified-release capsules) as a new 
therapy for treating acid-related disorders including symptomatic non-erosive gastroesophageal 
reflux disease (GERD), erosive esophagitis (EE), and maintenance of healed EE and relief of 
heartburn. Dexlansoprazole capsules are approved for use in adults (≥18 years of age) and 
adolescents (12 to 17 years of age) in over 35 countries in North and South America, Europe, Asia, 
and the Middle East. Dexlansoprazole capsules were first approved for use in adults in the United 
States (US) in January 2009. The international birth date (IBD) is 30 January 2009.
The dual delayed-release capsule formulation of dexlansoprazole consists of 2 types of 
enteric-coated granules contained within a single capsule. Each type of granule has a different 
pH-dependent release profile. The formulation has been designed to have drug released within 1 to 
2 hours of administration, followed by a second release phase within 4 to 5 hours of the dose. This 
dual delayed-release formulation is designed to extend the duration of drug exposure and maintain 
pharmacologically active levels of drug over a longer period of time, resulting in prolonged 
elevation of intragastric pH. 
The pharmacokinetic (PK), pharmacodynamic, efficacy, and safety profiles of dexlansoprazole 
capsules following administration of dexlansoprazole 30, 60, and 90 mg capsules in adults have 
been extensively studied. Dexlansoprazole 60 mg capsules are approved for the healing of EE and 
dexlansoprazole 30 mg capsules are approved for the treatment of symptomatic nonerosive 
GERD, and the maintenance of healed EE. Currently, dexlansoprazole granules (Granules-LL and 
Granules-H for 30 mg and Granules-LS and Granules-H for 60 mg) are manufactured and 
encapsulated into capsule product at Takeda Pharmaceutical Company, Ltd. (TPC) located in 
Osaka, Japan.
Rationale for the Proposed Study
4.1
The rationale for conducting this study is to qualify an additional production site (Takeda GmbH 
Plant Oranienburg [TOB]) for the manufacture of dexlansoprazole capsules by establishing the 
bioequivalence (BE) of dexlansoprazole 30 and 60 mg capsules manufactured by TOB with 
dexlansoprazole 30 and 60 mg capsules manufactured by the TPC plant in Osaka. Clinical studies 
in healthy subjects receiving dexlansoprazole (DEXILANT®) under various fed conditions 
compared to fasting conditions, demonstrated increases in Cmax ranging from 12 to 55%, increases 
in AUC ranging from 9 to 37%, and Tmax varied (ranging from a decrease of 0.7 hours to an 
increase of three hours) [1]. As the dual stage bioavailability of the drug is based on the solubility 
of the different excipients in different pH levels and as DEXILANT® is prescribed to be 
administered with or without food [1], it is important to confirm the BE under both fasted and fed 
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conditions. This study will complement study TAK-390MR-1001 which assessed the BE of the 
drug produced in the 2 plants under fasted conditions. 
Benefit/Risk Profile
4.2
The dose of dexlansoprazole administered in this study is not anticipated to induce any potential 
risk or benefit to subjects participating in this study, as it is a single dose administered according to 
the dosing recommendations found in the full prescribing information for DEXILANT 
(dexlansoprazole) delayed-release capsules.
The safety monitoring practices employed by this protocol (ie, 12-lead ECG, vital signs, clinical 
laboratory tests, adverse events (AE) questioning, and physical examination) are adequate to 
protect the subjects’ safety and should detect all expected treatment-emergent AEs (TEAEs).
There will be no direct health benefit for study participants from receipt of study drug. An indirect 
health benefit to the healthy subjects enrolled in this study is the free medical tests received at 
screening and during the study.
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5.0
TRIAL OBJECTIVES AND ENDPOINTS
Hypothesis
5.1
A conclusion of BE in the PK of dexlansoprazole between test product (dexlansoprazole capsule -
TOB) and the reference product (dexlansoprazole capsule - TPC) will be reached if the 90% 
confidence intervals (CIs) for Cmax and AUC are within the (0.80–1.25) interval.
Trial Objectives
5.2
5.2.1
Trial Primary Objective
The primary objectives of the study are:

To assess the BA of dexlansoprazole from a 30 mg capsule manufactured at TOB relative to 
that of dexlansoprazole from a 30 mg capsule manufactured at TPC.

To assess the BA of dexlansoprazole from a 60 mg capsule manufactured at TOB relative to 
that of dexlansoprazole from a 60 mg capsule manufactured at TPC.
5.2.2
Trial Secondary Objective
The secondary objective of the study is:
To evaluate the safety and tolerability of dexlansoprazole following oral administration of a single 
dexlansoprazole 30 or 60 mg capsule.
Endpoints
5.3
5.3.1
Primary Endpoint
The primary endpoint of the study is following plasma PK parameters of dexlansoprazole derived 
on Day 1 of each period:

Maximum observed concentration (Cmax).

Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast).

Area under the concentration-time curve from time 0 to infinity (AUC∞).
5.3.2
Additional Endpoints
The following plasma PK parameters for dexlansoprazole will be calculated: 

