Conditions: Heartburn Gastroesophageal Reflux Disease
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 217
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the efficacy and safety of dexlansoprazole compared to placebo in relief of daytime and nighttime heartburn over 4 weeks in Chinese participants with symptomatic non-erosive Gastroesophageal Reflux Disease (GERD).

Detailed description:
The drug being tested in this study is called dexlansoprazole. Dexlansoprazole is being tested to treat heartburn in people who have non-erosive gastroesophageal reflux disease (GERD). This study will look at heartburn relief in people who take dexlansoprazole.

The study will enroll approximately 200 participants. Participants will be randomly assigned to one of the two treatment groups with 1:1 ratio -which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Dexlansoprazole 30 mg
* Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient.

All participants will be asked to take one capsule at the same time each day throughout the study, and will be asked to record any time they have heartburn symptoms in a diary.

This multi-center trial will be conducted in China. The overall time to participate in this study is up to 7 weeks. Participants will make 4 visits to the clinic, and will be contacted by telephone 5 to 10 days after the last dose of study drug for a follow-up assessment.

Arms:
arm 1: Dexlansoprazole 30 mg, delayed-release capsule, orally, once daily for up to 4 weeks. arm 2: Dexlansoprazole placebo-matching capsules, orally, once daily for up to 4 weeks.

Interventions: intervention 1: Dexlansoprazole intervention 2: Placebo
Intervention descriptions: intervention 1: Dexlansoprazole delayed-release capsule intervention 2: Dexlansoprazole placebo-matching capsules

Protocol document:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A Phase 3 Double Blind Study to Evaluate the Efficacy and Safety of Dexlansoprazole (30 mg 
QD) compared to Placebo on Heartburn Relief in Subjects With Symptomatic Nonerosive 
Gastroesophageal Reflux Disease (GERD)
NCT Number: NCT02873689
Protocol Approve Date: 20 February 2017
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 or company confidential information. 
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.


1.0 TITLE PAGE
PROTOCOL AMENDMENT
A Phase 3 Double Blind Study to Evaluate the Efficacy and Safety of Dexlansoprazole 
(30 mg QD) compared to Placebo on Heartburn Relief in Subjects With Symptomatic 
Nonerosive Gastroesophageal Reflux Disease (GERD)
Sponsor:
Takeda Development Center Asia, Pte. Ltd.
21 Biopolis Road, Nucleos North Tower, Level 4, Singapore 138567
Study Number:
TAK-390MR_302
IND Number:
Not Applicable
EudraCT Number:
Not Applicable 
Compound:
Dexlansoprazole Capsules
Date:
20 February 2017
Amendment Number:
03
Amendment History: 
Date
Amendment Number
Amendment Type
Region
17 June 2011
Initial Protocol
Not applicable
China
26 January 2016
1
Nonsubstantial
China
09 June 2016
02
Nonsubstantial
China
20 February 2017
03
Nonsubstantial
China
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
TDC Asia sponsored Asia Pacific investigators will be provided with emergency medical contact 
information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Issue
Asia Pacific Contact
Serious adverse event, pregnancy, and special interest 
adverse event reporting
Medical Monitor
(medical advice on protocol, compound, and medical 
management of subjects)
Responsible Medical Officer 
(carries overall responsibility for the conduct of the study)
Personally Protected Data


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


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


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1.3
Protocol Amendment 03 Summary of Main Changes
This section describes the changes in reference to the protocol incorporating Amendment No. 03.
The primary reason for this amendment is to clarify acceptable windows for some screening 
procedures. Minor grammatical, editorial, and formatting changes are included for clarification 
purposes only.
For specific descriptions of the changes listed below and where these changes are located, see
Appendix H.
1. Update contract research organization (CRO) contact information.
2. Remove the requirement that the Screening Period be a minimum of 7 days.
3. Change the appropriate contact for confirming available brands of rescue medication.
4. Gastrin levels will be blinded to both investigators and medical monitors during the study 
period. 
5. Clarify acceptable windows for screening labs and endoscopy.
6. Update one of the definitions of an SAE.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Main Changes.................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Coordinating Investigator.........................................................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Corporate Identification...........................................................................................16
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.2
Rationale for the Proposed Study.............................................................................19
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................20
5.1
Objectives................................................................................................................20
5.1.1
Primary Objective ..............................................................................................20
5.1.2
Secondary Objective ..........................................................................................20
5.1.3
Additional Objectives.........................................................................................20
5.2
Endpoints.................................................................................................................20
5.2.1
Primary Endpoint...............................................................................................20
5.2.2
Secondary Endpoint ...........................................................................................20
5.2.3
Additional Endpoints .........................................................................................20
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................21
6.1
Study Design ...........................................................................................................21
6.2
Justification for Study Design, Dose, and Endpoints ................................................22
6.3
Premature Termination or Suspension of Study or Investigational Site.....................23
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................23
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........23
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................23
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............24
7.1
Inclusion Criteria .....................................................................................................24
7.2
Exclusion Criteria ....................................................................................................24
7.3
Excluded Medications and Treatments.....................................................................26


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7.4
Diet, Fluid, Activity Control ....................................................................................27
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................28
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................30
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT......................................................31
8.1
Study Medication and Materials...............................................................................31
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................31
8.1.2
Storage...............................................................................................................33
8.1.3
Dose and Regimen .............................................................................................33
8.1.4
Overdose............................................................................................................34
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................34
8.3
Randomization Code Creation and Storage..............................................................34
8.4
Investigational Drug Blind Maintenance ..................................................................35
8.5
Unblinding Procedure..............................................................................................35
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................35
9.0
STUDY PLAN ..............................................................................................................37
9.1
Study Procedures.....................................................................................................37
9.1.1
Informed Consent Procedure..............................................................................37
9.1.2
Demographics, Medical History, and Medication History Procedure..................37
9.1.3
Physical Examination Procedure ........................................................................37
9.1.4
Weight, Height...................................................................................................38
9.1.5
Vital Sign Procedure..........................................................................................38
9.1.6
GERD Symptoms Investigator Assessment ........................................................38
9.1.7
Daily eDiary ......................................................................................................39
9.1.8
Documentation of Concomitant Medications......................................................39
9.1.9
Documentation of Concurrent Medical Conditions.............................................39
9.1.10 Procedures for Clinical Laboratory Samples.......................................................39
9.1.11 Contraception and Pregnancy Avoidance Procedure...........................................41
9.1.12 Pregnancy ..........................................................................................................42
9.1.13 ECG...................................................................................................................43
9.1.14 Documentation of Screen Failure .......................................................................43
9.1.15 Documentation of Study Randomization ............................................................44
9.1.16 Endoscopy .........................................................................................................44
9.2
Monitoring Subject Treatment Compliance..............................................................44
9.3
Schedule of Observations and Procedures................................................................45
9.3.1
Screening...........................................................................................................45


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9.3.2
Study Randomization.........................................................................................46
9.3.3
Treatment Period................................................................................................47
9.3.4
Final Visit or Early Termination (± 3 Days) .......................................................47
9.3.5
Unscheduled Visit..............................................................................................48
9.3.6
Follow-up ..........................................................................................................48
9.3.7
Post Study Care..................................................................................................48
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................49
10.1
Definitions...............................................................................................................49
10.1.1 Pretreatment Events ...........................................................................................49
10.1.2 AEs....................................................................................................................49
10.1.3 Additional Points to Consider for PTEs and AEs................................................49
10.1.4 SAEs..................................................................................................................51
10.1.5 Severity of PTEs and AEs..................................................................................52
10.1.6 Causality of AEs ................................................................................................52
10.1.7 Relationship to Study Procedures.......................................................................52
10.1.8 Start Date...........................................................................................................53
10.1.9 Stop Date...........................................................................................................53
10.1.10
Frequency ....................................................................................................53
10.1.11
Action Concerning Study Medication...........................................................53
10.1.12
Outcome.......................................................................................................53
10.2
Procedures...............................................................................................................54
10.2.1 Collection and Reporting of AEs........................................................................54
10.2.2 Collection and Reporting of SAEs......................................................................55
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................56
10.3
Follow-up of SAEs ..................................................................................................56
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....56
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................57
12.0
DATA HANDLING AND RECORDKEEPING............................................................58
12.1
eCRF .......................................................................................................................58
12.2
Record Retention .....................................................................................................58
13.0
STATISTICAL METHODS..........................................................................................60
13.1
Statistical and Analytical Plans ................................................................................60
13.1.1 Analysis Sets......................................................................................................60
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................60
13.1.3 Efficacy Analysis...............................................................................................60


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13.1.4 Safety Analysis ..................................................................................................60
13.2
Interim Analysis and Criteria for Early Termination ................................................61
13.3
Determination of Sample Size..................................................................................61
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................62
14.1
Study-Site Monitoring Visits ...................................................................................62
14.2
Protocol Deviations..................................................................................................62
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................62
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................63
15.1
IRB and/or IEC Approval ........................................................................................63
15.2
Subject Information, Informed Consent, and Subject Authorization .........................64
15.3
Subject Confidentiality ............................................................................................65
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................65
15.4.1 Publication and Disclosure.................................................................................65
15.4.2 Clinical Trial Registration..................................................................................66
15.4.3 Clinical Trial Results Disclosure ........................................................................66
15.5
Insurance and Compensation for Injury....................................................................66
16.0
REFERENCES..............................................................................................................67
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications........................................................................................27
Table 8.a
Study Drugs.......................................................................................................31
Table 8.b
Rescue Medications ...........................................................................................32
Table 8.c
Sponsor-Supplied Drug......................................................................................33
Table 9.a
Clinical Laboratory Tests...................................................................................40
Table 10.a
Takeda Medically Significant AE List................................................................52
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................22
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................69
Appendix B
Responsibilities of the Investigator.....................................................................71
Appendix C
Elements of the Subject Informed Consent.........................................................73


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Appendix D
Investigator Consent to Use of Personal Information..........................................76
Appendix E
GERD Symptoms Investigator Assessment ........................................................77
Appendix F
Definition of Heartburn Severity (Daytime/Nighttime).......................................78
Appendix G
eDiary................................................................................................................79
Appendix H
Detailed Description of Amendments to Text.....................................................80


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Asia, Pte. Ltd.
Compound: 
Dexlansoprazole
Title of Protocol: A Phase 3 Double Blind Study to Evaluate the 
Efficacy and Safety of Dexlansoprazole (30 mg QD) compared to 
Placebo on Heartburn Relief in Subjects With Symptomatic 
Nonerosive Gastroesophageal Reflux Disease (GERD)
IND No.: Not applicable
EudraCT No.: Not 
applicable
Study Number: TAK-390MR_302
Phase: 3b
Study Design:
This is a phase 3, randomized, double-blind, multicenter, placebo-controlled, 2-arm study with a 4-week treatment 
period. The study is designed to evaluate heartburn relief in subjects with symptomatic nonerosive gastroesophageal 
reflux disease (GERD).
Primary Objectives:
To compare the efficacy of dexlansoprazole capsule (30 mg once daily [QD]) with placebo in relief of daytime and 
nighttime heartburn over 4 weeks in Chinese subjects with symptomatic nonerosive GERD as assessed by daily 
electronic diary (eDiary).
Secondary Objectives:
To compare the efficacy of dexlansoprazole capsules (30 mg QD) with placebo in relief of nighttime heartburn over 4 
weeks in Chinese subjects with symptomatic nonerosive GERD as assessed by daily eDiary. 
Subject Population: Subjects ≥18 years with symptomatic nonerosive GERD.
Number of Subjects:
Estimated total: 200 subjects
Per treatment group: 

100 subjects/dexlansoprazole 30 mg capsules

100 subjects/placebo
Number of Sites:
Estimated total: 20 sites in China
Dose Level(s):
Dexlansoprazole 30 mg capsules (QD)
Placebo (QD)
Route of Administration:
Oral 
Duration of Treatment:
4 weeks
Period of Evaluation:
11 weeks
Main Criteria for Inclusion:
The subject is capable of understanding and complying with protocol requirements. The subject or, when applicable, 
the subject’s legally acceptable representative signs and dates a written, informed consent form (ICF) and any required 
privacy authorization prior to the initiation of any study procedures. The subject is male or female and aged ≥18 years. 
Subjects identifying their main symptom as a burning feeling in the mid-epigastric area and/or chest area (ie, 
heartburn). The subject must have a history of symptomatic GERD for 6 months or longer prior to Screening with 
GERD symptoms that were responsive to acid-suppressive therapy. The subject must have episodes of heartburn for 
any 4 or more days during the 7 days prior to Day -1 as recorded in the eDiary. All women of childbearing potential, or 
men who are sexually active, agree to use adequate contraception from signing of informed consent form (ICF) 
throughout the duration of the study and for 30 days after the last dose of study medication.


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Main Criteria for Exclusion:
The subject has a history or clinical manifestations of serious neurologic, cardiovascular, pulmonary, hepatic, renal, 
metabolic, gastrointestinal, urological, endocrine, hematologic, dermatologic, immunologic, psychiatric disorders, or 
other abnormality which may impact the ability of the subjects to participate or potentially confound the study results. 
The subject is required to take excluded medications, or it is anticipated that the subject will require treatment with at 
least 1 of the disallowed concomitant medications during the study evaluation period as specified in the exclusion 
medication section (Section 7.3). Within 30 days prior to the Screening Visit, the subject has received any 
investigational drug or participate another clinical study (other than study TAK-390MR_301). The subject has a 
hypersensitivity to any proton pump inhibitor (PPI) (including, but not limited to, lansoprazole, omeprazole, 
rabeprazole, pantoprazole, esomeprazole or ilaprazole), any component of dexlansoprazole capsules, or antacid (eg, 
magnesium trisilicate or similar antacid). The subject has a history of cancer, (except basal cell carcinoma of the skin),
that has not been in remission for at least 5 years prior to Screening. The subject has a known history of Barrett’s 
esophagus with dysplastic changes or any changes suspicious of Barrett’s seen during screening endoscopy. The 
subject developed acute upper gastrointestinal bleeding, gastric ulcer (a mucosal defect with white coating) or 
duodenal ulcer (a mucosal defect with white coating), within 30 days before the start of the Screening Visit (with the 
possible inclusion of those with gastric or duodenal erosion). The subject requires chronic use (>12 doses per month) 
of nonsteroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase-2 (COX-2) NSAIDs within 30 days 
prior to the Screening Period and throughout the study. The subject has comorbidities that could affect the esophagus 
(eosinophilic esophagitis, esophageal varices, scleroderma, viral or fungal infection, esophageal strictures); a history 
of radiotherapy or cryotherapy of the esophagus; and a history of corrosive or physiochemical injury (with the possible 
inclusion in the study of those with Schatzki’s ring). The subject has a history of surgical procedures that may affect 
the esophagus (eg, fundoplication and mechanical dilatation for esophageal strictures) or a history of gastric or 
duodenal surgery other than endoscopic removal of benign polyps. Subjects with erosive esophagitis (EE) as shown by 
endoscopy, during the Screening Period. The subject has any abnormal laboratory value during screening or Day-1 
that suggests a clinically significant underlying disease or condition that may prevent the subject from entering the 
study, based on the medical judgment of the investigator; or the subject has creatinine >1.5 mg/dL or alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2.5 times the upper limit of normal (×ULN) or 
total bilirubin >2.0 mg/dL. The subject is known to have acquired immunodeficiency syndrome (AIDS) or hepatitis, 
including hepatitis virus carriers: hepatitis B surface antigen (HBsAg) positive or hepatitis C virus (HCV) antibody
positive. The subject has current Zollinger-Ellison syndrome (gastric acid hypersecretion) or a history of gastric acid 
hypersecretion. The subject is scheduled for surgery that requires hospitalization or requires surgical treatment during 
his/her participation in the study. The subject has donated or lost >300 mL blood volume, undergone plasmapheresis, 
or has had a transfusion of any blood product within 90 days prior to the first dose of study drug. The subject has a 
history of alcohol or drug abuse (defined as any illicit drug use), or drug addiction in the 12 months prior to Screening. 
If the subject is a pregnant or lactating woman; is intending to become pregnant before, during, or within 30 days after 
participating in this study; is intending to donate ova during this time period; or is a man who is intending to donate 
sperm. Any subject who, in the opinion of the investigator, is unable to comply with the requirements of the study or is 
unsuitable for any reason. The subject with positive serology result of Helicobacter pylori (H. pylori) that needs 
eradication therapy during the study participation period as anticipated by the investigator. The subject is an 
immediate family member, study site employee, is in a dependent relationship with a study site employee who is 
involved in conduct of this study (eg, spouse, parent, child, sibling), or may consent under duress.
Main Criteria for Evaluation and Analyses:
Primary Endpoint: The percentage of days with neither daytime nor nighttime heartburn during treatment as assessed 
by daily eDiary.
Secondary Endpoint: The percentage of days without nighttime heartburn during treatment as assessed by daily 
eDiary.
Additional Endpoints: The severity of GERD symptoms at Week 2 and Week 4 as assessed by the investigator. The 
percentage of days without rescue medication over 4 weeks as assessed by daily eDiary. Safety will be assessed by 
summarizing the incidence of adverse events (AEs), ECG results, physical examinations, clinical laboratory values, 
gastrin levels, and vital signs.


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Statistical Considerations:
Efficacy Assessments
The primary efficacy variable will be the percentage of days with neither daytime nor nighttime heartburn over 
4 weeks as assessed by daily eDiary. Comparisons between dexlansoprazole capsules and placebo will be made using 
a Wilcoxon rank-sum test. 
The secondary efficacy variable will be the percentage of days without nighttime heartburn over 4 weeks as assessed 
by daily eDiary. Comparisons between dexlansoprazole capsules and placebo will be made using a Wilcoxon 
rank-sum test. 
Safety Assessments
Safety will be assessed by summarizing the incidence of AEs, clinical laboratory values, physical examinations, 
gastrin levels, ECG, and vital signs using the safety analysis set.
Sample Size Justification:
A total of 200 subjects are planned to be enrolled into this study to ensure 160 subjects with symptomatic nonerosive 
GERD will complete the study (assuming a 20% dropout rate). The sample size of 80 subjects per treatment group will 
provide at least 95% power at the 0.05 two-sided significance level to detect a difference of 25% in the mean 
percentage of days without daytime or nighttime heartburn over 4 weeks between dexlansoprazole capsules (50%) and 
placebo (25%). The dexlansoprazole capsules and placebo rates were estimated from prior dexlansoprazole Study 
T-GD05-137. The common standard deviation was assumed to be 35%.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator
TDC Asia will select a signatory coordinating investigator (CI) from the investigators who 
participate in the study and enroll at least 1 subject. Selection criteria for this investigator will 
include significant knowledge of the study protocol, the study medication, their expertise in the 
therapeutic area and the conduct of clinical research as well as study participation. The signatory 
CI will be required to review and sign the clinical study report and by doing so agrees that it 
accurately describes the results of the study.


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3.3
List of Abbreviations
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
AST
aspartate aminotransferase 
AUC
area under the plasma concentration-time curve
BID
twice daily
BMI
body mass index
BUN
blood urea nitrogen
CI
coordinating investigator
Cmax
maximum observed plasma concentration
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
COX-2
cyclo-oxygenase-2
CRO
contract research organization 
CYP
cytochrome P450
ECG
electrocardiogram
ECL
enterochromaffin-like
eCRF
electronic case report form
EE
erosive esophagitis
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GI
gastrointestinal
GGT
γ-glutamyl transferase
(H+, K+)-ATPase
hydrogen, potassium adenosine triphosphatase
H2RA
histamine2-receptor antagonist
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
H. pylori
Helicobacter pylori
ICF
informed consent form
ICH
International Conference on Harmonisation 
ID
identification
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board


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IUD
intrauterine device
IWRS
interactive web response system
LA
Los Angeles
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MR
modified-release
NSAID
nonsteroidal anti-inflammatory drug
OE
over encapsulated
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
PPI
proton pump inhibitor
PTE
pretreatment event
QD
once daily
QOL
quality of life
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TCM
traditional Chinese medicine
TEAE
treatment-emergent adverse event
tmax
time to reach Cmax
Total CO2
bicarbonate
TRAE
treatment-related adverse event
ULN
upper limit of normal
US
United States
WHODRUG
World Health Organization Drug Dictionary
3.4
Corporate Identification 
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
TCH
Takeda (China) Holdings Co., LTD
TDC Americas
Takeda Development Center Americas, Inc.
TDC Asia
Takeda Development Center Asia, Pte. Ltd.
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Japan
Takeda Development Center Japan
TPC
Takeda Pharmaceutical Company Limited


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4.0
INTRODUCTION
4.1
Background
Gastroesophageal reflux disease (GERD) is a common recurring medical problem in the adult 
population with a prevalence between 10% to 20% in the Western world and less than 5% in Asia 
[1]. Prevalence of GERD-related symptoms ranges from at least once a month in approximately 
40%, once a week in 20%, to daily in 14% of patients [1,2]. A number of risk factors, such as 
advancing age, obesity, smoking, and alcohol and caffeine consumption have all been associated 
with the development of GERD [1]. Gastroesophageal reflux disease affects men and women in 
nearly equal proportions; however, men develop erosive esophagitis (EE) and Barrett’s esophagus 
more often than women [1], and women develop nonerosive GERD more often than men [3].
GERD results in substantial morbidity due to the occurrence of serious complications [4,5] and its 
adverse impact on quality of life (QOL) [6].
Gastroesophageal reflux disease comprises a spectrum of acid-related disorders, including 
nonerosive GERD and EE. Nonerosive GERD is defined as the presence of symptoms caused by 
intraesophageal acid reflux in patients with absence of endoscopically observed injury to the 
esophageal mucosa [7]. EE is defined as the presence of superficial esophageal erosions in patients 
with or without typical GERD symptoms.
Patients who do not receive treatment, or in whom acid reflux is not effectively controlled, are at 
risk of developing significant complications, such as bleeding, strictures, and Barrett’s esophagus 
[4]. Other complications of gastroesophageal reflux, such as dysphagia, chronic cough, laryngitis,
and sleep disturbance can be troublesome or painful for the patient, thereby impairing well-being.
Therapy for GERD is largely focused on the prevention of reflux of gastric acid into the 
esophagus, either by pharmacological or surgical means, with surgery usually reserved for 
intractable cases. Pharmacological management of GERD includes treatment with antacids, 
histamine2-receptor antagonists (H2RA), prokinetic agents, and proton pump inhibitors (PPIs). 
PPIs, which are labeled for once daily (QD) dosing, are the most effective medications for 
relieving GERD symptoms, healing the injured mucosa, maintaining a healed mucosa, and 
preventing the development of complications [8]. 
However, significant challenges remain in the treatment of patients with endoscopically negative 
GERD, moderate to severe esophageal erosions (Los Angeles [LA] Classification Grades C 
and D) [9] or ulcers, and other GERD-related symptoms. This is reflected by the high number of 
prescriptions written for twice daily (BID) dosing of currently available PPIs [10]. BID dosing 
with PPIs in itself represents a current challenge in treatment, because a dosing frequency for a PPI 
greater than QD has been shown to increase the probability of discontinuation of treatment and to 
reduce the rate of adherence to therapy [11]. In addition, concomitant antacid use has been 
reported by 37% of patients receiving PPIs [12]. This concomitant antacid use among some PPI 
users suggests that currently available PPIs may not achieve sufficient acid control when used as 
monotherapy for symptom relief. In addition, 79% of individuals with weekly heartburn also 
report nighttime heartburn. Approximately 60% of individuals with nighttime symptoms 
experience interference with sleep, which may affect daytime activities and quality-of-life [13].


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To further enhance the potential for dexlansoprazole capsules to demonstrate clinical benefit, 
especially in treating patients with unmet medical needs, Takeda Global Research & Development 
Center, Inc. now known as Takeda Development Center Americas, Inc. (TDC Americas) 
developed a dual delayed-release formulation of dexlansoprazole, referred to as dexlansoprazole 
modified-release (MR). This novel formulation consists of 2 types of granules contained within a 
single capsule. Each type of granule has a different pH-dependent release profile. The first peak 
occurs 1 to 2 hours after administration, followed by a second peak within 4 to 5 hours. This dual 
delayed release formulation is designed to extend the duration of drug exposure and maintain 
pharmacologically active levels of drug over a longer time period. As a result, the pharmacokinetic 
(PK) profile of dexlansoprazole following the administration of dexlansoprazole capsules is 
characterized by a concentration-time profile with 2 distinct peaks. In order to achieve this 2-peak, 
prolonged PK profile, dexlansoprazole MR releases drug substance over a longer period of time, 
thus requiring higher daily doses and consequently higher area under the plasma 
concentration-time curves (AUCs), without a commensurate increase in maximum observed 
plasma concentration (Cmax), compared with that following administration of the conventional 
lansoprazole formulation.
Dexlansoprazole 30 mg capsules are approved for use in adults in over 30 countries for treatment 
of heartburn associated with symptomatic nonerosive GERD, and maintenance of healed EE, and 
60 mg capsules are approved for healing of EE.
In the United States (US) registration trials, dexlansoprazole capsules were evaluated in 
5072 subjects in many phase 1 studies and in the phase 3 healing of EE, maintenance of healed EE, 
symptomatic nonerosive GERD, and long-term safety studies. A total of 282 subjects were 
exposed to doses of either 60 or 90 mg for ≥52 weeks, 382 subjects were exposed to doses of either 
60 or 90 mg for ≥48 weeks and 863 subjects to doses of 30, 60, or 90 mg for 6 months (≥24 weeks). 
No safety concerns were noted in phase 1 studies of dexlansoprazole capsules in healthy 
volunteers and selected patient groups. No prolongation of QT interval was observed using doses 
up to 300 mg (T-P104-092). Five separate drug-drug interaction studies using dexlansoprazole 
capsule 60 mg or 90 mg (in which no PK interactions were seen with diazepam, phenytoin, 
theophylline, or warfarin and no pharmacodynamic interactions were seen with warfarin or 
clopidogrel) revealed no trends in adverse events (AEs) (T-P105-134, T-P105-133, T-P105-132, 
T-P105-139, and TAK-390MR_101). As expected with PPI therapy, mean serum gastrin levels 
increased 1- to 2-fold during the first 3 months of receiving dexlansoprazole capsules in 2 6-month 
maintenance studies (T-EE04-086 and T-EE05-135) and a long-term (12-month) safety study 
(T-GI04-088), and then generally stabilized for the remainder of treatment. These increases in 
gastrin levels were not dependent on the dose of dexlansoprazole capsules. In a phase 1 study in 
healthy volunteers, gastrin levels returned to Baseline within 7 days of last dose of 
dexlansoprazole capsules [14]. In the maintenance of healed EE studies, and in the long term 
safety study, no clinically important differences in gastric biopsy results were observed between 
any of the dexlansoprazole capsule treatment groups and placebo. In the long-term safety study, 
chronic gastritis (in either antral or fundic tissue) was the most commonly reported abnormality in 
31% and 36% of patients in the dexlansoprazole capsules 60 and 90 mg groups respectively. There 