time to first occurrence of Cmax (tmax), 

terminal disposition phase half-life (t1/2z), 

terminal disposition phase rate constant (λz), 

apparent clearance after extravascular administration (CL/F), 
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
apparent volume of distribution during the terminal disposition phase after extravascular 
administration (Vz/F).
5.3.3
Safety Endpoints 
Safety will be assessed by summarizing the incidence of AEs, clinical laboratory values, physical 
examinations, ECGs, and vital signs.
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6.0
TRIAL DESIGN AND DESCRIPTION
Trial Design
6.1
This is a phase 1, randomized, open-label, single-center, single-dose, 2-part, 2-way crossover 
study in healthy subjects to assess the BA of 30 or 60 mg dexlansoprazole capsules manufactured 
at TOB relative to the corresponding 30 or 60 mg dexlansoprazole capsules manufactured at TPC 
under fed conditions. The study will be conducted in 2 parts. In Part 1, 60 healthy subjects will 
receive dexlansoprazole 30 mg capsules manufactured by TOB and TPC in a crossover fashion. In 
Part 2, an additional 60 healthy subjects will receive dexlansoprazole 60 mg capsules 
manufactured by TOB and TPC in a crossover fashion. Due to the difference between the 
Granules-L used in the 30 mg (Granules-LL) and 60 mg (Granules-LS) capsules, the relative BA 
of both dosage strengths will be assessed.
At Check-in (Day -1 of Period 1), approximately 120 subjects in total (60 in Part 1, 60 in Part 2), 
including both men and women, aged 18 to 55 years, inclusive, will be selected to participate in the 
study. Subjects who satisfy the Screening evaluation and selection criteria may be enrolled in the 
study. For each part, eligible subjects will be randomized on Day 1 of Period 1 in a 1:1 ratio to 1 of 
2 sequences, which defines the order in which they will receive dexlansoprazole regimens in 
Periods 1 and 2. The dosing between periods will be separated by a minimum 5-day washout 
interval. During Periods 1 and 2, blood samples will be collected predose and over 24 hours 
postdose to measure dexlansoprazole plasma concentrations.
The treatment sequences are outlined in Table 6.a (Part 1) and Table 6.b (Part 2).
Table 6.a
Part 1 Sequences
Sequences
Number of 
Subjects
Period 1
Period 2
1
30
A
B
2
30
B
A
Regimen A (test): A single dexlansoprazole 30 mg capsule manufactured at TOB administered orally on Day 1 
30 minutes following the beginning of a high-fat/high calorie breakfast.
Regimen B (reference): A single dexlansoprazole 30 mg capsule manufactured at TPC administered orally on Day 1 
30 minutes following the beginning of a high-fat/high calorie breakfast. 
Table 6.b
Part 2 Sequences
Sequences
Number of 
Subjects
Period 1
Period 2
3
30
C
D
4
30
D
C
Regimen C (test): A single dexlansoprazole 60 mg capsule manufactured at TOB administered orally on Day 1 
30 minutes following the beginning of a high-fat/high calorie breakfast.
Regimen D (reference): A single dexlansoprazole 60 mg capsule manufactured at TPC administered orally on Day 1 
30 minutes following the beginning of a high-fat/high calorie breakfast. 
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In each period of each part, subjects will be confined from Check-in Day -1 until all study 
procedures have been completed on Day 2. Study drug will be administered in the morning of
Day 1 of each period 30 minutes following the beginning of a high-fat/high calorie breakfast. The 
entire standardized breakfast is to be consumed within 25 minutes. Dosing may be staggered to 
help facilitate logistics at the site. Subjects will be instructed to swallow the intact capsule with 
240 mL of water.
Subjects will be discharged from the study site on Day 2 of each period (subjects will exit the study 
on Day 2 of Period 2 within each part).
A follow-up phone call will be made 10 (±2) days post last dose of study drug to inquire for any 
ongoing AEs or serious adverse events (SAEs), as well as new AEs or SAEs, and concomitant 
medications taken since final dose. Subjects who received at least one dose of study drug and 
terminate from the study early will still be contacted for a safety follow-up call. The contact will 
only be recorded in their source documents and the case report forms (CRFs), according to data 
protection regulations.
Primary completion date will be based on the final data collection for the primary endpoint, Day 2 
of Period 2. End of trial (study completion date) will be based on the final data collection date for 
the entire study, which is the follow-up phone call.
A schematic of the study design is included in Section 2.0. A schedule of assessments is listed in
Section 3.0.
Dose Escalation
6.2
NA
Rationale for Trial Design, Dose, and Endpoints
6.3
6.3.1
Rationale of Trial Design 
This phase 1 randomized, open-label, single-dose, 2-part, 2-way crossover relative BA study is 
designed in accordance with Health Canada Guidance Document - Comparative Bioavailability 
Standards: Formulations Used for System Effects (July 2018) [2].
A single-dose study under fed conditions for assessing the relative BA between formulations is 
recommended in the guidance referenced above for some dosage forms and will be used for 
comparison of the capsule formulations from each manufacturing site. 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. 
In humans, dexlansoprazole has a mean t1/2z of approximately 1 to 2 hours. Therefore, a minimum 
5-day washout interval between the doses is sufficient to ensure that there is no drug carryover 
effect, and collection of PK blood samples for 24 hours postdose is appropriate to characterize the 
PK of dexlansoprazole. The primary PK endpoints, Cmax and area under the concentration-time 
curve (AUC) are standard parameters to assess BA. The safety endpoints, including TEAEs, vital 
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signs, 12-lead ECGs, clinical laboratory tests and physical examination data, are standard methods 
for assessing safety and tolerability in clinical pharmacology studies.
6.3.2
Rationale for Dose
Due to the difference between the Granules-L used in the 30 mg (Granules-LL) and 60 mg 
(Granules-LS) capsules, the relative BA of both dosage strengths will be assessed. 
6.3.3
Rationale for Endpoints
The primary PK endpoints, Cmax and AUC are standard parameters to assess BA. The safety 
endpoints, including TEAEs, vital signs, 12-lead ECGs, clinical laboratory tests and physical 
examination data, are standard methods for assessing safety and tolerability in clinical 
pharmacology studies.
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures 
For this study, the blood collection for plasma dexlansoprazole concentrations is the critical 
procedure and is required to be collected as close to the scheduled times defined in this protocol as 
possible.
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
6.4
Parameters
The dose and administration of the study drug to any subject may not be modified. If necessary a 
subject must be discontinued for the reasons described in Section 7.5.
Trial Beginning and End/Completion
6.5
6.5.1
Definition of Beginning of the Trial
The beginning of the trial will be defined as the beginning of the screening (ie, signing of the ICF) 
of the first subject.
6.5.2
Definition of End of the Trial
The end of study is defined as the date of the last scheduled study procedure as outlined in the 
Schedule of Study Procedures (Section 3.0).
6.5.3
Definition of Trial Completion
The end of the study is scheduled after completion of the evaluations in the follow-up phone call 
for the last subject in the study.
This time period may change in the event that the study is terminated early or the last subject is lost 
to follow-up.
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6.5.4
Definition of Trial Discontinuation
Celerion reserves the right to terminate the study in the interest of subject welfare.
The Sponsor reserves the right to suspend or terminate the study at any time.
6.5.5
Criteria for Premature Termination or Suspension of the Trial
The study will be completed as planned unless one 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 medication 
that indicates a change in the known risk/benefit profile for the product, 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.
6.5.6
Criteria for Premature Termination or Suspension of a Site
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.
6.5.7
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the Sponsor, an institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of an investigational site, a study-specific 
procedure for early termination or suspension will be provided by the Sponsor; the procedure will 
be followed by applicable investigational sites during the course of termination or study 
suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
Inclusion Criteria
7.1
Attempts will be made to enroll an equal number of men and women. 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 signs and dates a written, ICF and any required privacy authorization prior to the 
initiation of any study procedures including requesting that a subject fast for any laboratory 
evaluations.
3. The subject is in good health as determined by a physician based upon medical history, vital 
signs, ECG, and physical examination findings at Screening and Check-in.
4. The subject is a man or woman aged 18 to 55 years, inclusive, at the time of informed consent 
and first study medication dose.
5. The subject has a body mass index (BMI) from 18 to 30 kg/m2, inclusive, at Screening.
6. A man who is nonsterilized* and sexually active with a woman of childbearing potential* 
agrees to use adequate contraception* from signing of informed consent throughout the 
duration of the study and for 30 days after last dose of study drug.
7. A woman of childbearing potential* who is sexually active with a nonsterilized* male partner 
agrees to routinely use adequate contraception* from signing of informed consent throughout 
the duration of the study, and for 30 days following the last dose of study drug.
*Definitions and acceptable methods of contraception and Pregnancy Avoidance 
Procedure and reporting responsibilities are defined in Appendix D.
8. Women must have a negative serum pregnancy test at Screening and Check-in (Day -1 of 
Period 1) and they must not be nursing.
9. Subject has clinical chemistry, hematology, and complete urinalysis (after fasting for at least 
12 hours) 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.
10. The subject is willing and able to consume the high-fat/high-calorie breakfasts administered 
during the study.
Exclusion Criteria
7.2
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 the first dose of 
study medication.
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2. The subject has 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 (eg, a history of 
malabsorption, severe esophageal reflux, peptic ulcer disease or erosive esophagitis with 
frequent [more than once per week] occurrence of heartburn). 
3. The subject has a history of drug abuse (defined as any illicit drug use) or drug addiction in the 
12 months prior to Screening or a history of alcohol abuse (defined as regular consumption 
exceeding 21 units per week [1 unit = 12 ounces (oz) beer, 1.5 oz hard liquor, or 5 oz wine]) 
within 1 year prior to the Screening Visit, or is unwilling to agree to abstain from alcohol and 
drugs throughout the study. 
4. The subject has a positive test result for drugs of abuse (defined as any illicit drug use) or 
alcohol at Screening or Check-in (Day -1 of Period 1). 
5. Subject has received any known hepatic or renal clearance altering agents (eg, erythromycin, 
cimetidine, barbiturates, phenothiazines, fluvoxamine, etc) for a period of 28 days prior to 
Day 1 of Period 1.
6. Subject has had an acute, clinically significant illness within 30 days prior to Day 1 of 
Period 1.
7. Subject has a systolic blood pressure >140 mm Hg or has a diastolic blood pressure 
>90 mm Hg at Screening or Check-in (Day -1 of Period 1).
8. Subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, or human immunodeficiency virus infection (HIV) at Screening.
9. Subject has abnormal Screening or Day -1 of Period 1 clinical laboratory test result that 
suggests a clinically significant underlying disease or subject with the following laboratory
abnormalities: creatinine >1.5 mg/dL, alanine aminotransferase (ALT) and or aspartate 
aminotransferase (AST) >2.5 x the upper limit of normal (ULN) or total bilirubin >2.0 mg/dL.
10. Subject has an abnormal (clinically significant) ECG at Screening or Check-in (Day -1 of 
Period 1). Entry of any subject with an abnormal (not clinically significant) ECG must be 
approved, and documented by the signature of the principal investigator.
11. Subject has donated blood products (such as plasma) within 30 days or has donated whole 
blood or lost 450 mL or more of his or her blood volume, or had a transfusion of any blood 
product within 56 days prior to Day 1 of Period 1.
12. With the exception of acetaminophen, the subject has taken any excluded medication, 
supplements, or food products listed in Section 7.3. Hormonal contraception (see Appendix D) 
and hormone replacement therapy are allowed, as long as the subject has been on a stable dose 
for a minimum of 90 days prior to Day 1 of Period 1.
13. Subject has used nicotine-containing products (including but not limited to cigarettes, pipes, 
cigars, chewing tobacco, nicotine patch nicotine gum, e-cigarettes) within 28 days prior to 
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Check-in (Day -1 of Period 1), or has a positive cotinine test at Screening or Check-in (Day -1 
of Period 1), or is unwilling to abstain from these products for the duration of the study.
14. The subject has received dexlansoprazole or lansoprazole in a previous clinical study or as a 
therapeutic agent within 6 months of screening.
15. The subject has a history (within 6 months) or clinical manifestations of clinically significant 
metabolic, hematologic, pulmonary, cardiovascular, GI, neurologic, hepatic, renal, urologic, 
immunologic, musculoskeletal or psychiatric disorder as defined by the investigator, which 
may impact the ability of the subject to participate or potentially confound the study results.
16. Subject has a history of cancer, except basal cell carcinoma that has been in remission for at 
least 5 years prior to Day 1 of Period 1.
17. The subject has poor peripheral venous access.
18. Subject has a known hypersensitivity to any component of the formulation of dexlansoprazole 
capsules or other drugs with the same mechanism of action (including lansoprazole, 
omeprazole, rabeprazole, pantoprazole, or esomeprazole), or related compounds.
19. The subject is lactose intolerant.
20. If a woman, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 30 days after participating in this study, or intending to donate ova during such time 
period. 
21. If a man, the subject intends to donate sperm from first dosing and during the course of this 
study or for 30 days thereafter.
22. 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/partner, parent, child, sibling) or may consent under duress.
Excluded Medications, Supplements, Dietary Products
7.3
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified and for the duration of the subject’s participation in the study. 
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Table 7.a
Prohibited Medications, Supplements, and Dietary Products
28 days prior to Check-in (Day -1 of 
Period 1)
7 days prior to Check-in (Day -1 of 
Period 1)
72 hours prior to Check-in 
(Day -1 of Period 1)
Prescription medications including 
oral contraceptives (a)
OTC medications (b)
Alcohol-containing products
Nicotine-containing products
Vitamin supplements
Nutraceuticals (eg, St. John’s wort, 
ginseng, kava kava, ginkgo biloba, 
Chinese herbs, and melatonin)
Foods or beverages containing grapefruit 
or grapefruit juice, star fruit or star fruit 
juice, Seville-type (sour) oranges and 
marmalade, apple, orange, or pineapple 
juice, vegetables from the mustard green 
family (eg, kale, broccoli, watercress, 
collard greens, kohlrabi, Brussels 
sprouts, mustard), and charbroiled meats
Products containing caffeine 
and/or xanthine
Hepatic or renal clearance altering 
agents
Immunization/Vaccines (c)
Intake of known OTC inhibitors/inducers 
of CYPs 3A4/5, 2C9, 2C19, 2D6, 1A2, 
2B6, 2E1, and 2A6 (d).
Poppy seeds
OTC=over-the-counter.
(a) Hormonal contraception and hormone replacement therapy (HRT) are allowed, as long as the subject has been on a 
stable dose for a minimum of 90 days prior to Day 1 of Period 1.
(b) Occasional use of acetaminophen (≤2 g/day) is allowed or other medication as approved by the investigator and 
Takeda on a case-by-case basis. Acetaminophen is not allowed on Day 1 of each period.
(c) Inclusive of but not limited to H1N1 and flu vaccinations.
(d) Inclusive of but not limited to esomeprazole, omeprazole, cimetidine, ranitidine, and chlorpheniramine.
Subjects must be instructed not to take any medications including OTC products, without first consulting with the 
investigator during the Washout Period, as well as during confinement.
Diet, Fluid, Activity 
7.4
7.4.1
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), with the exception 
of the high-fat/high-calorie breakfast served on Day 1 of each period. 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. 
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.
On Day 1 of each period, subjects will fast for a minimum of 10 hours until 30 minutes prior to 
their scheduled morning dose, when they will be given a high-fat/high-calorie breakfast which will 
be entirely consumed within 25 minutes. The high-fat/high-calorie breakfast will have 
approximately 50 percent of total caloric content of the meal come from fat and a total of 
approximately 800 to 1000 kilocalories (kcal). This meal will derive approximately 150, 250, and 
500-600 kcal from protein, carbohydrate, and fat, respectively. The composition of the meal will 
include a description of the protein, carbohydrate and fat content (specified in grams, calories and 
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relative caloric content (%). An example of high-fat/high-calorie breakfast will include 
approximately 910 kcal consisting of approximately 55% fat, 25% carbohydrates, and 18% 
protein, and would consist of 2 slices of buttered toast, 2 eggs fried in butter, 2 strips of bacon, 4 oz 
of hash brown potatoes, and 240 mL of whole milk. Subjects will fast for at least 4 hours postdose
on these days. Lunch will be served approximately 4 hours postdose. Dinner will be served 
approximately 9 hours postdose. A snack will be served approximately 12 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 CRF. Subjects will be fasting for a minimum of 12 hours 
prior to collection of scheduled safety laboratory assessments. 
7.4.2
Activity
Subjects should be instructed to refrain from strenuous exercise starting approximately 48 hours 
prior to confinement on Day -1 of Period 1 and up to release from the clinic on Day 2 of Period 2.
Criteria for Discontinuation or Withdrawal of a Subject
7.5
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the CRF using the following categories.
1. Pretreatment event or AE. The subject has experienced a pretreatment event 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 pretreatment event or AE.

Liver Function Test (LFT) Abnormalities 
Study medication 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 9.2.8), if the following circumstances occur at any time 
during study medication 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 
international normalized ratio (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 medication 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.
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4. Voluntary withdrawal. The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the CRF.
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).
5. Study termination. The Sponsor, contract research organization, IRB, 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 Appendix D.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the CRF.
Procedures for Discontinuation or Withdrawal of a Subject
7.6
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. Discontinued or withdrawn subjects may be replaced.
Subject Replacement
7.7
Discontinued or withdrawn subjects may be replaced. Any subjects that replace withdrawn or 
discontinued subjects will maintain the same treatment sequence as the discontinued subject.
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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.
Clinical Study Drug 
8.1
In this protocol, the term study medication refers to all or any of the drugs defined below.
The Sponsor will supply the 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)
Dexlansoprazole capsule
30 mg
Capsules manufactured at TOB
B (reference)
Dexlansoprazole capsule
30 mg
Capsules manufactured at TPC
C (test)
Dexlansoprazole capsule
60 mg
Capsules manufactured at TOB
D (reference)
Dexlansoprazole capsule
60 mg
Capsules manufactured at TPC
The study site will be supplied with 30-count bottles of dexlansoprazole delayed-release capsules 
30 mg manufactured at TOB (containing Granules-LL and Granules-H), and 30 mg capsules 
manufactured at TPC (containing Granules-LL and Granules-H). Also supplied will be 30-count 
bottles of dexlansoprazole delayed-release capsules 60 mg manufactured at TOB (containing 
Granules-LS and Granules-H), and 60 mg capsules manufactured at TPC (containing Granules-LS 
and Granules-H).
8.1.1
Clinical Study Drug Labeling
The bottles containing the study medication will be packaged in an open label manner. The bottles 
will bear a single-panel 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.” 
8.1.2
Clinical Study Drug Inventory and Storage
All drug supplies used to conduct this study must be kept in an appropriate, limited-access, secure 
place until it is used or returned to the Sponsor or designee for destruction. Drug supplies must be 
stored at controlled room temperature 20°C to 25°C (68°F to 77°F; see US Pharmacopeia); 
excursions allowed between 15°C and 30°C (59°F to 86°F), protected from moisture and in a 
secure location until dispensed to study subjects or returned to Takeda or its designee. Drug 
supplies will be counted and reconciled at the site before disposition or return to Takeda or 
designee. Each unused drug supply must be returned in its original container.
8.1.3
Clinical Study Drug Blinding
This is an open-label study.
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8.1.4
Randomization Code Creation and Storage 
The randomization schedule will be generated by Celerion prior to the start of the study, and 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.
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure
NA
8.1.6
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.
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, use by each subject, and 
return to the Sponsor or designee.
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 the 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:

Continuously monitoring expiration dates if expiry date is provided to the investigator or 
designee.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot 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.
The investigator or designee must record the current inventory of all sponsor-supplied drugs 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 of the person 
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dispensing the drug, and the date and amount returned to the site by the subject, including the 
initials 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 that was 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 CRO may be designated by 
the Sponsor to destruct any unused sponsor-supplied drug. The investigator or designee will retain 
the original documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and copies 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.
8.1.6.1
Reserve Study Medication Samples for Retention 
The investigator will retain a reserve sample of dexlansoprazole capsules in accordance with Food 
and Drug Administration (FDA) regulations. The investigator or the investigator’s designee will 
select the appropriate number of containers of study medication 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 BA 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 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 Section 3.0.
Administrative Procedures
9.1
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 13.2.
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.
9.1.1.1
Assignment of Screening and Randomization Numbers 
A unique subject identification number (subject ID = site + 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.
9.1.1.2
Study Drug Assignment
All subjects will receive the same treatments as detailed in Section 9.2.6.
9.1.2
Inclusion and Exclusion 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria as 
described in Section 7.0.
9.1.3
Medical History/Demography
Demographic information to be obtained will include date of birth, gender, 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.
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.
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.
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 the Screening examination. The condition (ie, diagnosis) 
should be described.
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9.1.4
Concomitant Medications
Subjects will be instructed not to take any medications during the study, including 
over-the-counter products, without first consulting with the investigator. Use of concomitant 
medications will not be allowed during the study unless deemed necessary in cases of medical 
emergency or approved by the Sponsor and the investigator on a case-by-case basis. Occasional 
use of acetaminophen (up to 2 g/day) is allowed. Acetaminophen is not allowed on Day 1 of each 
period. Hormonal contraception and HRT are allowed, as long as a subject has been on a stable 
dose for a minimum of 90 days prior to Day 1. 
All medications used within 28 days prior to Screening will be recorded in the source document 
and Medication History CRF. All medications taken from Screening through to the end of the 
study will be recorded in the source document and Concomitant Medication CRF.
Clinical Procedures and Assessments
9.2
9.2.1
Full Physical Exam
Physical exams will be performed at Screening, Check-in (Day -1 of Periods 1 and 2), Day 2 Study 
Exit for Period 2 only, Early Termination, and during Unscheduled Visits. A baseline physical 
examination (defined as the pretreatment assessment immediately prior to the start of study drug) 
will be performed at Check-in (Day -1) of Period 1. The exams 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; (11) genitourinary system; and (12) other. The 
genitourinary examination will not be required for this protocol but will be listed on the CRF page 
for physical examination and hard-coded as “not done.”
All physical examinations subsequent to Check-in (Day -1) of Period 1 should assess clinically 
significant changes from the Baseline Check-in (Day -1) of Period 1 examination. If a body system 
is not examined, “not done” should be indicated.
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 CRF. All CS findings/changes will be recorded as a pretreatment event 
(PTE) or concurrent medical condition in the source document and on the appropriate CRF
described in Section 9.1.4 or Section 10.0.
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately prior to the start of the study drug must be assessed as NCS or 
CS by the investigator and recorded in the source document and CRF. 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 CRF described in Section 10.0.
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9.2.2
Height and Weight
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The Takeda standard for collecting height is centimeters (cm) without decimal places and for 
weight it is kilograms (kg) with 1 decimal place.
9.2.3
BMI
The BMI is calculated using metric units with the formula provided below:
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. For example, if weight=79.2 kg and 
height=176 cm (1.76 m), 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 30 kg/m2
cut-off point, then this determination must be made after rounding.
9.2.4
Vital Signs
Vital signs will include oral body temperature, sitting blood pressure (resting 5 minutes), and pulse 
(beats per minute). Only blood pressure and pulse will be taken on Check-in (Day -1) through 
Day 2. Vital signs will be obtained at the time points stipulated in Schedule of Study Procedures 
(Section 3.0).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw.
9.2.5
12-Lead ECG
A standard 12-lead ECG will be recorded at Screening, Check-in (Day -1) of Period 1, and Day 2 
Study Exit of Periods 1 and 2 or if a subject terminates early from the study. The investigator (or a 
qualified observer at the investigational site) will interpret the ECG using 1 of the following 
categories: within normal limits, abnormal but not clinically significant, or abnormal and clinically 
significant. The results of the ECG will be captured on the source documents and appropriate CRF 
and the original hard copies should be kept as source documentation. ECGs on thermal paper must 
be photocopied and the copy should be kept in the subjects’ source documents. The following 
parameters will be recorded on the CRF from the subject’s ECG trace: heart rate, QT interval, and 
QRS interval.
9.2.6
Study Drug Administration
Subjects will fast for a minimum of 10 hours until 30 minutes prior to their scheduled morning 
dose in Periods 1 and 2, when they will be given a high-fat/high-calorie breakfast which will be 
entirely consumed within 25 minutes. In the morning of Day 1, subjects will be instructed to 
swallow the intact capsule with 240 mL of water. Dosing may be staggered to help facilitate 
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logistics at the site. 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.
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 they are assigned to (See Table 9.a).
The 4 dosing regimens are:
Regimen A: A single 30 mg dexlansoprazole capsule manufactured at TOB.
Regimen B: A single 30 mg dexlansoprazole capsule manufactured at TPC.
Regimen C: A single 60 mg dexlansoprazole capsule manufactured at TOB.
Regimen D: A single 60 mg dexlansoprazole capsule manufactured at TPC.
On Day 2 of Period 1, subjects will be discharged from the study site for a minimum washout 
interval of 5 days between the dose in the first period and the dose in the second period. 
Table 9.a
Dose and Regimen
Study Part
Sequence
Number of Subjects
Period 1
Regimen
Period 2
Regimen
Part 1
30 mg
1
30
A
B
2
30
B
A
Part 2
60 mg
3
30
C
D
4
30
D
C
Regimen A: A single 30 mg dexlansoprazole capsule manufactured at TOB administered orally on Day 1, 30 minutes 
following the beginning of a high-fat/high calorie breakfast.
Regimen B: A single 30 mg dexlansoprazole capsule manufactured at TPC administered orally on Day 1, 30 minutes 
following the beginning of a high-fat/high calorie breakfast. 
Regimen C: A single 60 mg dexlansoprazole capsule manufactured at TOB administered orally on Day 1, 30 minutes 
following the beginning of a high-fat/high calorie breakfast.
Regimen D: A single 60 mg dexlansoprazole capsule manufactured at TPC administered orally on Day 1, 30 minutes 
following the beginning of a high-fat/high calorie breakfast.
9.2.7
AE Monitoring
Subjects will be monitored throughout the study for adverse reactions to the study formulations 
and/or procedures as described in Section 10.0.
9.2.8
Laboratory Procedures and Assessments
All samples will be collected in accordance with acceptable laboratory procedures. Laboratory 
samples will be taken following a minimum 12-hour overnight fast at the time points stipulated in 
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the Schedule of Study Procedures (Section 3.0). If a 12-hour fast is not possible at early 
termination or due to re-checks, laboratory samples will still be collected.
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
RBC
Hematocrit
WBC with differential
Platelets
Hemoglobin
Chemistry 
Chemistry evaluations will consist of the following standard chemistry panel:
ALT
Blood urea nitrogen
Albumin
Uric acid
ALP
gamma-glutamyl transferase
AST
Calcium
Glucose
Phosphorus
Total bilirubin
Potassium
Total protein
Sodium
Total cholesterol
Chloride
Triglycerides 
Bicarbonate or carbon dioxide
Serum creatinine
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase
Urinalysis
Urinalysis will consist of the following tests:
Specific gravity
Glucose
pH
Bilirubin
Protein
Red blood cells and white blood cells
Ketones
Urobilinogen
Nitrite
Leukocyte esterase
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of 
RBC/high-power field, WBC/high-power field, bacteria, and casts.
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Other 
HIV
Urine drug screen, including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, cotinine and 
opiates.
Hepatitis panel, including HBsAg
and anti-HCV
Urine alcohol screen 
Serum hCG for pregnancy (female subjects only)
Serum FSH (postmenopausal women defined as 
amenorrhea >1 year)
FSH=follicle stimulating hormone, hCG= human chorionic gonadotropin, HBsAg=hepatitis B specific antibodies, 
HCV=hepatitis C virus, HIV=human immunodeficiency virus, RBC=red blood cells, WBC=white blood cells.
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis as referenced in Section 3.0. The results of laboratory tests will be returned to the 
investigator, who is responsible for filing and reviewing these results for clinical significance 
together with the data in the CRF.
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. All clinically significant laboratory abnormalities must be recorded as an AE in the 
subject’s source documents and on the appropriate CRF unless they are the result of pathology for 
which there is an overall diagnosis. The investigator will maintain a copy of the laboratory 
accreditation and the reference ranges for the laboratory used. 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.
Biomarker, PK, PD, and PGx, Samples
9.3
Primary specimen collection parameters are provided in Table 9.b.
Table 9.b
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample for PK
Plasma
Plasma sample for PK analysis
Mandatory
9.3.1
PK Measurements 
Plasma PK parameters of dexlansoprazole will be derived using noncompartmental analysis 
methods. The PK parameters of dexlansoprazole will be determined from the concentration-time 
data for all evaluable subjects. Actual sampling times, rather than scheduled sampling times, will 
be used in all PK computations involving blood sampling times. The following PK parameters for 
dexlansoprazole will be determined. Additional PK parameters may be calculated as appropriate.
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The following PK parameters will be calculated from plasma concentrations of dexlansoprazole, 
unless otherwise specified:
AUClast
Area under the concentration-time curve from time 0 to time of the last quantifiable concentration.
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.
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.
9.3.1.1
Plasma for PK Measurements
Blood samples (4 mL) for dexlansoprazole plasma concentrations will be collected beginning on 
Day 1 of each period of each part, as shown in Table 9.c.
Instructions for sample processing and shipment are provided in Appendix E.
Table 9.c
Collection of Blood Samples for PK Analysis
Sample 
Type
Dosing Day
Time (hours)
(Periods 1 and 2)
Plasma
1
Predose (within 1 hour prior to dose) and at 1, 2, 3, 4, 5, 6, 6.5, 7, 8, 10, 12, 
14, 16, and 24 hours postdose.
The actual time of sample collection will be recorded on the source document and CRF. The PK 
sample should not be collected at the Early Termination Visit if a PK collection is not scheduled.
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 CRF. However, 
blood samples not collected as displayed in Table 9.d should be reported (see Section 12.2).
Table 9.d
Windows for PK Sample Collection
Minutes
Nominal Sampling Time
No more than 1 hour predose
0 hour
±5
Immediately postdose to ≤6 hours
±10
>6 hours to ≤12 hours postdose
±15
>12 hours to ≤24 hours
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9.3.2
Biomarker Measurements
NA
9.3.3
PGx Measurements 
NA
9.3.4
Confinement
Subjects enrolled in this study will be confined in the clinical research unit for 2 consecutive nights 
in each period, beginning at Check-in (Day -1) to Day 2. There will be a minimum 5-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.
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10.0
ADVERSE EVENTS
Definitions and Elements of AEs
10.1
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or complication 
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of such a concurrent medical history condition, the worsening or complication should be 
recorded appropriately as an AE (worsening or complication occurs after informed consent is 
signed). Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, 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 severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as 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 AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the Sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the (e)CRF, in order to capture this important safety information consistently in the 
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database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 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. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May 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).
Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
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AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2 Special Interest AEs
NA
AE Procedures
10.2
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
Moderate:
An adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
10.2.2 Assigning Causality of AEs
The relationship of each AE to study medication(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 a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
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10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5 Pattern of Adverse Event (Frequency)
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6 Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet
started or dosing with study medication 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.