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were no reports of enterochromaffin cell-like (ECL) hyperplasia in the phase 3 studies of 6 months 
to 1 year duration.
Gender had no effect on either the rate (time to reach Cmax [tmax]) or extent (Cmax and AUC) of 
dexlansoprazole absorption following the administration of dexlansoprazole capsules 
(T-P105-119). Although mean tmax values were approximately 2 hours shorter in subjects 18 to 
40 years of age compared with subjects 65 to 80 years of age, the extent of absorption as measured 
by Cmax and AUC was not statistically significantly different between young and elderly subjects 
(T-P105-119). While hepatic impairment had no effect on the rate of absorption, dexlansoprazole 
Cmax and AUC values in subjects with moderate hepatic impairment were approximately 2 times 
higher compared with those in subjects who have normal hepatic function, likely due to decreased 
clearance (T-P105-115).
Dexlansoprazole is extensively metabolized in the liver to inactive metabolites by oxidation, 
reduction, and subsequent formation of sulfate, glucuronide, and glutathione conjugates. 
Oxidative metabolites are formed by the cytochrome P450 (CYP) enzyme system, including 
hydroxylation mainly by CYP2C19 and oxidation by CYP3A4. Following the administration of a 
[14C]dexlansoprazole dose, the major circulating component in plasma was dexlansoprazole 
regardless of CYP2C19 metabolizer status, and no single metabolite accounted for more than 10% 
of the plasma total radioactivity through 6 hours postdose (T-P106-141). Although 51% of the 
administered [14C]dexlansoprazole dose was excreted in the urine, no unchanged dexlansoprazole 
was present in the urine. The remaining 48% of the radioactive dose was recovered in the feces.
All dexlansoprazole capsule doses were well tolerated and demonstrated an acceptable safety 
profile similar to that of lansoprazole 30 mg.
4.2
Rationale for the Proposed Study 
Phase 3 studies performed in the United States have demonstrated positive results using 
dexlansoprazole capsules on the relief of heartburn in subjects with symptomatic nonerosive 
GERD. This study will be the first to examine the effectiveness and safety of dexlansoprazole 
capsules in Chinese subjects with symptomatic nonerosive GERD. Takeda has developed 
dexlansoprazole in a dual delayed-release capsule formulation (dexlansoprazole capsules) as a 
new therapy for treating acid related disorders including symptomatic nonerosive GERD, healing 
of EE, and maintenance of healed EE. All tested dexlansoprazole doses were effective in 
controlling and preventing the return of heartburn and other GERD symptoms, healing EE, 
preventing relapse of EE and maintaining QOL.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to compare the efficacy of dexlansoprazole capsule (30 mg QD) and 
placebo in relief of daytime and nighttime heartburn over 4 weeks in Chinese subjects with 
symptomatic nonerosive GERD as assessed by daily electronic diary (eDiary).
5.1.2
Secondary Objective 
To compare the efficacy of dexlansoprazole capsules (30 mg QD) and placebo in relief of 
nighttime heartburn over 4 weeks in Chinese subjects with symptomatic nonerosive GERD as 
assessed by daily eDiary. 
5.1.3
Additional Objectives 

To compare the efficacy of dexlansoprazole capsule (30 mg QD) with placebo as measured by 
the severity of GERD symptoms at Week 2 and Week 4 as assessed by the investigator.

To compare the efficacy of dexlansoprazole capsule (30 mg QD) with placebo in Chinese 
subjects with symptomatic nonerosive GERD as measured by the percentage of days without 
rescue medication over 4 weeks as assessed by daily eDiary.

To compare the safety of dexlansoprazole capsule (30 mg QD) with placebo in Chinese 
subjects with symptomatic nonerosive GERD.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint is the percentage of days with neither daytime nor nighttime heartburn over 
4 weeks as assessed by daily eDiary.
5.2.2
Secondary Endpoint
The secondary endpoint is the percentage of days without nighttime heartburn over 4 weeks as 
assessed by daily eDiary. 
5.2.3
Additional Endpoints

The severity of GERD symptoms at Weeks 2 and 4 as assessed by the investigator.

The percentage of days without rescue medication over 4 weeks as assessed by daily eDiary.

Safety will be assessed by summarizing the incidence of AEs, electrocardiogram (ECG) 
results, clinical laboratory values, gastrin levels, physical examinations, and vital signs.


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is a phase 3, randomized, double-blind, multicenter, placebo-controlled, 2-arm study with a 
4-week treatment period. This study will compare the efficacy of dexlansoprazole capsule (30 mg 
QD) with that of placebo when administered orally as a single daily dose in the morning, without 
regard to food. The study is designed to evaluate heartburn relief in subjects with symptomatic 
nonerosive GERD. Approximately 200 subjects, 18 years and above will be enrolled at 
approximately 20 sites across China.
The study consists of 2 periods: a Screening Period, which will last a maximum of 21 days, and a 
Treatment Period, which will last 4 weeks. 
After signing an informed consent form (ICF), subjects will undergo a Screening Period. Subjects 
will be instructed that lifestyle or behavioral modifications designed to treat their symptoms of 
GERD should not be altered throughout the study. 
During the Screening Period, subjects will undergo various procedures to determine eligibility for 
the Treatment Period. Screening evaluations will include the following: demographics, medical 
and social history, physical examination including vital signs, height and weight, ECG, 
endoscopy, clinical laboratory evaluations including hepatitis panel, urine and serum pregnancy 
test (all women subjects of childbearing potential), and concomitant medication assessment. The 
screening clinical laboratory tests, hepatitis panel, and endoscopy must be performed within 
14 days prior to randomization. Subjects will be given rescue medication and eDiary on the first 
day of the Screening Period. Throughout the Screening Period, subjects will record their usage of 
rescue medication and document the presence and maximum severity of daytime and nighttime 
heartburn symptoms each day in their eDiary. Endoscopy data will be collected to exclude subjects 
with EE. Endoscopic pictures will be taken by the study site and kept in the site’s source document 
files according to the site’s practice. It may be collected by Takeda as necessary.
Subjects who satisfy the screening evaluation and selection criteria may be entered into the study. 
Subjects who identified heartburn as their primary symptom, had a history of heartburn episodes 
for 6 months or longer, experienced heartburn on at least 4 of the 7 days preceding Study Day -1, 
and showed macroscopically normal esophageal mucosa at the Screening endoscopy, will be 
eligible for the Treatment Period in this study. Subjects having an esophageal stricture will be 
excluded from the study. The endoscope must pass freely into the stomach during the endoscopy. 
The rescue medication will be supplied during the screening period.
All subjects will return to the investigative site on Day -1, which will be deemed as the Baseline. 
Subjects who have completed all of the Screening procedures and met all eligibility requirements 
and none of the exclusion criteria will have routine fasting laboratory evaluations including fasting 
serum gastrin, a urine pregnancy test (all women subjects of childbearing potential), a physical 
examination and vital signs measurements to assure continued eligibility. In addition, subjects will 
be assessed for GERD symptoms such as heartburn, acid regurgitation, dysphagia, belching, and 
epigastric pain by investigator assessment. 


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Subjects will be dispensed study drug on Day -1 according to an Interactive Web Response System 
(IWRS) and will begin taking study drug at the following day (Day 1). Rescue medication will 
continue to be supplied during the Treatment Period.
Subjects will be randomized in a 1:1 ratio to one of the following 2 treatment groups during the 
4-week Treatment Period:
Group I: 
dexlansoprazole capsules (30 mg QD)
Group II: 
placebo (QD)
During this 4-week Treatment Period, study drug will be self-administered, orally, once a day, in 
the morning, without regard to food. Subjects will continue to document the presence and 
maximum severity of daytime and nighttime heartburn symptoms and record usage of rescue 
medication using an eDiary. Subject visits will be conducted at Weeks 2 and 4 of the Treatment 
Period to collect and/or dispense study drug, assess GERD symptoms, review concomitant 
medication use, assess adverse events and subject will undergo a physical examination including 
vital signs. In addition, at the Week 4/ Final Visit, all subjects will undergo laboratory evaluations, 
ECG, fasting serum gastrin and urine pregnancy test (all women of childbearing potential). 
Subjects who prematurely discontinue during the study after the randomization should undergo 
Week 4/Final Visit procedures no later than 5 days after the last dose of study drug.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Figure 6.a
Schematic of Study Design
dexlansoprazole (30 mg QD)
Screening Period 
OR
(up to 21 days)
placebo (QD) 
Treatment Period
Day -1
Day 1
Week 2
Week 4/Final Visit
Randomize
1st Dose
6.2
Justification for Study Design, Dose, and Endpoints
Subjects with history of heartburn episodes for 6 months or longer and endoscopically proven 
normal esophageal mucosa is an appropriate population to evaluate efficacy and safety of 
dexlansoprazole 30 mg capsules QD compared with that of placebo when administered orally as a 
single daily dose in the morning. The study is designed to evaluate symptom relief in subjects with 
symptomatic nonerosive GERD. The study design, endpoints and dose of dexlansoprazole 30 mg 
capsules QD has been selected based on the results of completed multicenter controlled 


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registration phase 3 studies, where 30 mg of dexlansoprazole capsules (QD) was found to be the 
lowest effective dose tested.
The efficacy and safety measurements and the clinical and routine laboratory procedures used in 
this study are considered standard and generally accepted. 
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria 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 compound, such that the 
risk/benefit 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.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of 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
All entry criteria, including test results, need to be confirmed prior to randomization.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures. 
3. The subject is a man or woman and aged at least 18 years.
4. Subjects identifying their main symptom as a burning feeling in the mid epigastric area and/or 
chest area (ie, heartburn).
5. The subject must have a history of symptomatic GERD for 6 months or longer prior to 
Screening with GERD symptoms that were responsive to acid-suppressive therapy.
6. The subject must have episodes of heartburn for any 4 or more days during the 7 days prior to 
Day -1 as recorded in the eDiary.
7. All women subjects of child bearing potential who are sexually active agree to routinely use 
adequate contraception from signing of the informed consent throughout the duration of the 
study and for 30 days after the last dose of study medication. 
8. All men subjects who are nonsterilized* and sexually active with women partner of 
childbearing potential* agree to use adequate contraception* from signing of informed consent 
throughout the duration of the study and for 30 days after the last dose of study medication.
*Definitions and acceptable methods of contraception are defined in Section 9.1.11
Contraception and Pregnancy Avoidance Procedure and reporting responsibilities are defined 
in Section 9.1.12 Pregnancy.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has a history or clinical manifestations of serious neurologic, cardiovascular, 
pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, endocrine, hematologic, 
dermatologic, immunologic, psychiatric disorders, or other abnormality which may impact the 
ability of the subjects to participate or potentially confound the study results. 
2. The subject is required to take excluded medications, or it is anticipated that the subject will 
require treatment with at least 1 of the disallowed concomitant medications during the study 
evaluation period as specified in the exclusion medication section (section 7.3).


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3. The subject has received any investigational drug or participated in another clinical study 
(other than study TAK-390MR_301) within 30 days prior to the Screening Visit. 
4. The subject has a hypersensitivity to any PPI (including, but not limited to, lansoprazole, 
omeprazole, rabeprazole, pantoprazole, esomeprazole or ilaprazole), any component of 
dexlansoprazole, or antacid (eg, magnesium trisilicate or similar antacid).
5. The subject has a history of cancer, (except basal cell carcinoma of the skin), that has not been 
in remission for at least 5 years prior to Screening. 
6. The subject has a known history of Barrett’s esophagus with dysplastic changes or any changes 
suspicious of Barrett’s seen during screening endoscopy. 
7. The subject developed acute upper gastrointestinal bleeding, gastric ulcer (a mucosal defect 
with white coating) or duodenal ulcer (a mucosal defect with white coating), within 30 days 
before the start of the Screening Visit (with the possible inclusion of those with gastric or 
duodenal erosion). The subject requires chronic use (>12 doses per month) of nonsteroidal 
anti-inflammatory drugs (NSAIDs) including cyclooxygenase-2 (COX-2) NSAIDs within 
30 days prior to the Screening Period and throughout the study.
8. The subject has comorbidities that could affect the esophagus (eosinophilic esophagitis, 
esophageal varices, scleroderma, viral or fungal infection, esophageal strictures); a history of 
radiotherapy or cryotherapy of the esophagus; and a history of corrosive or physiochemical 
injury (with the possible inclusion in the study of those with Schatzki’s ring).
9. The subject has a history of surgical procedures that may affect the esophagus (eg, 
fundoplication and mechanical dilatation for esophageal strictures) or a history of gastric or 
duodenal surgery other than endoscopic removal of benign polyps.
10. Subjects with EE as shown by endoscopy, during the Screening Period.
11. The subject has any abnormal laboratory value during screening or Day-1 that suggests a 
clinically significant underlying disease or condition that may prevent the subject from 
entering the study, based on the medical judgment of the investigator, or the subject has: 
a) Creatinine >1.5 mg/dL or
b) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2.5 times the 
upper limit of normal (×ULN) or
c) Total bilirubin >2.0 mg/dL 
12. The subject is known to have acquired immunodeficiency syndrome (AIDS) or hepatitis, 
including hepatitis virus carriers: (ie, hepatitis B surface antigen HBs-antigen (HBsAg) 
positive or hepatitis C virus (HCV)-antibody positive).
13. The subject has current Zollinger-Ellison syndrome or a history of gastric acid hypersecretion.
14. The subject is scheduled for surgery that requires hospitalization or requires surgical treatment 
during his/her participation in the study.


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15. The subject has donated or lost >300 mL blood volume, undergone plasmapheresis, or has had 
a transfusion of any blood product within 90 days prior to the first dose of study drug.
16. The subject has a history of alcohol or drug abuse (defined as any illicit drug use), or drug 
addiction in the 12 months prior to Screening.
17. If the subject is a pregnant or lactating woman; is intending to become pregnant before, during, 
or within 30 days after participating in this study; is intending to donate ova during this time 
period; or is a man who is intending to donate sperm.
18. Any subject who, in the opinion of the investigator, is unable to comply with the requirements 
of the study or is unsuitable for any reason.
19. The subject with positive serology result of Helicobacter pylori (H. pylori) that needs 
eradication therapy during the study participation period as anticipated by the investigator. 
20. The subject is an immediate family member, study site employee, is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling), or may consent under duress.
7.3
Excluded Medications and Treatments
The substances listed in Table 7.a are excluded from the time points indicated and for the duration 
of subject’s participation in the study. Subjects must be instructed not to take any medications, 
including over-the-counter products or traditional Chinese medicines (TCM) without first 
consulting with the investigator.


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Table 7.a
Excluded Medications
Excluded Medications
Period of Exclusion
Prescription or nonprescription H2RA
During Screening and throughout the study.
Antacids (except the rescue medications or similar 
antacid)
During Screening and throughout the study. 
PPIs (except study-supplied dexlansoprazole)
During Screening and throughout the study.
NSAIDs, chronic use (>12 doses/month) including COX 
2 NSAIDs 
Within 30 days prior to Screening and throughout the 
study. 
Drugs with significant anticholinergic effects such as 
tricyclic antidepressants or drugs with CNS effects that 
could mask perception of symptoms (eg, SSRI, 
benzodiazepines). 
During Screening and throughout the study. However, 
subjects who have remained on a stable regimen and dose 
of these medications for 30 days prior to Day -1 and who 
agree to maintain the same regimen and dose during the 
trial including the screening and treatment period will 
qualify. Also, short-term use of anticholinergics for 
trial-related procedures is not exclusionary.
Misoprostol
During Screening and throughout the study.
Prokinetics (including metoclopramide, cisapride, 
tegaserod)
During Screening and throughout the study.
Anticoagulant or antiplatelet therapy
During Screening and throughout the study.
Medications with pH-dependent absorption*
During Screening and throughout the study
Methotrexate **
During Screening and throughout the study
Other: bethanechol
During Screening and throughout the study
H2RA=histamine 2-receptor antagonist, SSRI=selective serotonin reuptake inhibitor.
*Consideration of coadministration is based on clinically meaningful differences in efficacy or safety of medication 
due to pH dependent absorption.
**The investigator or designee should discuss methotrexate use with the medical monitor on a case by case basis if the 
methotrexate treatment is necessary throughout the study.
7.4
Diet, Fluid, Activity Control 
The principal investigator, the coinvestigators, and the study collaborators are to explain, and give 
instructions on, the following before the start of the study or during the study, as well as to check to 
see if the subjects keep to the instructions at the time of their scheduled visits.

Every subject should keep to the scheduled visits, seek medical consultation, and undergo 
predetermined laboratory tests.

The subject should ensure that all study medications are swallowed with approximately 
240 mL water according to the administration, and dosing schedule. Subjects should be 
instructed according to Section 8.1.3.1 (Missed Doses) and 9.2 (Compliance). Details of any 
missed or forgotten doses should be reported to the Investigator or designee at the subsequent 
study visit.

The subject should store all medications in a cool, dry, safe place which is out of reach of
children and to bring all study supplies (empty / used / unused drug packets and diaries alike) 
to each study visit.


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
The subject should record his/her nighttime (during sleep) subjective symptoms and the 
previous daytime subjective symptoms in his/her subject eDiary upon rising in the morning on 
a daily basis. The subject should also record the use of rescue medication during Screening 
Period and his/her rescue medication and study medication compliance status during the 
Treatment Phase. 

The subject will be required to fast for at least 8 hours before each visit at which fasted blood 
tests will be drawn and/or endoscopy will be performed, after the ICF is signed. Fasting is 
defined as no food or nutritional drinks for 8 hours before the blood draw. Water is allowed. 
Any medication that needs to be taken with food and any study medications should be held 
until after the fasting blood has been drawn and/or the endoscopy has been performed. 
Medication that does not need to be taken with food should be continued. The investigator 
must instruct the subject accordingly prior to visits in which serum gastrin is measured and 
endoscopy is performed.

After the first dose of study drug during the Treatment Phase, the subject should present to the 
clinic in the morning as scheduled.

The subject should consult with the study investigator or designee prior to being treated by 
physicians other than the study investigator. All other medications such as over-the-counter 
drugs beyond those prescribed for the study should be reported at the next study visit.

The subject should report on all subjective or objective symptoms experienced (ie, including 
details of day of onset, severity, outcome, and day of outcome) at every visit. In case of 
emergency such as occurrence of a serious adverse event (SAE), the subject, family, or legal 
designee should contact the principal investigator as soon as possible.

The subject should use contraception without fail. A woman of childbearing potential will 
agree to use contraception from signing of informed consent throughout the duration of the 
study and 30 days after the final dose of the study medication. Pregnancy in a female subject, if 
found, should be reported immediately.

The subject should not donate blood during the study.

The subject should refrain from excessive drinking and eating, and any extreme diet change 
(eg, change to an extremely high-fat diet) or excessive exercise throughout the study. Subjects 
will be instructed to maintain usual food intake, sleep habits, consistent activity, and caffeine 
intake throughout the study.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.14.
1. Pretreatment event (PTE) or adverse event (AE). The subject has experienced a PTE or AE that 
requires early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE.


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
Liver Function Test 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 9.1.10), 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 postrandomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE or lack of efficacy should not be recorded in the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.12.
7. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject. 
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF, for example:
noncompliance.


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7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may terminate 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. In 
addition, efforts should be made to perform all procedures scheduled for the Early Termination 
Visit. Discontinued or withdrawn subjects will not be replaced. 


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
Once a subject meets all eligibility criteria, the site will randomize the subject via IWRS, which 
will assign a unique study drug identification number. The subject will be randomized in a 1:1 
ratio into 1 of 2 treatment groups in the study:

Dexlansoprazole 30 mg capsules.

Placebo capsules.
Subjects will receive study drug for 4 Weeks.
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to all or any of the drugs defined below.
The study sites will be supplied with double-blind study medication containing dexlansoprazole 
30 mg capsules or matching placebo blister cards, as shown in Table 8.a.
Table 8.a
Study Drugs
Study Drugs
Dosage Strength/Dosage Form
Manufacturer
Dexlansoprazole 
30 mg capsules
Takeda Pharmaceutical Company Ltd.
Placebo
capsules (dose is not applicable)
Takeda Pharmaceutical Company Ltd.
The study sites will be supplied with study medication that is blinded via over encapsulation (OE) 
of dexlansoprazole 30 mg capsules and placebo. The study drug will be foil/foil blistered and 
packaged in 7-day child resistant blister cards containing 7 OE capsules. Each card will have a 
single-panel multilingual label that will contain, but will not be limited to: protocol number, 
medication identification (ID) number, name and strength of the product, quantity of dosage unit, 
directions for use, storage conditions, country specific regulatory caution statement, and name and 
address of the sponsor. The matching placebo capsules will be manufactured by Takeda 
Pharmaceutical Company Ltd. The study medication is overencapsulated, foil/foil blistered, 
packaged, labeled and distributed by Fisher Clinical Services.
8.1.1.1
Investigational Drug 
The investigational drugs are manufactured by Takeda Pharmaceutical Company Limited, Osaka, 
Japan. The active capsule contains drug substance and excipients. The placebo capsules contain 
excipients only. The study medication is overencapsulated, foil/foil blistered, packaged, labeled, 
and distributed by Fisher Clinical Services.


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
OE dexlansoprazole 30 mg capsules.

OE placebo.
8.1.1.2
Rescue Medication
During the study, including the during Screening Period, over-the-counter medications such as 
Talcid chewable tablets (hydrotalcite) or Gaviscon tablets can be used as rescue medication if the 
symptoms caused by acid reflux cannot be tolerated by the subjects. The investigator or designee 
will give medical instructions to the subject regarding the use of rescue medication during the 
dispensing visits. Subjects shall be instructed to refrain from using rescue medication unless 
necessary to manage symptoms. Proper documentation of use is required. Subjects shall contact 
the investigators if they would like to take the rescue medication at a dose higher than approved in 
the local package insert.
The use of rescue medication shall be recorded in the subject daily eDiary.
The institution or its designee will help to source the rescue medication for the subjects as 
necessary, or alternatively, subject may buy the rescue medication from the pharmacy and be 
reimbursed.
Rescue medications include those listed in Table 8.b:
Table 8.b
Rescue Medications
Rescue Medication (Active 
Ingredients in Each Tablet)
Dosage Strength (mg)
Manufacturer
Talcid chewable tablets 
(hydrotalcite)
500 mg
Bayer China Ltd.
Gaviscon Tablets
aluminum hydroxide 0.05 g 
magnesium trisilicate 0.0125 g
alginic acid 0.25g
Local China domestic companies
If the listed rescue medications are not available, the subject should contact the subject’s 
responsible investigator for confirmation of available brand. During the rescue medication 
administration, the following should be noted:
1. The administration of rescue medication shall be in accordance with the local package insert;
2. For aluminum based medications, an interval of at least 2 hours must be maintained between 
administration of study medication (or placebo) and rescue medication;
3. When rescue medication has been taken for more than 7 consecutive days, or more than 25% of 
the days in whole study period, the investigator should discuss with CRO/sponsor and decide 
whether to withdraw the subject.


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8.1.1.3
Sponsor-Supplied Drug 

OE dexlansoprazole 30 mg capsules.

OE placebo capsules.
8.1.2
Storage
All clinical trial material must be kept in an appropriate, limited-access, secure location until it is 
used or returned to the sponsor or designee for destruction. All sponsor-supplied drugs must be 
stored under the conditions specified on the label, and remain in the original container until 
dispensed.
All study medication supplied for the study must be stored as follows:
Store at: 20°C to 25°C; excursions allowed between 15°C and 30°C.
A daily temperature log of the drug storage area must be maintained every working day.
Temperature excursions must be reported to the sponsor or designee.
The investigator should ensure that study drug is used only in accordance with the approved 
protocol. Study drug shall be dispensed only to subjects enrolled in the study. 
8.1.3
Dose and Regimen
Once a subject meets all inclusion criteria and none of the exclusion criteria, the site will 
randomize the subject on Study Day -1 via the IWRS, which will assign a study drug kit number. 
The study drug kit number will encode the subject’s randomization to 1 of the 2 arms 
(dexlansoprazole 30 mg capsules QD or placebo QD) of the study at a ratio of 1:1, according to the 
randomization schedules generated prior to study start.
Subjects will receive three 7-day cards on Study Day -1 and Week 2. All subjects will 
self-administer 1 dexlansoprazole capsule QD or placebo QD at approximately the same time each 
morning without regard to food. The dose of study drug will be taken with a sip of water on the day 
of the fasting lab visit. Subjects should continue taking study drug so that the last dose is taken in 
the morning of the day before the Final Visit (Visit 4).
Table 8.c
Sponsor-Supplied Drug
Investigational 
Product
Formulation
Dosage
Mode of 
Administration
Manufacturer and Location
Dexlansoprazole 
30 mg capsule
30 mg QD AM
Oral
Takeda Pharmaceutical 
Company Ltd.
Placebo
0 mg capsule
0 mg QD AM
Oral
Takeda Pharmaceutical 
Company Ltd.


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8.1.3.1
Missed Doses
Subjects should be instructed that all doses of study medication (dexlansoprazole capsules or 
placebo) should be taken on time. Subjects should also be instructed that if any dose is missed 
inadvertently it is acceptable for that dose to be taken within 12 hours of the time that it was due. If 
more than 12 hours have passed since the dose was due, it should not be taken, but instead subjects 
should be instructed to report the missed dose to the investigator or designee during the next visit.
8.1.4
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. 
All cases of overdose (with or without associated AEs) will be documented on an overdose page of 
the eCRF, in order to capture this important safety information consistently in the database. AEs 
associated with an overdose will be documented on AE eCRF(s) according to Section 10.0, 
Pretreatment Events and Adverse Event.
Serious adverse events (SAEs) of overdose should be reported according to the procedure outlined 
in Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically by the investigator.
8.2
Investigational Drug Assignment and Dispensing Procedures
An IWRS will be used for the study.
The investigator or investigator’s designee will access the IWRS at Screening to obtain the subject 
identification number. The investigator or the investigator’s designee will utilize the IWRS to 
enroll the subject into the study. During this contact, the investigator or designee will provide the 
necessary subject-identifying information, including the subject number assigned at Screening. 
The medication ID number of the investigational drug to be dispensed will then be provided by the 
IWRS. If sponsor-supplied drug is lost or damaged, the site can request a replacement from IWRS. 
(Refer to IWRS manual provided separately). At subsequent drug-dispensing visits, the 
investigator or designee will again contact the IWRS to request additional investigational drug for 
a subject. 
8.3
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule 
prior to the start of the study.
Once a subject meets all admission criteria, the site will randomize the subject via the IWRS, 
which will assign a study drug kit number for the Treatment Period. The study drug kit number 
will encode the subject’s randomization to 1 of the 2 arms (dexlansoprazole 30 mg QD, or placebo 
QD) at a ratio of 1:1, according to the randomization schedules generated prior to study start. 