Drug interrupted – the dose was interrupted due to the particular AE.
10.2.7 Outcome 

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE 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 become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.
Unknown – the course of the AE cannot be followed up due to hospital change or residence change 
at the end of the subject’s participation in the study.
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10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at
the time the subject signs the informed consent. Routine collection of AEs will continue until the 
follow-up phone call on Day 10 (± 2 days) of Period 2, approximately 10 days after the last dose of 
investigational product. For subjects who discontinue prior to the administration of study 
medication, AEs will be followed until the subject discontinues study participation. 
10.2.8.2 Reporting AEs
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 an
SAE prior to the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to Baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure 
to investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
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 AEs will be documented in the AE page of the CRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with trial drug.

Outcome of event.

Seriousness.
10.2.8.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the
procedure outlined below:
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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 medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
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 SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-Up
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 immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be 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.
10.2.8.4 Reporting Special Interest AEs 
NA
10.2.8.5 Reporting of Abnormal LFTs
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 CRF 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 10.2.8.3. 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. Follow-up laboratory tests as described in Section 9.2.8 must also be 
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performed. In addition, an LFT Increases CRF must be completed and transmitted with the Takeda 
SAE form (as per Section 10.2.9).
10.2.9 Safety Reporting to Investigators, IRBs or IECs, 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 or 
IECs, 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 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 an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STATISTICAL METHODS
Statistical and Analytical Plans
11.1
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.
A targeted data review will be conducted prior to database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
All subjects who enroll into the study and take at least 1 dose of study drug will be included in the 
safety set.
11.1.1.2 PK Set
All subjects in the safety set who have at least 1 valid plasma concentration of dexlansoprazole at 
scheduled sample collection time will be included in the PK set.
11.1.2 Analysis of Demography and Other Baseline Characteristics
For each part, demographic and baseline characteristics will be summarized by sequence and 
overall. Summary statistics (number of subjects, mean, median, standard deviation and range) will 
be generated for continuous variables (eg, age, weight, and BMI) and the number and percentage 
of subjects within each category will be presented for categorical variables (eg, gender, race, and 
ethnicity).
11.1.3 PK Analysis
For each regimen of each part, dexlansoprazole plasma concentrations and PK parameter estimates 
will be tabulated and descriptive statistics computed.
For each part, analysis of variance (ANOVA) will be performed on natural logarithms of 
dexlansoprazole Cmax and AUC with factors for sequence, the subject nested within sequence, 
period and regimen. The factor of the subject nested within sequence will be the error term for 
testing the sequence effect. Other factors will be tested with the residual as the error term. For the 
relative BA determination, pairwise comparisons will be performed to assess the relative BA of 
dexlansoprazole via point estimates and 90% CI for the ratio of Cmax and AUC central values of the 
dexlansoprazole 30 mg or 60 mg capsules manufactured at TOB compared with the respective 
dexlansoprazole 30 mg or 60 mg capsules manufactured at TPC. A conclusion of BE in the PK of 
dexlansoprazole between test regimen (dexlansoprazole capsule - TOB) and the reference regimen 
(dexlansoprazole capsule - TPC) will be reached if the 90% CIs for Cmax and AUC are within the 
(0.80-1.25) interval. 
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Statistical analyses of other plasma PK parameters will be performed if appropriate.
11.1.4 PD Analysis 
NA
11.1.5 Safety Analysis
11.1.5.1 AEs
AEs will be summarized using the safety analysis set. AEs that started or worsened in severity 
after the first dose of study drug will be summarized by regimen. AEs will be classified according 
to MedDRA® system organ class, high-level term and preferred term. Summary tables for AEs 
will include numbers and percentages of subjects experiencing AEs by system organ class and 
preferred term. The following summary tables will be included in the report by intervals: summary 
of AEs, drug-related AEs, relationship of AEs to study drug, severity of AEs and related AEs. AEs 
leading to study drug discontinuation and SAEs will be listed.
11.1.5.2 Clinical Laboratory Evaluation
Baseline, postdose, and change from Baseline to postdose laboratory values will be summarized 
by regimen utilizing descriptive statistics. Criteria for markedly abnormal laboratory values
(markedly abnormal values [MAVs]) will be presented and the number and percentage of subjects 
with at least 1 markedly abnormal laboratory test result will also be summarized by regimen.
11.1.5.3 Vital Signs
Baseline, postdose, and change from Baseline to postdose vital sign values will be summarized by 
regimen utilizing descriptive statistics. Criteria for markedly abnormal vital sign values (MAVs) 
will be presented.
11.1.5.4 Other Safety Parameters
Physical examination findings will be presented in the data listings.
ECGs will be summarized by treatment and point of time of collection. Shift tables for character 
ECG results will be provided overall to tabulate the number and percentage of subjects who 
changed status after dosing.
Interim Analysis and Criteria for Early Termination
11.2
NA
Determination of Sample Size
11.3
For each part, a sample size of 60 (30 per sequence) will be used in this study. This sample size will 
allow for up to 6 dropouts (10.0% dropout rate) and provide 90% probability of concluding
equivalence on dexlansoprazole Cmax between the 2 regimens if the true difference between 
dexlansoprazole Cmax central values from 2 regimens is no more than 5%. The power for 
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concluding equivalence on dexlansoprazole AUC between 2 regimens would be over 95%. This 
sample size was based on the intrasubject variance of 0.0884 for log(Cmax) and 0.0365 for 
log(AUC) from the Part 1 (30 mg) of the TAK-390MR-1001 study. Part 1 was used because the 
intrasubject variance of log(Cmax) was higher than in Part 2 (60 mg).
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
Study-Site Monitoring Visits
12.1
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 verificatio n of data 
recorded on the CRFs. 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, trial drug, subject medical records, informed consent documentation, and 
review of CRFs 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.
Protocol Deviations
12.2
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial 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.
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.
Quality Assurance Audits and Regulatory Agency Inspections
12.3
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 guarantees access for quality assurance auditors to all study 
documents as described in Section 12.1.
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13.0
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 International Council for Harminsation (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 A. The principles of Helsinki are addressed through 
the protocol and through appendices containing requirements for informed consent and 
investigator responsibilities.
IRB and/or IEC Approval
13.1
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, the Investigator’s Brochure, a copy of 
the ICF, 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/notify site 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 trial. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
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 or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and 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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Subject Information, Informed Consent, and Subject Authorization
13.2
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 ICF, 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 ICF 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 ICF 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 ICF 
and, if applicable, the subject authorization form. The ICF, 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 ICF, 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 ICFand 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 ICF 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 ICF, 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.
All revised ICFs 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 
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revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
Subject Confidentiality
13.3
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 study database or documentation via a unique 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 its monitor or designee’s monitor, 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 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 13.2).
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 CRF).
Publication, Disclosure, and Clinical Trial Registration Policy
13.4
13.4.1 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 clinical 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 Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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13.4.2 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 American 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.
13.4.3 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.
Insurance and Compensation for Injury
13.5
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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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
Administrative Information
14.1
14.1.1 Study Contact Information 
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
Fax: 224-554-1052
Email: PVSafetyAmericas@tpna.com
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14.1.2 INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert 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 Council for 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 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C 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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14.1.3 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.
14.1.4 Protocol Amendment 01 Summary of Changes
Rationale for Amendment No. 01
The purpose of this amendment is to update the protocol to exclude true abstinence as an 
acceptable method of contraception. For specific descriptions of text changes and where the 
changes are located, see Appendix F.
14.1.5 List of Abbreviations
λz
terminal disposition phase rate constant
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC∞
AUC from time 0 to infinity
AUClast
AUC from time 0 to time of the last quantifiable concentration
BA
bioavailability
BE
bioequivalence
BMI
body mass index
CI
confidence interval
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed concentration
CRF
case report form
CRO
contract research organization
CS
clinically significant
CYP
cytochrome P-450
DNA
deoxyribonucleic acid
ECG
electrocardiogram
EDTA
ethylenediamine tetraacetic acid
EE
erosive esophagitis
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
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hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IBD
international birth date
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IND
Investigational New Drug
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
kcal
kilocalories
LFT
liver function test
MAV
markedly abnormal value
MedDRA®
Medical Dictionary for Regulatory Activities
NCS
not clinically significant
NDA
New Drug Application
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PPI
proton-pump inhibitor
PTE
pretreatment event
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
tmax
time to first occurrence of Cmax
ULN
upper limit of normal
US
United States
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration.
WHO
World Health Organization Drug Dictionary
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15.0
DATA HANDLING AND RECORD KEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
CRFs
15.1
The Sponsor or its designee will supply investigative sites with access to CRFs. The Sponsor or its 
designee will train appropriate site staff in the use of the CRF. These forms are used to transmit the 
information collected in the performance of this study to the Sponsor and regulatory authorities. 
CRFs must be completed in English. 
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 CRFs for completeness and accuracy and must sign and 
date the appropriate CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the CRFs should be made by the investigator with use of change and modification records of the 
CRFs. The principal investigator must review the data change for completeness and accuracy, and 
must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. 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 CRFs. The completed CRFs 
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.
Record Retention
15.2
The investigator agrees to keep the records stipulated in Section 15.1 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), 
copy of CRFs, including the audit trail, and detailed records of drug disposition to 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, 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 
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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 Clinical Study Site Agreement 
between the investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
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16.0
REFERENCES
1. Dexilant (dexlansoprazole) Delayed Release Capsules. Full Prescribing Information. 
Deerfield, IL: Takeda Pharmaceuticals America, Inc., Revised October 2016.
2. Guidance Document - Comparative Bioavailability Standards: Formulations Used for System 
Effects, Health Canada. July 2018.
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17.0
APPENDICES
Appendix A
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 investigator(s) 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 by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. 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.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. 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.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. 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.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
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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.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject, as 
applicable: 
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.
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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 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. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. 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 medication(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.
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f)
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 signing the informed consent and throughout the duration of the 
study, and for 30 days after the last dose of study drug. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. 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. 
g) Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 30 after the 
last dose of study drug. If the partner or wife of the subject is found to be pregnant during 
the study, 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 C
Investigator Consent to the 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 medication.

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.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Dexlansoprazole Delayed-Release Capsules
Study No. TAK-390MR-1002
Page 68 of 77
Protocol – Amendment 1
09 January 2019
Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 30 days after last 
dose of study drug, nonsterilized** male subjects who are sexually active with a female partner of 
childbearing potential* must use barrier contraception (eg, condom with or without spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period. Females 
of childbearing potential who are partners of male subjects are also advised to use additional 
contraception as shown in the list containing highly effective/effective contraception below.
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 30 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/effective method of contraception (from 
the list below). 
In addition they must be advised not to donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
* A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as 
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 year 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.
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).
–
Bilateral tubal occlusion.
–
Vasectomised partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomised partner has received medical assessment of the 
surgical success.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Dexlansoprazole Delayed-Release Capsules
Study No. TAK-390MR-1002
Page 69 of 77
Protocol – Amendment 1
09 January 2019

Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the 
efficacy of the contraception method (Evaluate on compound-by-compound and protocol –
by-protocol basis and obtain clinical pharmacology justification).
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 90 days 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 90 days;

Oral †.

Intravaginal † (eg, ring).

transdermal †.
–
Progestogen-only hormonal contraception associated with inhibition of 
ovulationinitiated at least 90 days 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 90 days;

oral †.

Injectable.

Implantable.
2. Effective methods of contraception (there may be a higher than 1% failure rate) are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams PLUS male condom).

Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action PLUS condom with or without spermicide.
3. Unacceptable methods of contraception are:

Sexual abstinence is NOT an acceptable method of contraception.

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
4. 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, {and 
sperm donation} during the course of the study.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Dexlansoprazole Delayed-Release Capsules
Study No. TAK-390MR-1002
Page 70 of 77
Protocol – Amendment 1
09 January 2019
5. During the course of the study, regular serum human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for women and all subjects (male and female) will receive 
continued guidance with respect to the avoidance of pregnancy and sperm donation as part of 
the study procedures. Such guidance should include a reminder of the following:
a) contraceptive requirements of the study
b) reasons for use of barrier methods (ie, condom) in males with pregnant partners
c) 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?
6. 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 within 2 daysprior to receiving any 
dose of study medication. In addition, subjects must also have a negative serumhCG pregnancy 
test within 2 days prior to receiving first dose of investigational drug as close as possible and 
prior to first dose of investigational drug, preferably on the same day.
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

contraceptive requirements of the study.

reasons for use of barrier methods (ie, condom) in males with pregnant partners.

assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)?
–
Is there a chance you could be pregnant?
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
Sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 30 days after the last dose, should also be recorded 
following authorization from the subject’s partner. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Dexlansoprazole Delayed-Release Capsules
Study No. TAK-390MR-1002
Page 71 of 77
Protocol – Amendment 1
09 January 2019
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 (blinded or 
unblinded, as applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug 
(including comparator, if applicable) will be followed up to final outcome, using the pregnancy 
form. Pregnancies will remain blinded to the study team. The outcome, including any premature 
termination, must be reported to the Sponsor. An evaluation after the birth of the child will also be 
conducted.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Dexlansoprazole Delayed-Release Capsules
Study No. TAK-390MR-1002
Page 72 of 77
Protocol – Amendment 1
09 January 2019
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples
1. Collect 4 mL of venous blood into a chilled Becton-Dickinson Vacutainer. All 
dexlansoprazole 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 a relative centrifugal force of approximately 1100 
to 1300 in a refrigerated centrifuge. Note: if using a collection device other than the 
Becton-Dickinson Vacutainer, 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 0.6 mL needs to be obtained for
each sample. Labeling may include protocol number [TAK-390MR-1002], sample matrix (ie, 
plasma), randomization number, period, nominal day and time, analyte (dexlansoprazole), 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 
. No more 
than 45 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 standard operating 
procedures (SOPs) for labeling, packaging, or shipping of PK samples.
1. Biological samples should be shipped on sufficient dry ice to prevent thawing during transit. 
Samples should be shipped to arrive at the destination during normal business hours (local 
time). For US domestic shipments, it is recommended that samples be shipped on Monday, 
Tuesday or Wednesday and 2 days before a national holiday, in order to minimize the 
possibility of samples arriving at their destination on a weekend or holiday. For shipments 
outside these periods, and for international shipments, it is recommended that a premium 
carrier who will replenish dry ice during shipment as necessary be used. Other shipping 
arrangements may be allowed with the agreement of the Sponsor. 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 a self-sealing bag (eg, Ziploc) containing additional 
absorbent material.
5. Using a permanent marker, write the 4-digit randomization sequence number, sample matrix 
(ie, plasma), number of samples, and “SET 1” on each self-sealing bag.
Property of Takeda: For non-commercial use onl
nd subject to the applicable Terms of Use
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CCI


Dexlansoprazole Delayed-Release Capsules
Study No. TAK-390MR-1002
Page 73 of 77
Protocol – Amendment 1
09 January 2019
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. 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 medication (dexlansoprazole delayed-release capsule), 
protocol number (TAK-390MR-1002), investigator’s name, sample type (ie, plasma), 
randomization number, period, nominal 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 to 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 polystyrene plastic (eg, 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 
polystyrene plastic container. Place the lid on the polystyrene plastic container and seal 
completely with strapping tape. Place the polystyrene plastic 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 dexlansoprazole delayed-release capsules:
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)
Property of T
12.
12. A
-commercial use only and subject to the applicable Terms of Use
clude the
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PPD


Dexlansoprazole Delayed-Release Capsules
Study No. TAK-390MR-1002
Page 74 of 77
Protocol – Amendment 1
09 January 2019
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.
15. After shipping of the samples, please contact the following to notify them of next day delivery.
When calling, provide the following information:
Name of courier or transport company
Time and date the shipment left the clinical site
Airway bill number
Property of Takeda: For non-commercial use only and subject to the
ble Terms of Use
elivery.
ivery
PPD