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All randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.4
Investigational Drug Blind Maintenance 
The investigational drug blind will be maintained using the IWRS.
8.5
Unblinding Procedure 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. In the 
event of a medical emergency, if possible, the medical monitor should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding.
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by 
accessing the IWRS.
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF.
If any site personnel is unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study. 
8.6
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 approved protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug (dexlansoprazole 30 mg capsules, placebo), the 
investigator must maintain records of all sponsor-supplied drug delivery to the site, site inventory, 
dispensation and use by each subject, and return to the sponsor or designee.
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; the 
medication is received within the labeled storage conditions, and is in good condition. If quantity 
and conditions are acceptable, investigator or designee should acknowledge the receipt of the 
shipment by recording in IWRS. 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 must maintain 100% accountability for all sponsor-supplied drugs received and 
dispensed during his or her entire participation in the study. Proper drug accountability includes, 
but is not limited to:

Frequently verifying that actual inventory matches documented inventory.


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
Verifying that the log is completed for the drug lot (or medication ID number) used to prepare 
each dose.

Verifying that all containers used and unused 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 must record the current inventory of all sponsor-supplied drugs (dexlansoprazole 
30 mg capsules, placebo) 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, date and amount dispensed 
including initials of the person 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.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the sponsor or its designee for destruction. The investigator will retain the 
original documentation regarding clinical study material accountability and return, copies (as 
required) will be sent to the sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of clinical study 
material 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 
clinical study material for return to the sponsor or its designee for destruction.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include: date of birth, sex, race as described by the 
subject, smoking status, history of use of alcohol and caffeine-containing drinks, history of 
H. pylori eradication therapy (eg, triple therapy with PPI + amoxicillin + clarithromycin), and date 
of completion of such therapy (within the past 1 year/more than 1 year) of the subject at Screening 
Period. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of
informed consent. Ongoing conditions are considered concurrent medical conditions 
(see Section 9.1.9). Medical history will include the following:

Nonerosive GERD.

Other upper gastrointestinal (GI) diseases including gastric ulcer, duodenal ulcer, or 
procedures.
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 90 days prior to signing of the informed 
consent form. Medication history will include the following:

PPIs.

H2RA.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the pretreatment assessment immediately prior to the 
start of investigational drug) 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; 


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(10) lymph nodes; (11) other. All subsequent physical examinations should assess clinically 
significant changes from the baseline examination.
9.1.4
Weight, Height 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. Body mass index (BMI) is calculated by sponsor or its designee using metric units with the 
formula provided below. 
BMI = weight (kg)/height (m)2
9.1.5
Vital Sign Procedure
Vital sign measurements including body temperature (oral, tympanic, or infra-axillary in
Centigrade), blood pressure (systolic and diastolic) and pulse (beats per minute) will be collected. 
Blood pressure and pulse will be measured while the subjects are in a sitting position after they 
have been seated for at least 5 minutes. Vital signs will be assessed at all time points specified in 
the Schedule of Study Procedures (Appendix A).
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 withdrawal.
9.1.6
GERD Symptoms Investigator Assessment
Subjects will have a GERD symptom assessment performed by the investigator during the 
Screening Period (on Day -1) and at the Week 4/Final Visits of the Treatment Period. The 
maximum severity of the GERD symptoms of heartburn, acid regurgitation, dysphagia, belching 
and epigastric pain will be assessed by appropriate site personnel as either none, mild, moderate, 
severe, or very severe as defined below, during the 7 days prior to the subject’s study visit and 
recorded on the appropriate eCRF. The definitions for the symptoms being assessed are:

Heartburn: A burning feeling in the mid epigastric area and/or chest area.

Acid regurgitation: Flow of sour or bitter fluid into the mouth.

Dysphagia: Difficulty in swallowing.

Belching: The voiding of gas from the stomach through the mouth, which may be associated 
with acid regurgitation.

Epigastric pain: Central upper abdominal pain.

None: No symptoms.

Mild: Symptom does not last long and is easily tolerated.

Moderate: Symptom causes discomfort and/or interrupts usual activities (including sleep).

Severe: Symptom causes great interference with usual activities and may be incapacitating 
(including sleep).


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
Very Severe: Symptom causes intense and constant discomfort and/or marked interference
with usual activities (including sleep).
9.1.7
Daily eDiary 
Subjects will be given an eDiary on the first day of the Screening Period. Throughout the 
Screening Period and Treatment Period, subjects will document the presence and maximum 
severity of daytime and nighttime heartburn symptoms each day in their daily eDiary. Subjects 
will also record the use of rescue medication. If the subject experiences no heartburn on any given 
day, they should also provide this information. The daily eDiary should be completed every 
morning upon waking and every evening before bedtime. The last entry for the Treatment Period is 
in the morning prior to their Week 4/Final Visit site visit. 
The electronic diaries will be reviewed at subsequent visits. Subjects must bring their electronic 
dairy device at every visit. The severity of heartburn will be graded by the subject according to the 
definitions outlined in Appendix F. Should the electronic diaries be lost or destroyed, the subject 
should contact the site immediately to receive additional eDiary to insure continuity of symptom 
reporting.
9.1.8
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF.
9.1.9
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at screening/baseline examination. The condition (ie, diagnosis) 
should be described and assessed during subsequent site visits where physical examination is 
required.
9.1.10 Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 20 mL, and the approximate total volume of 
blood for the study is 140 mL. Details of these procedures and required safety monitoring will be 
given in the laboratory manual.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBCs
WBCs with Differential
Hemoglobin
Hematocrit
Platelets
ALT
AST
Alkaline phosphatase (ALP)
Albumin
Glucose (a)
Gastrin (a,b)
Total bilirubin
Total protein
Serum Creatinine
Blood urea nitrogen (BUN)
Creatine kinase
Bicarbonate(Total CO2)
γ-glutamyl transferase (GGT)
Lactate dehydrogenase (LDH)
Potassium
Sodium
Magnesium (c)
Calcium 
Phosphorus
Chloride
Serum iron
Uric acid
Total cholesterol
Triglycerides (a)
Vitamin B12
Specific gravity
pH
Protein
Ketones
Glucose
Bilirubin
RBC 
WBC
Other: H. pylori serology screening visit only
Serum
Urine
hCG (if child-bearing potential)
FSH (if menopausal)
Hepatitis panel including: HBsAg, HCV-antibody (d)
Urine Pregnancy test (if child-bearing potential)
FSH=follicle-stimulating hormone, hCG=human chorionic gonadotropin, RBC=red blood cell, WBC=white blood 
cell.
(a) To be measured under fasting conditions except the Screening Visit (Days -21 to -2).
(b) Gastrin levels to be measured under fasting conditions. Gastrin levels will be blinded to both investigators and the 
medical monitor during the study period.
(c) If, at any time after enrollment into the study, a subject’s serum magnesium is less than or equal to 1.1 mEq/L 
(≤0.55 mmol/L), a 24 hour urine for magnesium will be collected to verify the serum chemistry result.
(d) Hepatitis panel including HBsAg and HCV-antibody can be measured either at the central laboratory or the local 
laboratory, depending on the site capability.


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The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results.
The investigator is responsible for transcribing laboratory results which were conducted locally to 
the eCRF. The investigator will maintain a copy of the laboratory accreditation and the reference 
ranges for the laboratory used.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was found. (Please 
refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate guidance on 
reporting of abnormal liver function tests in relation to ALT or AST >3 ×ULN in conjunction with 
total bilirubin >2 ×ULN.)
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements).
Given the possibility that the use of dexlansoprazole may be associated with increases in serum 
gastrin, the subjects will be examined for gastrin to investigate the magnitude of these increases 
during the Treatment Phase. Gastrin levels will be blinded to both investigators and the medical 
monitor during the study period.
The screening clinical laboratory, including hepatitis panel, must be performed within 14 days 
prior to randomization. 
9.1.11 Contraception and Pregnancy Avoidance Procedure
From signing of the ICF, throughout the duration of the study, and for 30 days after last dose of 
study drug, nonsterilized** men subjects who are sexually active with women of childbearing 
potential* must use double-barrier contraception (eg, condom with spermicidal cream or jelly). In 
addition, they must be advised not to donate sperm during this period.
From the signing of the informed consent, throughout the duration of the study, and for 30 days 
after last dose of study medication, women subjects of childbearing potential* who are sexually 
active ** must use adequate contraception. In addition they must be advised not to donate ova 
during this period.


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*Women NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy, or tubal ligation) or who are postmenopausal (eg, defined 
as at least 1 year since last regular menses with an FSH>40 IU/L or at least 5 years since last 
regular menses, confirmed before any study medication is implemented).
**Sterilized men should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are included, the only 
acceptable methods of contraception are:
Barrier methods (each time the subject 
has intercourse) where applicable*:
Intrauterine devices (IUDs):
Hormonal contraceptives:

Cap (plus spermicidal cream or jelly) 
PLUS male condom and spermicide

Diaphragm (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide

Copper T PLUS condom or 
spermicide

Progesterone T PLUS 
condom or spermicide

Implants

Hormone shot/injection

Combined pill

Minipill

Patch

Vaginal ring PLUS male 
condom and spermicide
*Barrier methods is only applicable in countries where spermicide is commercially available.
Subjects will be provided with information on acceptable 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.
During the course of the study, regular hCG pregnancy tests will be performed only for women of 
childbearing potential and subjects will receive continued guidance with respect to the avoidance 
of pregnancy and sperm donation as part of the study procedures (Appendix A). In addition to a 
negative serum and urine hCG pregnancy test at Screening, subjects also must have a negative 
urine hCG pregnancy test at Day -1.
9.1.12 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (dexlansoprazole 30 mg capsules, matching placebo) should be 
discontinued immediately. In addition, any pregnancies in the partner of a man subject during the 
study or for 30 days after the last dose should be recorded following authorization from the 
subject’s partner. 
If the pregnancy occurs during administration of active study medication, eg, after Visit 2 or within 
30 days of the last dose of active study medication, the pregnancy should be reported immediately, 
using a pregnancy notification form, to the contact listed in Section 1.0.


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Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
If the woman subject and/or woman partner of a man who is a subject agrees to the primary care 
physician being informed, the investigator should notify the primary care physician that the 
subject/woman partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of treatment the subject received (blinded or unblinded, as 
applicable).
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.
9.1.13 ECG
A standard 12-lead ECG will be recorded. 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 time that the ECG was performed will be recorded. The following parameters will be recorded 
on the eCRF from the subject’s ECG tracing: heart rate, RR interval, PR interval, QT interval, and 
QRS interval. 
As ECG tracings on thermal paper fade over time, any such tracings should be completely 
photocopied and both the original tracing and the counter-signed copy should be filed in the 
subject’s medical record.
9.1.14 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If the subject is found to be 
not eligible at this visit, the investigator should complete the eCRF. 
The IWRS should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

Pretreatment event/AE.

Did not meet inclusion criteria or did meet exclusion criteria.

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal.

Study termination.

Other.


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Subject numbers assigned to subjects who fail screening should not be reused.
9.1.15 Documentation of Study Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the Treatment Phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
All screening procedures and test must be reviewed prior to randomization. Subjects who meet all 
the inclusion and none of the exclusion criteria will be randomized via IWRS.
Instructions on accessing and using the IWRS will be provided in a separate manual. Blinded 
details of subject treatment allocation (medication ID numbers) provided via the IWRS should be 
documented in the subject’s medical record and/or eCRF.
9.1.16 Endoscopy 
During Screening Visit an endoscopy will be performed on all subjects to document the 
presence/absence of EE. Endoscopy should be performed while subjects are fasted and according 
to the usual practice of the institution (ie, with regard to premedications or concomitant therapies,
as long as they are not prohibited in Section 1 of this protocol). Subjects with macroscopic normal 
esophagus will be eligible for the study. 
The screening endoscopy must be performed within 14 days prior to randomization. Any reliable, 
documented results available from an endoscopy performed in a routine clinical setting (before 
signing of informed consent) in the same institution will be accepted, given the invasive nature of 
the procedure.
Any subjects with suspicious Barrett’s esophagus seen during screening endoscopy will be 
excluded from the study. These Endoscopy assessments will be recorded on the eCRF and a copy 
of the results should be kept with the subject’s notes. Digital images of the endoscopy should be 
captured and stored at the investigational site; images may be accessed by Takeda as necessary for 
quality assurance purpose. 
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study medication containers and unused medications to each 
dispensing site visit and final visit. Investigators or designee should perform subject treatment 
compliance checks by reviewing the subject’s eDiary and returned medications.
If a subject is persistently noncompliant with the study medication [dexlansoprazole 30 mg 
capsules or placebo] (eg, at more than 2 consecutive compliance checks to have taken less than 
80% or more than 120% of the study medication), the subject should be withdrawn from the study. 
At each applicable study visit it should be documented in the subject’s medical record that study 
medication was dispensed or collected, and/or checked for compliance. All subjects should be 


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reinstructed about the dosing requirement during study contacts. The authorized study personnel 
conducting the re-education must document the process in the subject source records. 
When rescue medication has been taken for more than 7 consecutive days during the study 
Treatment Period, the investigator should discuss with CRO/sponsor and decide whether to 
withdraw the subject.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
9.3.1
Screening 
Subjects will be screened within 21 days prior to randomization. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Sections 9.1.14 for procedures for screening failures.
The clinical laboratory tests, hepatitis panel and endoscopy must be performed within 14 days 
prior to randomization.
Any reliable, documented results available from an endoscopy performed in a routine clinical 
setting (before signing of informed consent) in the same institution will be accepted, given the 
invasive nature of the procedure.
Procedures to be Completed During the Screening Period (Days -21 to Day -2) include:

Informed consent.