Dexlansoprazole Delayed-Release Capsules
Study No. TAK-390MR-1002
Page 75 of 77
Protocol – Amendment 1
09 January 2019
Appendix F
Detailed Description of Amendments to Text
The primary change occurs in Appendix D - Pregnancy and Contraception under Definitions and 
Procedures for Contraception and Pregnancy Avoidance. 
Change 1. Removal of true abstinence from the list of highly effective non-hormonal methods of 
contraception.
The primary change occurs in Appendix D - Pregnancy and Contraception under Definitions and 
Procedures for Contraception and Pregnancy Avoidance, Item number 1, Bullet 1.
Initial 
wording:
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).
–
Bilateral tubal occlusion.
–
Vasectomised partner (provided that partner is the sole sexual partner of 
the trial participant and that the vasectomised partner has received 
medical assessment of the surgical success.
–
True sexual abstinence, only if this is in line with the preferred and usual 
lifestyle of the subject. True abstinence is defined as refraining from 
heterosexual intercourse during the entire period of the study, from 
1 month prior to the first dose until 30 days after last dose.
Amended
or new
wording:
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).
–
Bilateral tubal occlusion.
–
Vasectomised partner (provided that partner is the sole sexual partner of 
the trial participant and that the vasectomised partner has received 
medical assessment of the surgical success.
–
True sexual abstinence, only if this is in line with the preferred and usual 
lifestyle of the subject. True abstinence is defined as refraining from 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Dexlansoprazole Delayed-Release Capsules
Study No. TAK-390MR-1002
Page 76 of 77
Protocol – Amendment 1
09 January 2019
heterosexual intercourse during the entire period of the study, from 1 
month prior to the first dose until 30 days after last dose.
Rational for Change:
Clarifies that true abstinence is not an acceptable method of contraception.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Dexlansoprazole Delayed-Release Capsules
Study No. TAK-390MR-1002
Page 77 of 77
Protocol – Amendment 1
09 January 2019
Change 2. Update of the list of unacceptable methods of contraception to include all types of 
abstinence.
The primary change occurs in Appendix D - Pregnancy and Contraception under Definitions and 
Procedures for Contraception and Pregnancy Avoidance, Item number 3.
Initial 
wording:
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation
methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
Amended
or new
wording:
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation
methods).

Sexual abstinence is NOT an acceptable method of contraception

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
Rationale for Change:
Clarifies that all types of abstinence is considered an unacceptable methods of contraception and 
not only periodic abstinence.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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SAP_001.pdf: 


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, Single-Center, Single-Dose, Two-Period, Two-Part 
Crossover Study in Healthy Subjects to Compare the Bioavailability of Dexlansoprazole from 
Dexlansoprazole Delayed-Release Capsules 30 mg and 60 mg Manufactured by Takeda GmbH Plant 
Oranienburg Relative to Dexlansoprazole Delayed-Release Capsules 30 mg and 60 mg Manufactured 
by Takeda Pharmaceutical Company Limited Osaka Plant Following a High-Fat Meal
NCT Number: NCT03801148
SAP Approve Date: 29 January 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information or 
company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
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: TAK-390MR-1002
CELERION STUDY NUMBER: CA24021
A Phase 1, Randomized, Open-Label, Single-Center, Single-Dose, Two-Period, Two-Part 
Crossover Study in Healthy Subjects to Compare the Bioavailability of Dexlansoprazole 
from Dexlansoprazole Delayed-Release Capsules 30 mg and 60 mg Manufactured by 
Takeda GmbH Plant Oranienburg Relative to Dexlansoprazole Delayed-Release Capsules 
30 mg and 60 mg Manufactured by Takeda Pharmaceutical Company Limited Osaka 
Plant Following a High-Fat Meal
PHASE 1
Version: Final
Date: 29 January 2019
Prepared by:
Based on:
Protocol Dated: 17 December 2018
Protocol Amendment 1: 09 January 2019
PPD
Property of Taked
d on:
d on:
mmercial use only and subject to the applicable Terms of Use
Dose, Tw
ose, T
availabi
availab
mg and 
g and
nsopraz
opra
rmaceut
maceu
High
gh-Fa
F
HASE 1
ASE 1
Vers
Ver
Date
Dat
Pr
P
eda: For non-com


TAK-390MR-1002
Celerion Study Number CA24021
Page 2 of 19
Statistical Analysis Plan Final
29 January 2019
1.1
Approval Signatures
Study Title:
A Phase 1, Randomized, Open-Label, Single-Center, Single-Dose, 
Two-Period, Two-Part Crossover Study in Healthy Subjects to Compare the 
Bioavailability of Dexlansoprazole from Dexlansoprazole Delayed-Release 
Capsules 30 mg and 60 mg Manufactured by Takeda GmbH Plant 
Oranienburg Relative to Dexlansoprazole Delayed-Release Capsules 30 mg 
and 60 mg Manufactured by Takeda Pharmaceutical Company Limited 
Osaka Plant Following a High-Fat Meal
Date
Date
Date
Date
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
 the
he
elease
elease
sules 30
ules 3
ny
ny Limi
Lim
y
ti
e applic
keda: For non-commercial use only and subject to the


TAK-390MR-1002
Celerion Study Number CA24021
Page 3 of 19
Statistical Analysis Plan Final
29 January 2019
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
Hypothesis.................................................................................................................6
4.2
Primary Objectives ....................................................................................................6
4.3
Secondary Objective..................................................................................................6
4.4
Study Design .............................................................................................................6
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoint.......................................................................................................9
5.2
Additional Endpoints .................................................................................................9
5.3
Safety Endpoints........................................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Study Definitions ...............................................................................................12
7.1.2
Definition of Study Days....................................................................................12
7.2
Analysis Sets ...........................................................................................................12
7.3
Disposition of Subjects ............................................................................................13
7.4
Demographic and Other Baseline Characteristics.....................................................13
7.5
Medical History and Concurrent Medical Conditions...............................................13
7.6
Medication History and Concomitant Medications...................................................13
7.7
Study Drug Exposure and Compliance.....................................................................14
7.8
Efficacy Analysis.....................................................................................................14
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................14
7.9.1
Pharmacokinetic Analysis ..................................................................................14
7.9.2
Pharmacodynamic Analysis ...............................................................................15
7.10
Other Outcomes.......................................................................................................15
7.11
Safety Analysis........................................................................................................16
7.11.1 Adverse Events ..................................................................................................16
7.11.2 Clinical Laboratory Evaluations .........................................................................16
7.11.3 Vital Signs .........................................................................................................17
7.11.4 12-Lead ECGs ...................................................................................................17
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7.11.5 Physical Exams..................................................................................................18
7.11.6 Overdose............................................................................................................18
7.12
Interim Analysis ......................................................................................................18
7.13
Preliminary Analysis................................................................................................18
7.14
Changes in the Statistical Analysis Plan...................................................................18
8.0
REFERENCES..............................................................................................................19
LIST OF IN-TEXT TABLES
Table 4.a
Part 1 Sequences..................................................................................................7
Table 4.b
Part 2 Sequences..................................................................................................7
Table 7.a
Collection of Blood Samples for Pharmacokinetic Analysis ...............................14
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ..................................................................................7
Figure 4.b
Schematic ............................................................................................................8
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
AUC
area under the curve
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUClast
area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
Cmax
maximum observed plasma concentration
CPAP
Clinical Pharmacology Analysis Plan
CRF
case report form
CS
clinically significant
CSR
clinical study report
CV
coefficient of variation
DMP
Data Management Plan
ECG
electrocardiogram
eCRF
electronic case report form
Geom CV
geometric coefficient of variation
Geom Mean
geometric mean
ICF
informed consent form
ICH
International Conference on Harmonisation
λz
Terminal disposition phase rate constant
ln
natural log
LSM
least-square means
Mean
arithmetic mean
MedDRA
Medical Dictionary for Regulatory Activities
PI
Principal Investigator
PK
pharmacokinetics
SAE
serious adverse event
SD
standard deviation
SEM
standard error of the mean
SOC
system organ class
t½z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
TFL
tables, figures and listings
tmax
time to first occurrence of Cmax
WHO
World Health Organisation
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4.0
OBJECTIVES
4.1
Hypothesis
A conclusion of bioequivalence (BE) in the pharmacokinetics (PK) of dexlansoprazole between 
test products (dexlansoprazole capsule – Takeda GmbH Plant Oranienburg (TOB)) and the 
reference product (dexlansoprazole capsule – Takeda Pharmaceutical Company Ltd. (TPC)) will 
be reached if the 90% confidence interval (CI) for the ratio of Cmax TOB to Cmax TPC and the 
90% CI for the ratio of AUC TOB to AUC TPC are each within the (0.80, 1.25) interval.
4.2
Primary Objectives

To assess the bioavailability (BA) of dexlansoprazole from a 30 mg capsule manufactured at 
TOB relative to that of dexlansoprazole from a 30 mg capsule manufactured at TPC.