Demographics, medical and social history.

Medication history.

Physical examination.

Vital signs.

Weight and height.

Concomitant medication(s).

Concurrent medical condition(s).

Pretreatment events assessment.

Prescribe rescue medication and give the medical instruction, as necessary.

Screening clinical laboratory tests and hematology (to be performed within 14 days prior to 
randomization).

Urinalysis.

Serum and urine hCG (women of child-bearing potential only).

FSH (only performed if menopause is suspected).


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
Guidance on the avoidance of pregnancy.

Instructions on how to make entries in the subject eDiary, provision of the eDiary, and 
commencement of eDiary entry.

ECG.

Hepatitis panel including: HBsAg and HCV-antibody (to be performed within 14 days prior to 
randomization).

Endoscopy (to be performed within 14 days prior to randomization) 
9.3.2
Study Randomization
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IWRS system, as described in 
Section 8.2. Subjects will be instructed when to take the first dose of investigational drug as 
described in Section 6.1. The procedure for documenting Screening failures is provided in 
Section 9.1.14.
9.3.2.1
Day -1

Physical exam.

Vitals signs.

Weight.

Clinical laboratory tests (subjects should be fasting for a minimum of 8 hours prior to all labs) 
to include:
–
Urine and serum pregnancy test (baseline serum pregnancy test will not be needed if the 
screening pregnancy test is within 14 days of randomization).
–
Fasting gastrin.

GERD symptoms investigator assessment.

Daily eDiary review including compliance check.

Concomitant medication(s).

Pretreatment events assessment.

IWRS randomization.

Dispense study medication via IWRS.

Rescue medication compliance and accountability.

Dispense rescue medication as needed.


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9.3.3
Treatment Period
9.3.3.1
Day 1

Begin study medication.

Complete daily eDiary.
9.3.3.2
Week 2 Visit (± 3Days)
Procedures to be completed at Week 2 Visit include:

Physical examination.

GERD symptoms investigator assessment.

Vital signs.

Weight.

AE assessment.

Concomitant medication(s).

Daily eDiary review and compliance check.

Study drug compliance and accountability.

Rescue medication compliance and accountability.

Dispense study medication via IWRS.
9.3.4
Final Visit or Early Termination (± 3 Days)
Procedures to be completed at Week 4/Final Visit include:

Physical examination.

GERD symptoms investigator assessment.

Vital signs.

Weight.

AE assessment.

Concomitant medication(s).

Clinical laboratory tests (subjects should be fasting for a minimum of 8 hours prior to all labs) 
to include:
–
Chemistry panel and hematology.
–
Serum and urine hCG.
–
Urinalysis.


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–
Fasting gastrin.

ECG.

Daily eDiary review.

Return of study medication.

Study drug compliance and accountability.

Rescue medication compliance and accountability.
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
9.3.5
Unscheduled Visit
An unscheduled visit may occur when the subject returns to the clinic at any time during the 
Treatment Period of the study for the evaluation of symptoms or side effects.
At minimum, the following procedures are to be completed with additional procedures at the 
investigator’s discretion:

Physical examination.

GERD symptoms investigator assessment.

Vital signs.

Weight.

AE assessment.

Fasting gastrin.

Concomitant medication(s).
9.3.6
Follow-up 
The study center staff will follow up with a phone call 5 to 10 days post-treatment and any new 
AEs will be recorded in the eCRFs and subject’s source documents. Follow-up will begin the first 
day after the Final Visit/Early Termination and will continue until 10 days post treatment. 
9.3.7
Post Study Care
The study medication will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies as required.


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


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intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent 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 PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
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/PTEs:

If the subject experiences changes in severity of AEs/PTE, the event should be captured once 
with the maximum severity recorded.


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Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The principal investigator must make the distinction between exacerbation of 
pre-existing illness and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. 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.


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
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
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizures
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6 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 possible involvement of the drug can be 
argued, 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 drugs and concurrent treatments.
10.1.7 Relationship to Study Procedures
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The relationship should be assessed as “Related” if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship should 
be assessed as “Not related”.
10.1.8 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.9 Stop Date 
The stop date of the AE/ PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.10 Frequency
Episodic AEs/ PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.11 Action Concerning Study Medication 

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 was already 
stopped before the onset of the AE.

Dose reduced – the dose was reduced due to the particular AE.

Dose Interrupted - The study medication was temporarily interrupted (discontinued) (including 
voluntary drug interruption by the subject) due to the particular AE, and resumed at a later 
date.
10.1.12 Outcome 

Recovered/resolved – Subject returned to first assessment status with respect to the AEs/PTE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AEs/PTE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 


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subject died from another cause with the particular AEs/PTE state remaining “Not 
recovered/not resolved.”

Resolved with sequelae – the subject recovered from an acute AEs/PTE but was left with
permanent/significant impairment (eg, recovered from a cardiovascular accident but with
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death.

Unknown – the course of the AEs/PTE cannot be followed up due to hospital change or
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication or until 
screen failure. For subjects who discontinue prior to study medication administration, PTEs are 
collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication. Routine collection of AEs will continue until the Final Visit or Early Termination. A 
follow-up phone call will be made to each subject 5 to 10 days following the last dose of study 
drug to collect any AEs that may have occurred.
The stop date of the AEs/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or there is a satisfactory explanation for the change. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study 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 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. All PTEs and AEs will be documented in the PTE/AE page of the 


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eCRF, whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:

Event term.

Start and stop date and time.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of study
medication(s) (related or not related) (not completed for PTEs).

Investigator’s opinion of the causal relationship to study procedure(s), including the details of
the suspected procedure.

Action concerning study medication (not applicable for PTEs).

Outcome of event.

Seriousness.
Subject eDiary and questionnaire will not be used as a primary means to collect AEs. However, 
should the investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the patient for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 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.


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Also, investigators should report any SAE in appropriate format (ie, locally required form) to 
related authorities, IRB/IECs in accordance with local GCP and/or local regulations.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If during the treatment or follow up period a subject is noted to have ALT or AST >3 ×ULN and 
total bilirubin >2 ×ULN for which an alternative etiology has not been identified, the event should 
be recorded as an SAE and reported as per Section 10.2.2. The investigator must contact the 
Medical Monitor for discussion of the relevant subject details and possible alternative etiologies, 
such as acute viral hepatitis A or B or other acute liver disease. Follow-up laboratory tests as 
described in Section 9.1.10 must also be performed. In addition, an LFT Increases eCRF must be 
completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information 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.
10.3.1 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
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
Drug Dictionary (WHODRUG).
12.1
eCRF 
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRF must be completed in English. Data are entered directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date of the correction was made and the 
reason for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs 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 eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper should be 
copied and certified, source worksheets, all original signed and dated informed consent forms, 
subject authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. Furthermore, International Conference on Harmonisation (ICH) E6 Section 4.9.5 
requires the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 
2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 


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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 should contact and receive written approval from the sponsor before disposing of any 
such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. 
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject evaluability, 
and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
All efficacy analyses will be performed on the full analysis set (FAS), which will be defined as all 
randomized subjects who receive at least 1 dose of study drug and have post-baseline (post Day-1) 
data for the appropriate efficacy variable. The safety analysis set will include all randomized 
subjects who receive at least one dose of study drug.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline variables will be summarized using the safety analysis set and analyzed 
to assess the comparability of the treatment groups provided by randomization. Summary statistics 
(N, mean, median, SD, and range) will be generated for continuous variables (eg, age and weight). 
The numbers and percentages of subjects will be presented for categorical variables (eg, gender, 
race).
13.1.3 Efficacy Analysis
The primary efficacy variable will be the percentage of days without daytime or night time 
heartburn over 4 weeks as assessed by daily eDiary. Comparisons between dexlansoprazole 
capsules and placebo will be made using a Wilcoxon rank-sum test. 
The secondary efficacy variable will be the percentage of days without nighttime heartburn over 
4 weeks as assessed by daily eDiary. Comparisons between dexlansoprazole capsules and placebo 
will be made using a Wilcoxon rank-sum test. 
An additional efficacy variable will be the severity of GERD symptoms at Weeks 2 and 4 as 
assessed by the investigator. The severity of GERD symptoms at Weeks 2 and 4 will be analyzed 
using a Cochran-Mantel-Haenszel (CMH) test for ordered responses with baseline severity as the 
stratum. The percentage of days without rescue medication over 4 weeks as assessed by daily 
eDiary will be analyzed using Wilcoxon rank-sum test.
13.1.4 Safety Analysis
Safety will be assessed by summarizing the incidence of AEs, clinical laboratory tests, gastrin 
levels, ECG and vital signs using the safety analysis set.


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All AEs will be coded using MedDRA. Treatment-emergent adverse events (TEAE) will be 
summarized using preferred term and primary system organ class overall, by severity, and by 
relationship to study drug for each treatment group. Separate summaries will also be generated for 
treatment-related adverse events (TRAEs) overall and by severity. Adverse events that were 
reported more than once by a subject during the treatment period will be counted only once for that 
subject at the maximum severity.
Other safety assessments (ECG results, clinical laboratory values, gastrin levels, physical exams 
and vital signs) will be summarized by treatment group at all visits assessed using descriptive 
statistics. Values outside the reference ranges and markedly abnormal laboratory values will be 
flagged and tabulated.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
A total of 200 subjects are planned to be enrolled into this study to ensure 160 subjects with 
symptomatic nonerosive GERD will complete the study (assuming a 20% dropout rate). The 
sample size of 80 subjects per treatment group will provide at least 95% power at the 
0.05 two-sided significance level to detect a difference of 25% in the mean percentage of days 
without daytime or nighttime heartburn over 4 weeks between dexlansoprazole capsules (50%) 
and placebo (25%). The dexlansoprazole and placebo rates were estimated from prior 
dexlansoprazole study T-GD05-137. The common standard deviation was assumed to be 35%.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution 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 designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the medical 
monitor (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospective approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. The Significant Protocol Deviation eCRF is to be completed for deviations that are 
identified as significant by the sponsor.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and 
Medical Devices Agency of Japan [PMDA]). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all study documents as described in 
Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those US 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 informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will [ship drug/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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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical 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 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During 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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15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, Takeda will, at a minimum register all 
clinical trials conducted in patients that it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before trial initiation. Takeda contact information, along with 
investigator’s city, state (for US investigators), country, and recruiting status will be registered and 
available for public viewing. 
For some registries, Takeda will assist callers in locating trial 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 Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of this clinical trial, regardless of outcome, on ClinicalTrials.gov or 
other publicly accessible websites, as required by applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.


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16.0
REFERENCES
1. Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux
disease: a systematic review. Gut 2005;54(5):710-7.
2. Locke GR, 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ, 3rd. Prevalence and clinical
spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota.
Gastroenterology 1997;112(5):1448-56.
3. Fass R. Erosive esophagitis and nonerosive reflux disease (NERD): comparison of
epidemiologic, physiologic, and therapeutic characteristics. J Clin Gastroenterol
2007;41(2):131-7.
4. Fennerty MB, Castell D, Fendrick AM, Halpern M, Johnson D, Kahrilas PJ, et al. The
diagnosis and treatment of gastroesophageal reflux disease in a managed care environment.
Suggested disease management guidelines. Arch Intern Med 1996;156(5):477-84.
5. Hillman LC, Chiragakis L, Shadbolt B, Kaye GL, Clarke AC. Proton-pump inhibitor therapy
and the development of dysplasia in patients with Barrett's oesophagus. Med J Aust
2004;180(8):387-91.
6. Revicki DA, Wood M, Maton PN, Sorensen S. The impact of gastroesophageal reflux disease
on health-related quality of life. Am J Med 1998;104(3):252-8.
7. Fass R, Fennerty MB, Vakil N. Nonerosive reflux disease - current concepts and dilemmas.
Am J Gastroenterol 2001;96(2):303-14.
8. Freston JW. Therapeutic choices in reflux disease: defining the criteria for selecting a proton
pump inhibitor. Am J Med 2004;117(Suppl 5A):14S-22S.
9. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of oesophagitis: clinical and
functional correlates and further validation of the Los Angeles classification. Gut
1999;45:172-80.
10. Hunt RH. Review article: the unmet needs in delayed-release proton-pump inhibitor therapy in
2005. Aliment Pharmacol Ther 2005;22(Suppl 3):10-9.
11. Van Soest EM, Siersema PD, Dieleman JP, Sturkenboom MCJM, Kuipers EJ. Persistence and
adherence to proton pump inhibitors in daily clinical practice. Aliment Pharmacol Ther
2006;24(2):377-85.
12. Crawley JA, Schmitt CM. How satisfied are chronic heartburn sufferers with their prescription
medications? Results of the Patient Unmet Needs Survey. J Clin Outcomes Manage
2000;7(11):29-34.
13. Shaker R, Castell DO, Schoenfeld PS, Spechler SJ. Nighttime heartburn is an
under-appreciated clinical problem that impacts sleep and daytime function: the results of a
Gallup survey conducted on behalf of the American Gastroenterological Association. Am J
Gastroenterol 2003;98(7):1487-93.


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14. Zhang W, Wu J, Atkinson SN. Effects of dexlansoprazole MR, a novel dual delayed release 
formulation of a proton pump inhibitor, on plasma gastrin levels in healthy subjects. J Clin 
Pharmacol 2009;49(4):444-54.


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Appendix A
Schedule of Study Procedures
Screening Period
Treatment Period
Screening
Study 
Day -1
Baseline
Study 
Day 1
Week 2 
(a)
Week 4 
or Final 
Visit (a)
Unscheduled 
Visit
Follow-up 
Phone Call (m)
Study Day/Week:
Days -21 to 
-2
Day -1
Day 1
Week 2
Week 4 
Last dose+5 to 10 
days
Visit Windows (Days):
±3
±3
Visit Number:
1
2
3
4
5
Informed consent
X
Demographics/medical/social 
history
X
Medication history
X
Physical examination
X
X
X
X
X
Concurrent medical 
condition(s)
X
Vital signs, body weight and 
height 
X(b)
X
X
X
X
ECG
X
X
Endoscopy
X (c)
H. pylori serology
X
Clinical laboratory tests 
X (c)
X (d)
Hepatitis panel(l)
X (c)
Fasting serum gastrin (d)
X
X
X
Urine pregnancy test(k) 
X
X
X
Serum hCG(k) 
X
X 
X
Serum FSH
X (e)
Guidance on avoidance of 
pregnancy and ova and sperm 
donation
X
X
X
X
IWRS randomization
X
First day of study drug
X
Concomitant medication(s)
X
X
X
X
X
AEs assessment
X
X
X
X
X
X
GERD symptoms investigator 
assessment
X
X
X
X
Daily eDiary review/dispense 
(f) 
X
X
X
X
X
Dispense study drug via IWRS
X (g)
X
Study Drug 
return/accountability
X (h)
X
Dispense rescue medication 
X
X (i)
X (i)
Rescue medication 
return/accountability
X (j)
X (j)
X
Footnotes are on last table page.


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(a) Subjects who prematurely discontinue from the Treatment Period should undergo Final Visit procedures no later than 5 days
after the last dose of study drug.
(b) Height is measured only at Screening.
(c) The screening clinical laboratory tests, hepatitis panel and endoscopy must be performed within 14 days prior to randomization. 
Any reliable, documented results available from an endoscopy performed in a routine clinical setting (before signing of informed 
consent) in the same institution will be accepted instead, given the invasive nature of the procedure. 
(d) Except for Visit 1 (Screening Days -21 to -2), subjects should be fasting for a minimum of 8 hours prior to the specimen 
collection. During the study drug treatment period, subjects should be instructed to take their dose of study medication on the 
morning of their visit with a sip of water before specimen collection occurs. Breakfast should be eaten only after specimen 
collection.
(e) Only if menopause is suspected.
(f) Subjects should complete the eDiary every morning (for nighttime symptoms) and every evening (for daytime symptoms). The 
eDiary will be dispensed at Screening and reviewed at corresponding visit. eDiary needs to be checked carefully on Day -1 visit to 
assure the compliance and reeducate subjects accordingly if it’s necessary.
(g) Study drug dispensed on Study Day -1 of the Screening Period Visit after the subject has completed all of the Screening Period 
procedures and subject has met all admission criteria for the study. Study drug will be self-administered on a daily basis for 4 
weeks.
(h) Study drug will be returned at the Week 2 Visit for compliance verification.
(i) Rescue medication will be dispensed at Screening and may be dispensed at Study day -1 and Week 2 if needed.
(j) Rescue medication will be returned at Study day -1, Week 2 and Week 4 for accountability.
(k) Women of childbearing potential only. Baseline serum pregnancy test will not be needed if the screening pregnancy test is 
within 14 days of randomization.
(l) Hepatitis panel including HBsAg and HCV-antibody can be done either at the central laboratory or the local laboratory, 
depending on the site capability
(m) Follow-up phone call will occur for all subjects from 5 to 10 days after their last dose of study medication.


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


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12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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


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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 pharmacogenomic 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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25. Women subjects of childbearing potential (eg, nonsterilized, premenopausal women subjects)
who are sexually active must use adequate contraception (as defined in the informed consent)
from Screening and throughout the duration of the study. Regular pregnancy tests will be
performed throughout the study for all women subjects of childbearing potential. If a subject is
found to be pregnant during study, study medication will be discontinued and the investigator
will offer the subject the choice to receive unblinded treatment information.
26. Man subjects must use adequate contraception (as defined in the informed consent) from
Screening throughout the duration of the study. 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.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly
accessible website, such as ClinicalTrials.gov.


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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to
regulatory agencies relating to other medications used in other clinical studies that may contain
the same chemical compound present in the study 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.


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Appendix E
GERD Symptoms Investigator Assessment
Definitions of GERD Symptoms Assessed by Investigator
Symptom
Definition
Heartburn
A burning feeling in the mid-epigastric area and/or chest area.
Acid Regurgitation
Flow of sour or bitter fluid into the mouth.
Dysphagia
Difficulty in swallowing.
Belching
The voiding of gas from the stomach through the mouth, which may have been associated 
with acid regurgitation.
Epigastric Pain
Central upper abdominal pain.
Definitions of GERD Symptoms Severity by Investigator
Severity
Definition
None
No symptoms.
Mild
Symptom did not last long and was easily tolerated.
Moderate
Symptom caused discomfort and/or interrupted usual activities (including sleep).
Severe
Symptom caused great interference with usual activities and may have been incapacitating 
(including sleep).
Very Severe
Symptom caused intense and constant discomfort and/or marked interference with usual 
activities (including sleep).


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Appendix F
Definition of Heartburn Severity (Daytime/Nighttime)
Definitions of Daytime Heartburn Severity (Daytime=Awake Time)
None
No heartburn.
Mild
Occasional heartburn, can be ignored, does not influence daily routine.
Moderate
Heartburn cannot be ignored and/or occasionally influences daily routine.
Severe
Heartburn present most of day and/or regularly influences daily routine.
Very Severe
Constant heartburn and/or markedly influences daily routine.
Definitions of Nighttime Heartburn Severity (Nighttime=Sleep Time)
None
No heartburn.
Mild
Occasional heartburn, can be ignored, does not influence sleep.
Moderate
Heartburn cannot be ignored and/or occasionally influences sleep.
Severe
Heartburn present most of night and/or regularly influences sleep.
Very Severe
Constant heartburn and/or markedly influences sleep.


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Appendix G
eDiary
The following diary questions will be asked in the morning:
1. Did you have heartburn last night?
Yes 
No 
If yes, what was the maximum severity? Choose 1.

Mild

Moderate

Severe

Very Severe
2. Did you take any rescue medication last night? (such as Talcid
chewable tablets, Gaviscon tablets and/or other antacids)
Yes 
No 
The following diary questions will be asked in the evening: 
1. Did you have heartburn today?
Yes 
No 
If yes, what was the maximum severity? Choose 1.

Mild

Moderate

Severe

Very Severe
2. Did you take any rescue medication today? (such as Talcid chewable
tablets, Gaviscon tablets and/or other antacids)
Yes 
No 


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Appendix H
Detailed Description of Amendments to Text
This appendix describes content changes in reference to Protocol Incorporating Amendment 
No. 03, dated 20 February 2017.
Change 1: Update contract research organization (CRO) contact information.
The change occurs in Section 1.1 Contacts:
Description of 
change:
Changed the contact for SAE, pregnancy, and special interest adverse event 
reporting from 
to
. The methods of contact were updated 
accordingly.
Rationale for Change: The contact was updated to reflect a change in responsibilities at the CRO.
Change 2: Remove the requirement that the Screening Period be a minimum of 7 days.
The primary change occurs in 6.1 Study Design: 
Initial 
wording:
The study consists of 2 periods: a Screening Period, which will last a minimum of 7 
days and a maximum of 21 days, and a Treatment Period, which will last 4 weeks. 
Amended 
or new 
wording:
The study consists of 2 periods: a Screening Period, which will last a minimum of 7 
days and a maximum of 21 days, and a Treatment Period, which will last 4 weeks.
This change also appears in Section 6.1 Study Design, including Figure 6.a.
Rationale for Change: This change was made to correct an error in the protocol. If a subject has 
heartburn on at least 4 days and has eligible based on all other protocol-required screening 
procedures, it is possible that the Screening Period may be fewer than 7 days. 
Change 3: Change the appropriate contact for confirming available brands of rescue medication.
The change occurs in Section 8.1.1.2 Rescue Medication:
Initial 
wording:
If the listed rescue medications are not available, the subject should contact the 
contract research organization (CRO) or Takeda Medical Advisor for confirmation of 
available brand. 
Amended 
or new 
wording:
If the listed rescue medications are not available, the subject should contact the 
contract research organization (CRO) or Takeda Medical Advisor subject’s 
responsible investigator for confirmation of available brand. During the rescue 
medication administration, the following should be noted:
Rationale for Change: The subject does not need to contact the CRO or Takeda Medical Advisor, 
but can discuss available rescue medications with the investigator directly.
Personally
Protected Data
Persona
lly
Protecte
d Data


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Change 4: Gastrin levels will be blinded to both investigators and medical monitors during the 
study period.
The change occurs in Section 9.1.10, Procedures for Clinical Laboratory Samples, footnote b:
Initial 
wording:
(b) Gastrin levels to be measured under fasting conditions. Gastrin levels above the 
upper limit of normal will be evaluated by the medical monitor and principal 
investigator on a case-by-case basis.
Amended 
or new 
wording:
(b) Gastrin levels to be measured under fasting conditions. Gastrin levels above the 
upper limit of normal will be evaluated by the medical monitor and principal 
investigator on a case-by-case basis. Gastrin levels will be blinded to both 
investigators and the medical monitor during the study period.
Rationale for Change: Because PPI treatment will be associated with increases in gastrin levels, 
reviewing these data during the study may reveal the subject’s treatment assignment. 
This change also appears in a later paragraph within the text of Section 9.1.10 Procedures for 
Clinical Laboratory Samples.
Change 5: Clarify acceptable windows for screening labs and endoscopy.
The primary change occurs in Section 9.3.1 Screening.
Initial 
wording:
The clinical laboratory tests, hepatitis panel and endoscopy must be performed within 
7 days prior to randomization.
Amended 
or new 
wording:
The clinical laboratory tests, hepatitis panel and endoscopy must be performed within
7 14 days prior to randomization.
Rationale for Change: The window for screening labs and endoscopy was extended to 14 days 
prior to randomization in order to allow greater flexibility for scheduling procedures for subjects 
who may be eligible for study entry, but without compromising their safety.
The following sections also contain this change:

Section 6.1 Study Design.

Section 9.1.10 Procedures for Clinical Laboratory Samples.

Section 9.1.16 Endoscopy.

Section 9.3.2.1 Day -1.

Appendix A Schedule of Study Procedures.


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CONFIDENTIAL
Change 6: Update one of the definitions of an SAE.
The change occurs in Section 10.1.4 SAEs:
Initial 
wording:
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
Amended 
or new 
wording:
5. Leads to Is a CONGENITAL ANOMALY/BIRTH DEFECT.
Rationale for Change: Updated to be the correct definition.


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SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 


• 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 3 Double Blind Study to Evaluate the Efficacy and Safety of Dexlansoprazole 
(30 mg QD) compared to Placebo on Heartburn Relief in Subjects With Symptomatic 
Nonerosive Gastroesophageal Reflux Disease (GERD
NCT Number: NCT02873689
SAP Approve Date: 07 Dec 2018 
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 information or company confidential information. 
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.


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Dexlansoprazole Capsules 
Study No. TAK-390MR_302 
Amendment No. 01
Statistical Analysis Report 
Page 3 of 54
 
CONFIDENTIAL 
PREVIOUS AMENDMENTS 
There were no previous amendments to the statistical analysis report. 
REASON FOR AMENDMENT 
After the original statistical analysis report was approved, some errors in data presentation were 
identified. These errors have been corrected in this amendment. In addition, some other 
modifications have been made for consistency with presentation of information in the clinical 
study report. 
DESCRIPTION OF CHANGES 
All affected sections have been updated to reflect the correct data or consistent presentation of 
results. Changes are listed below, and a more detailed description of each change is provided in 
Section 12.7. 
1. Correct the incidence of TEAEs that were mild in intensity and recovered/resolved 
(Synopsis). 
2. Correct the cross-references for some data presented (Section 8.1) and correct the description 
of how many adverse events that led to premature discontinuation had recovered or resolved 
(Section 8.1). 
3. Add the information about adverse events that led to study discontinuation as “other 
significant adverse events” (Section 8.1.2.3). 
4. Clarify the type of markedly abnormal hematology values observed during the study (Section 
8.2.1). 
5. Correct the cross-references for some data presented and add the number of subjects at visit 4 
(week 4) for gastrin results (Section 8.2.4). 
6. Modify the language in the safety conclusion regarding the SAE or AE that led to premature 
discontinuation for consistency with the clinical study report (Section 8.6). 
7. Replace the table of efficacy results with one that does not include the ad hoc analyses. 
Update references in text accordingly. 
 