To assess the BA of dexlansoprazole from a 60 mg capsule manufactured at TOB relative to 
that of dexlansoprazole from a 60 mg capsule manufactured at TPC.
4.3
Secondary Objective
To evaluate the safety and tolerability of dexlansoprazole following oral administration of a 
single dexlansoprazole 30 or 60 mg capsule.
4.4
Study Design
This is a phase 1, randomized, open-label, single-center, single-dose, 2-part, 2-way crossover 
study in healthy subjects to assess the BA of 30 or 60 mg dexlansoprazole capsules 
manufactured at TOB relative to the corresponding 30 or 60 mg dexlansoprazole capsules 
manufactured at TPC under fed conditions. The study will be conducted in 2 parts. In Part 1, 
60 healthy subjects will receive dexlansoprazole 30 mg capsules manufactured by TOB and TPC 
in a crossover fashion. In Part 2, an additional 60 healthy subjects will receive dexlansoprazole 
60 mg capsules manufactured by TOB and TPC in a crossover fashion. Due to the difference 
between the Granules-L used in the 30 mg (Granules-LL) and 60 mg (Granules-LS) capsules, the 
relative BA of both dosage strengths will be assessed.
At Check-in (Day -1 of Period 1), approximately 120 subjects in total (60 in Part 1, 60 in Part 2), 
including both men and women, aged 18 to 55 years, inclusive, will be selected to participate in 
the study. Subjects who satisfy the Screening evaluation and selection criteria may be enrolled in 
the study. For each part, eligible subjects will be randomized on Day 1 of Period 1 in a 1:1 ratio 
to 1 of 2 sequences, which defines the order in which they will receive dexlansoprazole regimens 
in Periods 1 and 2. The dosing between periods will be separated by a minimum 5-day washout 
interval. During Periods 1 and 2, blood samples will be collected predose and over 24 hours 
postdose to measure dexlansoprazole plasma concentrations.
The treatment sequences are outlined in Table 4.a (Part 1) and Table 4.b (Part 2).
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Table 4.a
Part 1 Sequences
Sequences
Number of 
Subjects
Period 1
Period 2
1
30
A
B
2
30
B
A
Regimen A (test): A single dexlansoprazole 30 mg capsule manufactured at TOB administered orally on Day 1 
30 minutes following the beginning of a high-fat/high calorie breakfast.
Regimen B (reference): A single dexlansoprazole 30 mg capsule manufactured at TPC administered orally on Day 1 
30 minutes following the beginning of a high-fat/high calorie breakfast. 
Table 4.b
Part 2 Sequences
Sequences
Number of 
Subjects
Period 1
Period 2
3
30
C
D
4
30
D
C
Regimen C (test): A single dexlansoprazole 60 mg capsule manufactured at TOB administered orally on Day 1 
30 minutes following the beginning of a high-fat/high calorie breakfast.
Regimen D (reference): A single dexlansoprazole 60 mg capsule manufactured at TPC administered orally on Day 1 
30 minutes following the beginning of a high-fat/high calorie breakfast. 
Subjects were screened up to 28 days prior to dosing, to determine eligibility before 
randomization. Eligible subjects returned to the clinic at Check-in (Day -1). 
A schematic of the study design is included as Figure 4.a.
Figure 4.a
Schematic of Study Design
Screening 
Period
Check-in
(Periods 1 
and 2)
Treatment Periods 1 and 2
Study Exit 
(Period 2)
Follow-up
Phone Call
Dexlansoprazole 30 
and 60 mg capsule 
Single Dose PK
Discharge
(Period 1)
Days -28 to -2
Day -1
Day 1
Day 2 Period 1
Day 2
Day 10 (±2 
days)
Confinement 
Note: There is a minimum 5-day washout period between the dose in Period 1 and the dose in Period 2. A follow-up 
phone call will be made for collection of adverse events (AEs), serious adverse events (SAEs), and concomitant 
medications taken since the final dose.
A schematic of the crossover design is included as Figure 4.b.
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Figure 4.b
Schematic
In each period of each part, subjects will be confined from Check-in Day -1 until all study 
procedures have been completed on Day 2. Study drug will be administered in the morning of
Day 1 of each period 30 minutes following the beginning of a high-fat/high calorie breakfast. 
The entire standardized breakfast is to be consumed within 25 minutes. Dosing may be staggered 
to help facilitate logistics at the site. Subjects will be instructed to swallow the intact capsule 
with 240 mL of water.
Subjects will be discharged from the study site on Day 2 of each period (subjects will exit the 
study on Day 2 of Period 2 within each part).
A follow-up phone call will be made 10 (±2) days post last dose of study drug to inquire for any 
ongoing AEs or serious adverse events (SAEs), as well as new AEs or SAEs, and concomitant 
medications taken since final dose. Subjects who received at least one dose of study drug and 
terminate from the study early will still be contacted for a safety follow-up call. The contact will 
only be recorded in their source documents and the case report forms (CRFs), according to data 
protection regulations.
Primary completion date will be based on the final data collection for the primary endpoint, 
Day 2 of Period 2. End of trial (study completion date) will be based on the final data collection 
date for the entire study, which is the follow-up phone call.
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoints of the study are the following plasma PK parameters of dexlansoprazole 
derived on Day 1 of each period:

Maximum observed concentration (Cmax).

Area under the plasma concentration-time curve (AUC) from time 0 to time of the last 
quantifiable concentration (AUClast).

AUC from time 0 to infinity (AUC∞).
5.2
Additional Endpoints
The following additional plasma PK parameters for dexlansoprazole will be calculated:

Percent of AUC∞extrapolated (AUC%extrap).

Time to first occurrence of Cmax (tmax).

Terminal disposition phase half-life (t½z).

Terminal disposition phase rate constant (λz).

Apparent clearance after extravascular administration (CL/F).

Apparent volume of distribution during the terminal disposition phase after extravascular 
administration (Vz/F).
5.3
Safety Endpoints
Safety will be assessed by summarizing the incidence of AEs, clinical laboratory values, physical 
examinations, ECGs, and vital signs.
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6.0
DETERMINATION OF SAMPLE SIZE
For each part, a sample size of 60 (30 per sequence) will be used in this study. This sample size 
will allow for up to 6 dropouts (10.0% dropout rate) and provide 90% probability of concluding 
bioequivalence on dexlansoprazole Cmax between the 2 regimens if the true difference between 
dexlansoprazole Cmax central values from 2 regimens is no more than 5%. The power for 
concluding equivalence on dexlansoprazole AUC between 2 regimens would be over 95%. This 
sample size was based on the intrasubject variance of 0.0884 for log(Cmax) and 0.0365 for 
log(AUC) from the Part 1 (30 mg) of the TAK-390MR-1001 study. Part 1 was used because the 
intrasubject variance of log(Cmax) was higher than in Part 2 (60 mg).
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All PK analyses will be conducted using Phoenix® WinNonlin® Version 7.0, or higher. All 
statistical analyses will be conducted using SAS® Version 9.3, or higher. All analyses will be 
performed by study part separately. All data recorded on the CRF will be listed by subject. All 
tables, figures and listings (TFLs) shells and numbering list will be included in the Clinical 
Pharmacology Analysis Plan (CPAP).
Arithmetic mean (mean), median, and geometric mean (Geom Mean) values will be presented to 
1 more level of precision than the individual values. Standard deviation (SD) and standard error 
of the mean (SEM) will be presented to 2 more levels of precision than the individual values. 
Minimum and maximum values will be presented to the same precision as the individual values. 
Arithmetic percent coefficient of variation (CV%) and geometric percent coefficient of variation 
(Geom CV%) will be presented to 1 decimal place. 
Geometric least-squares means (LSMs) will be reported with 1 more level of precision than the 
recorded data. Geometric LSMs are least-squares means derived from the analysis of variance 
(ANOVA) model for the analyses of ln-transformed AUClast, AUC∞, and Cmax which have been 
exponentiated to provide estimates on the original scale. The difference in the LSM on the 
ln-scale and associated 90% CIs will be exponentiated to produce geometric mean ratios (GMRs) 
and 90% CIs around the ratio and will be reported using 2 decimal places. These ratios will be 
expressed relative to the reference treatment (i.e., Treatments B and D, for Parts 1 and 2, 
respectively). 
Concentration values below the limit of quantitation (BLQ) will be presented as ‘BLQ’ in the 
concentration table listings and footnoted accordingly. BLQ values will be treated as zero for the 
calculation of summary statistics, the generation of concentration plots, and the calculation of PK 
parameters, unless they are obvious outliers (e.g. BLQ value between 2 measurable values), in 
which case they will be treated as missing.
For the calculation of PK parameters, if actual times are missing, nominal times will be used 
instead.
A subject’s PK parameter data will be included in the listings but excluded from the descriptive 
statistics and statistical evaluation if one or more of the following criteria are met: 

A predose (0 hr) concentration is greater than 5% of that subject’s Cmax value in that period. 

A subject did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic 
Scientist).

A subject deviates substantially from the protocol defined study procedures including but not 
limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by the 
Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist).
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The details on PK parameter calculations will be outlined in the CPAP including specifics on the 
following:

Insufficient data to determine a reliable t½ value and other terminal disposition phase rate 
constant dependent parameters.

PK parameters presented by treatment, including the units, precision, and summary statistics 
that will be presented in in-text and end-of-text tables.

Concentration data presented by treatment, including the units, precision, and summary 
statistics that will be presented in end-of-text tables.

Concentration data file used for PK analysis.

PK parameter WinNonlin® output file used to generate the TFLs.

ANOVA results presented in in-text and end-of-text tables.

Arithmetic mean concentration-time figures presented as in-text and end-of-text figures.

Individual concentration-time figures presented in Appendix 16.2.6.
For demographic data where appropriate, variables will be summarized descriptively by 
treatment sequence and overall for each part. For the categorical variables, the count and 
proportions of each possible value will be tabulated by treatment sequence, and overall for each 
part, where applicable. The denominator for the proportion will be based on the number of 
subjects who provided non missing responses to the categorical variable. For continuous 
variables, the number of subjects with non-missing values, mean, SD, minimum, median, and 
maximum values will be tabulated.
7.1.1
Study Definitions
7.1.2
Definition of Study Days
Day 1 for each period of each part is defined as the date on which a subject is administered their 
first dose of the study drug(s) in each period. Other study days are defined relative to Day 1 with 
Day -1 being the day prior to Day 1 of each period. Study day prior to the first dose of each 
treatment will be calculated as: date of assessment/event-date of treatment; study day on or after 
the date of first dose will be calculated as: date of assessment/event-date of treatment +1.
7.2
Analysis Sets
Safety Set:
All subjects who enrolled into the study and received at least one dose of the study drug(s) will 
be included in the safety set. Subjects in this analysis set will be used for demographic, baseline 
characteristics and safety summaries.
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PK Set:
Samples from all subjects will be assayed even if the subjects did not complete the study. All 
subjects in the safety set who have at least 1 valid plasma concentration of dexlansoprazole will 
be in the PK set. All subjects who comply sufficiently with the protocol and display an evaluable 
PK profile (eg, exposure to treatment, availability of measurements and absence of major 
protocol violations) will be included in the statistical analyses. In terms of criteria for evaluable 
subjects, please see CPAP.
7.3
Disposition of Subjects
For each study part, disposition of subjects (number of subjects dosed, completed the study, 
discontinued from the study, and reason(s) for discontinuation) will be summarized for each 
treatment sequence and overall. Study completion status, including reason for discontinuation, 
will also be listed by subject. 
7.4
Demographic and Other Baseline Characteristics
For each study part, demographic and baseline characteristics will be summarized by treatment 
sequence and overall. Summary statistics (number of subjects [n], mean, SD, minimum, median, 
and maximum) will be generated for continuous variables (age [calculated from the date of 
signed Informed Consent Form [ICF], weight, height and body mass index [BMI]) and the 
number and percentage of subjects within each category will be presented for categorical 
variables (sex, race, and ethnicity). Height, weight, and BMI collected at screening will be used 
in the baseline summaries. Height will be recorded without decimals and weight will be recorded 
with one decimal place. BMI will be calculated using the following formula: weight (kg)/[height 
(m)]2 and will be recorded with one decimal place by rounding. Demographics data will also be 
listed as recorded on the CRF, including the date of informed consent. 
7.5
Medical History and Concurrent Medical Conditions
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 before signing the 
ICF. Ongoing conditions are considered concurrent medical conditions. Concurrent medical 
conditions are those significant ongoing conditions or diseases that are present at signing the 
ICF. Each subject’s medical history and concurrent medical conditions will be listed. Any 
medical condition started after taking the study drug will be classified as an adverse event. The 
medical history listing will include whether the event was medical or surgical, the body system 
or organ class involved, start date (if known) and end date or whether the condition was ongoing, 
and a description of the condition or event. There will be no statistical analysis of medical 
history.
7.6
Medication History and Concomitant Medications
Medication history to be obtained includes any medication relevant to eligibility criteria and
efficacy/safety evaluation stopped at or within 28 days prior to signing the ICF. Concomitant 
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medication includes any medication other than study drug taken at any time between time of 
signing the ICF through the end of the study (including follow-up visit). All medication history 
and concomitant medications recorded during the study will be coded with the World Health 
Organization (WHO) Dictionary, as described in the Data Management Plan (DMP), and listed. 
If appropriate, the listing will include the medication name, coded term, dosage, route of 
administration, start date and time (if known), end date and time, or whether it continued after 
study completion, and indication for use. 
7.7
Study Drug Exposure and Compliance
Not applicable.
7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Blood samples (one 4 mL sample per scheduled time) for PK analysis of dexlansoprazole will be 
collected as specified in Table 7.a following administration of different formulations on Day 1 of 
each period of each part under fed conditions.
Table 7.a
Collection of Blood Samples for Pharmacokinetic Analysis
Sample 
Type
Dosing Day
Time (hours)
(Periods 1 and 2)
Plasma
1
Predose (within 1 hour prior to dose) and at 1, 2, 3, 4, 5, 6, 6.5, 7, 8, 10, 12, 
14, 16, and 24 hours postdose.
The actual date and time of sample collection will be recorded on the source document and 
electronic case report form (eCRF).
The PK parameters of dexlansoprazole will be listed in the CPAP for this study and will be 
determined from the concentration-time profiles for subjects in the PK set using a 
noncompartmental analysis method. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. If actual sample times are 
missing, nominal times may be used.
Concentrations will be listed and summarized descriptively by PK sampling time. Summary will 
be done by treatment using the summary statistics listed in the CPAP. Excluded concentrations 
will be presented and footnoted as such in the concentration table listings, and those values will 
be excluded from the descriptive summary statistics. Individual subject and arithmetic mean 
profiles of the concentration-time data will be plotted by treatment on linear (with and without 
SD) and semi-log scales. For summary statistics and arithmetic mean plots by sampling time, the 
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nominal PK sampling time will be used, for individual subject plots by time, the actual PK 
sampling time will be used. 
PK parameters will be summarized descriptively by treatment using the summary statistics listed 
in the CPAP. Excluded parameters will be presented and footnoted as such in the PK parameter 
table listings, and those values will be excluded from the descriptive summary statistics. 
Relative Bioavailability (Treatments A-D)
For each study part, natural log (ln)-transformed AUClast, AUC∞, and Cmax will be analyzed 
using an ANOVA model to assess the relative bioavailability of dexlansoprazole 30 mg or 60 mg 
capsules manufactured at TOB compared with the respective dexlansoprazole 30 mg or 60 mg 
capsules manufactured at TPC. The model will include sequence, treatment, and period as fixed 
effects, and subject nested within sequence as a random effect. Each ANOVA will include 
calculation of LSM as well as the difference between treatment LSM. Geometric LSM ratios will 
be calculated using the exponentiation of the difference between treatment LSM from the 
analyses on the ln-transformed AUClast, AUC∞, and Cmax. These ratios will be expressed relative 
to the reference treatments (ie, Treatments B and D, for Parts 1 and 2, respectively). The 
following SAS® code will be used by study part for the analysis:
PROC MIXED DATA=XXXX;
CLASS Sequence Treatment Period Subject;
MODEL <PK_Parameter> = Sequence Treatment Period / DDFM=KR;
RANDOM Subject(Sequence);
/*For Part 1*/
ESTIMATE ‘Treatment A vs B ‘ Treatment 1 -1 / CL ALPHA = 0.10 E;
/*For Part 2*/
ESTIMATE ‘Treatment C vs D ‘ Treatment 1 -1 / CL ALPHA = 0.10 E;
LSMEANS Treatment;
Run;
Consistent with the two one-sided test, 90% CIs for the ratios will be derived by exponentiation 
of the CIs obtained for the difference between treatment LSM resulting from the analyses on the 
ln-transformed AUClast, AUC∞, and Cmax. The CIs will be expressed as a ratio relative to the 
reference treatments (ie, Treatments B and D, for study parts 1 and 2, respectively). 
Bioequivalence (Treatment A versus Treatment B and Treatment C versus Treatment D) will be 
claimed if the 90% CIs of the ratios of geometric LSMs of PK parameters AUClast, AUC∞, and 
Cmax of TAK-831 fall entirely within (0.80, 1.25).
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
Not applicable.
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7.11
Safety Analysis
For each study part, safety will be evaluated by the incidence of treatment-emergent adverse 
events (TEAEs), severity and type of TEAEs, changes from baseline in the subjects’ clinical 
laboratory results, vital signs, and ECG’s using the safety set. Reasons for discontinuation will 
be tabulated. All clinical safety data will be listed by subject and assessment time points, 
including rechecks, unscheduled assessments, and early termination, chronologically. 
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators.
7.11.1 Adverse Events 
For each study part, all AEs captured in the database will be listed in by-subject data listings 
including verbatim term, coded term, severity (mild, moderate or severe), relationship to study 
drug (s) (related or not related), action relative to the study drug(s), and procedures. All AEs 
occurring during this study will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®), as described in the DMP. However, only TEAEs occurring after administration of 
the first dose of study drug and through the end of the study (approximately 10 (± 2) days after 
the last dose of investigational product administration) will be summarized. A TEAE is defined 
as an AE that is starting or worsening at the time of or after study drug administration. 
For each study part and treatment, TEAEs will be coded using MedDRA® and tabulated by 
System Organ Class (SOC) and Preferred Term. Summary tables will include number of subjects 
reporting the AE and as percent of safety set by treatment. The most commonly reported TEAEs 
(i.e., those events reported by >5% of all subjects in each treatment group or at least 2 subjects, 
excluding SAEs) will also be summarized. For the list of all AE summary tables see CPAP.
In addition, TEAEs will be summarized as number of AEs and percentage of AEs for each 
treatment for the overview of TEAEs. 
Additional TEAE summary tables will be presented by severity and relationship to study drug. If 
a subject has multiple AEs with different severity levels within the same term, the subject will be 
counted in the most severe category only. If a subject has both related and unrelated AEs with 
the same term, the subject will be counted as having related TEAEs only. 
Should any SAEs occur they will be summarized the same way as TEAE. All AEs will be 
displayed in the data listings and TEAEs will be discussed in the text of the study report. AEs 
leading to study drug discontinuation and SAEs will also be listed.
7.11.2 Clinical Laboratory Evaluations
Hematology, serum chemistry, and urinalysis will be performed at screening, check-in (Day -1) 
and Day 2 in each period, or upon early termination. In addition, laboratory safety tests may be 
performed at various unscheduled time points, if deemed necessary by the Principal Investigator 
(PI).
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For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by treatment and assessment time 
points, by study part. Change from baseline will be summarized. Baseline is defined as the last 
assessment including rechecks taken prior to dosing in each period (Day -1). 
For each laboratory test, a shift table will be developed comparing the frequency of the results at 
treatment baseline (above normal (H), normal (N), or below normal (L)) with those postdose 
time points for each regimen. For urinalysis tests, the categories are normal (N) and abnormal 
(A). Out-of-range values and corresponding recheck results will be listed. 
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. If a value fails the reference range, it will 
automatically be compared to a clinically significant (CS) range. If the value falls within the CS 
range, it will be noted as “N” for not clinical significant. If the value fails the CS range, it will be 
flagged with a “Y” which prompts the PI to determine how the out-of-range value should be 
followed using 4 Investigator flags: “N”, not clinically significant, “R”, requesting a recheck, 
“^”, checking at the next scheduled visit, or “Y”, clinically significant. All clinically significant 
laboratory tests and the corresponding values will be listed by subject. All clinical laboratory 
data will be presented in by-subject data listings.
7.11.3 Vital Signs
Single measurements of heart rate and blood pressure will be obtained at screening, check-in 
(Day -1), Day 1 predose, Day 1 Hour 8, and Day 2 in each period, or upon early termination. 
Respiration rate, temperature, and orthostatic vital signs are collected at screening only. 
Additional unscheduled vital signs measurements may be taken at other times, if deemed 
necessary by the PI.
For each study part, summary statistics (n, mean, SD, minimum, median, and maximum) will be 
reported for vital sign results (blood pressure and heart rate) and change from baseline by 
treatment and time point of collection. Baseline is defined as the last assessment including 
rechecks taken prior to dosing in each period (Day 1 Predose). Vital signs will also be displayed 
in a data listing by subject.
7.11.4 12-Lead ECGs
Standard 12-lead ECGs will be recorded at screening, check-in (Day -1 of Period 1), Day 2 in 
each period or upon early termination. Additional unscheduled ECGs may be recorded at other 
times if deemed necessary by the PI. 
For each study part, summary statistics (n, mean, SD, minimum, median, and maximum) will be 
reported for ECG results and change from baseline by treatment and time point of collection. 
Baseline is defined as the last assessment including rechecks taken prior to dosing in Period 1 
(Day -1 of Period 1). ECG data will also be displayed in a data listing by subject.
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TAK-390MR-1002
Celerion Study Number CA24021
Page 18 of 19
Statistical Analysis Plan Final
29 January 2019
7.11.5 Physical Exams
A full physical exam will be performed at screening, check-in in each period (Day -1 of 
Periods 1 and 2), and Day 2 of Period 2 or upon early termination. Symptom driven physical 
exams may be performed at other times at the discretion of the PI. Physical exam findings, as 
recorded on the CRF, will be presented in a data listing by subject. Reproductive system findings 
will also be listed by subject.
7.11.6 Overdose 
All cases of overdose will be presented in a data listing by subject. Any AEs associated with 
overdose will be documented as AEs. 
7.12
Interim Analysis
No interim analysis was performed.
7.13
Preliminary Analysis
Analysis will be completed as described in the CPAP and Section 7.9.1 of the SAP, with the 
following changes: (1) QCed data will be used (not QAed); (2) nominal times will be used for 
the calculation of PK parameters (not actual sampling times); (3) tables and figures will be 
created using Phoenix® WinNonlin® Version 7.0.
7.14
Changes in the Statistical Analysis Plan 
The protocol states that values of subjects with markedly abnormal values for clinical laboratory 
tests and vital signs will be presented and tabulated. However, after agreement between Celerion 
and Takeda, it was decided that these would not be presented.
There are no other changes in the statistical analysis plan.
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TAK-390MR-1002
Celerion Study Number CA24021
Page 19 of 19
Statistical Analysis Plan Final
29 January 2019
8.0
REFERENCES
Not applicable.
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