 
 
 
 


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Synopsis 
Name of Sponsor/Company: 
Takeda Development Center Asia, Pte. Ltd 
(For National Authority Use Only) 
Name of Finished Product: 
Dexlansoprazole capsule 
Name of Active Ingredient: 
Dexlansoprazole 
Title of Study: 
A Phase 3 Double Blind Study to Evaluate the Efficacy and Safety of Dexlansoprazole (30 mg QD) compared to 
Placebo on Heartburn Relief in Subjects With Symptomatic Nonerosive Gastroesophageal Reflux Disease 
(GERD) 
Protocol No: Protocol Incorporating Amendment No. 03 
Objectives: 
 
Primary Objective: 
To compare the efficacy of dexlansoprazole capsule (30 mg QD) and placebo in relief of daytime and nighttime 
heartburn over 4 weeks in Chinese subjects with symptomatic nonerosive GERD as assessed by daily electronic 
diary (eDiary). 
 
Secondary Objective: 
To compare the efficacy of dexlansoprazole capsules (30 mg QD) and placebo in relief of nighttime heartburn 
over 4 weeks in Chinese subjects with symptomatic nonerosive GERD as assessed by daily eDiary. 
Methodology: 
This was a phase 3, randomized, double-blind, multicenter, placebo-controlled, 2-arm study with a 4-week 
treatment period. This study compared the efficacy of dexlansoprazole capsule (30 mg QD) with that of placebo 
when administered orally as a single daily dose in the morning, without regard to food. The study was designed to 
evaluate heartburn relief in subjects with symptomatic nonerosive GERD. Two hundred and seventeen subjects 
over 18 years of age were randomized in the study at 20 sites in China: 108 subjects in Group I (dexlansoprazole 
30 mg QD) and 109 subjects in Group II (placebo QD). 
The study consisted of 2 periods: a screening period, which lasted a maximum of 21 days, and a treatment period, 
which lasted 4 weeks. 
Number of subjects (planned and analyzed): 
Planned = 200; Analyzed = 217. 
Endpoints: 
The primary endpoint for this study was the percentage of days with neither daytime nor nighttime heartburn over 
4 weeks as assessed by daily eDiary. 
The secondary endpoint was the percentage of days without nighttime heartburn over 4 weeks as assessed by 
daily eDiary. 
Additional endpoints of this study were as follows: 
 
The severity of GERD symptoms at Weeks 2 and 4 as assessed by the investigator. 
 
The percentage of days without rescue medication over 4 weeks as assessed by daily eDiary. 
Safety was assessed by adverse events (AEs), clinical laboratory evaluations (including gastrin), vital signs, 
physical examination, and electrocardiograms (ECGs). 
Statistical methods: 
Efficacy Analysis: 


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Name of Sponsor/Company: 
Takeda Development Center Asia, Pte. Ltd 
(For National Authority Use Only) 
Name of Finished Product: 
Dexlansoprazole capsule 
Name of Active Ingredient: 
Dexlansoprazole 
Primary Efficacy Endpoint: 
The Full Analysis Set (FAS) was used for the summary of the efficacy endpoints. The percentage of days with 
neither daytime nor nighttime heartburn over the 4 weeks of treatment was summarized descriptively (mean, 
median, standard deviation, minimum, and maximum). Comparisons between dexlansoprazole capsules and 
placebo were made using a Wilcoxon rank-sum test with a two-sided  p-value for the difference between 
dexlansoprazole capsules and placebo. Statistical significance was determined at the 0.05 level. 
The above descriptive statistics and analysis were also performed on the primary endpoint to summarize the 
treatment effects by subgroup. 
Secondary Efficacy Endpoint: 
The statistical methods performed on the primary endpoint were likewise performed on the secondary endpoint. 
Pharmacokinetic/Pharmacodynamic Analysis: 
Not applicable. 
Other Outcomes: 
Not applicable. 
Safety Analysis: 
Adverse Events: 
All AEs were coded by system organ class (SOC) and preferred term (PT) using the MedDRA Dictionary 
(Version 21.0). Treatment-emergent adverse events (TEAEs) with onset occurring within 30 days (onset date – 
last date of dose ≤30) after study drug administration were included in the summary tables. All AEs were 
presented in the listings. 
Clinical Laboratory Evaluations, Vital Signs, and 12-Lead ECGs: 
Summaries of descriptive statistics and individual listings were presented. Markedly abnormal value (MAV) 
tables and listings were also presented in the unit specified in the MAV criteria. 
Other Observations Related to Safety: 
Physical examination results were presented in data listings only. 


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Name of Sponsor/Company: 
Takeda Development Center Asia, Pte. Ltd 
(For National Authority Use Only) 
Name of Finished Product: 
Dexlansoprazole capsule 
Name of Active Ingredient: 
Dexlansoprazole 
Summary: 
Disposition: 
A total of 325 subjects were screened. Of the subjects screened, 108 (33.2%) were ineligible for entrance into the 
treatment period. The primary reasons for screen failure were subject did not meet entrance criteria (80.6%), 
withdrawal by subject (13.9%), and other reasons (5.6%). 
Of the subjects screened, 217 (66.8%) entered the treatment period at 20 sites in China: 108 subjects were 
randomized to the dexlansoprazole capsules group and 109 subjects were randomized to the placebo group. Of 
note, one subject in each group never received any study drug. 
A total of 10 subjects prematurely discontinued study drug, and 205 subjects completed all the study drug and 
planned study visits. 
Efficacy Analysis: 
Primary Efficacy Endpoint: 
For the percentage of days with neither daytime nor nighttime heartburn over the 4 weeks, the median value of 
dexlansoprazole capsules group (51.72) was greater than placebo group (32.67). The difference between the 
dexlansoprazole and placebo groups was not statistically significant (P=0.057). 
Secondary Efficacy Endpoint: 
For the percentage of days without nighttime heartburn over 4 weeks, the median value of dexlansoprazole 
capsules group (67.86) was greater compared with placebo group (54.67) and the difference was not statistically 
significant (P=0.268). 
Safety Analysis: 
Adverse Events: 
The incidence of TEAEs was similar between dexlansoprazole capsules group (36.4%) and placebo group 
(32.4%). Most of TEAEs were mild in intensity and recovered and resolved. The most frequently reported 
adverse event occurring in ≥5% of subjects were upper respiratory tract infection and nasopharyngitis, both of 
which were reported less frequently for dexlansoprazole capsules group than placebo group. The incidence of 
TEAEs leading to study drug discontinuation was low, occurring in 2 subjects (1.9%) in each treatment group. 
One SAE (animal scratch in a subject in the placebo group) was reported; the investigator assessed this event as 
not related to study drug. No deaths were reported. 
Clinical Laboratory Evaluations, Vital Signs, and12-Lead ECGs: 
The MAVs for a few of laboratory parameters were observed but weren’t reported as TEAEs or SAEs. None of 
the clinical laboratory results were clinically concerning. No subjects had any clinically concerning ECG or vital 
signs results. 
Conclusion: 
In this 4-week study of dexlansoprazole 30 mg or placebo in Chinese subjects with symptomatic nonerosive 
GERD, dexlansoprazole was safe and well tolerated. Subjects taking dexlansoprazole had a greater percentage of 
days without daytime or nighttime heartburn (difference of 19 percentage points) and without nighttime heartburn 
alone (difference of 13 percentage points) than subjects taking placebo, but the differences between the treatment 
groups were not statistically significant. Statistically significant improvements were observed, however, in 
several investigator-assessed GERD symptoms after 4 weeks of treatment with dexlansoprazole (an additional 
endpoint). In addition, subjects taking dexlansoprazole used statistically significantly less rescue medication than 


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Name of Sponsor/Company: 
Takeda Development Center Asia, Pte. Ltd 
(For National Authority Use Only) 
Name of Finished Product: 
Dexlansoprazole capsule 
Name of Active Ingredient: 
Dexlansoprazole 
those taking placebo. 
 
Date of the report: 07 December 2018 
 


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TABLE OF CONTENTS 
1.0 
STUDY OBJECTIVES ......................................................................................................13 
1.1 
Primary Objective ........................................................................................................13 
1.2 
Secondary Objectives...................................................................................................13 
2.0 
STUDY DESIGN...............................................................................................................14 
3.0 
ENDPOINTS .....................................................................................................................16 
3.1 
Primary Endpoint .........................................................................................................16 
3.2 
Secondary Endpoints ...................................................................................................16 
3.3 
Additional Endpoints ...................................................................................................16 
3.4 
Safety Assessments ......................................................................................................16 
4.0 
SAMPLE SIZE CALCULATIONS ...................................................................................17 
5.0 
STATISTICAL METHODS ..............................................................................................18 
5.1 
Data Analysis Methods ................................................................................................18 
5.1.1 General Considerations ..........................................................................................18 
5.2 
Data Handling Conventions .........................................................................................18 
5.2.1 Premature Withdrawal ...........................................................................................18 
5.2.2 Handling of Missing Data ......................................................................................18 
5.2.3 Handling of Missing/Partial Date ..........................................................................18 
5.2.4 Definition of Baseline and Change from Baseline ................................................19 
5.2.5 Definition of Study Days and Visit Window .........................................................19 
5.3 
Analysis Sets ................................................................................................................20 
5.4 
Disposition of Subjects ................................................................................................20 
5.5 
Significant Protocol Deviations ...................................................................................20 
5.6 
Demographic and Other Baseline Characteristics .......................................................20 
5.7 
Medical History and Concurrent Medical Conditions .................................................21 
5.8 
Medication History and Concomitant Medications .....................................................21 
5.9 
Study Drug Exposure and Overdose ............................................................................21 
5.10 
Efficacy Analysis .........................................................................................................22 
5.10.1 Primary Efficacy Endpoint ....................................................................................22 
5.10.2 Secondary Efficacy Endpoints ...............................................................................23 
5.10.3 Additional Efficacy Endpoints ...............................................................................23 
5.11 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................24 
5.12 
Other Outcomes ...........................................................................................................24 
5.13 
Safety Analysis ............................................................................................................24 
5.13.1 Adverse Events ......................................................................................................24 


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5.13.2 Clinical Laboratory Evaluations ............................................................................25 
5.13.3 Vital Signs ..............................................................................................................25 
5.13.4 12-Lead ECGs ........................................................................................................25 
5.13.5 Other Observations Related to Safety ....................................................................25 
5.14 
Interim Analysis ...........................................................................................................25 
5.15 
Changes in the Statistical Analysis Plan ......................................................................26 
6.0 
STUDY RESULTS ............................................................................................................27 
6.1 
Disposition of Subjects ................................................................................................27 
6.2 
Significant Protocol Deviation .....................................................................................29 
6.3 
Analysis Sets ................................................................................................................30 
6.4 
Demographics and Other Baseline Characteristics ......................................................30 
6.5 
Medical History and Concurrent Medical Conditions .................................................30 
6.6 
Medication History and Concomitant Medications .....................................................30 
6.6.1 Medication History ................................................................................................30 
6.6.2 Concomitant Medications ......................................................................................31 
6.7 
Study Drug Exposure and Overdose ............................................................................31 
7.0 
EFFICACY EVALUATION .............................................................................................32 
7.1 
Primary and Secondary Efficacy Endpoint ..................................................................32 
7.2 
Additional Efficacy Endpoints .....................................................................................35 
7.2.1 Symptom Severity ..................................................................................................35 
7.2.2 Rescue Medication Use..........................................................................................36 
7.3 
Efficacy Conclusions ...................................................................................................36 
8.0 
SAFETY EVALUATION .................................................................................................38 
8.1 
Adverse Events ............................................................................................................38 
8.1.1 Display of Adverse Events.....................................................................................38 
8.1.2 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events ...39 
8.2 
Clinical Laboratory Evaluation ....................................................................................39 
8.2.1 Hematology ............................................................................................................39 
8.2.2 Serum Chemistry ...................................................................................................40 
8.2.3 Urinalysis ...............................................................................................................40 
8.2.4 Serum Gastrin ........................................................................................................40 
8.3 
Vital Signs ....................................................................................................................41 
8.4 
12-Lead ECGs ..............................................................................................................41 
8.5 
Other Observations Related to Safety ..........................................................................41 
8.6 
Safety Conclusions.......................................................................................................41 


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9.0 
DISCUSSION AND OVERALL CONCLUSIONS ..........................................................42 
9.1 
Discussion ....................................................................................................................42 
9.2 
Conclusion ...................................................................................................................44 
10.0 
REFERENCES ..................................................................................................................45 
11.0 
DATA ISSUE NARRATIVES ..........................................................................................49 
12.0 
APPENDIX ........................................................................................................................50 
12.1 
Source Database, Analytic Database and Corresponding Variable Specification 
Document .....................................................................................................................50 
12.2 
Flow Chart of Subject Disposition ...............................................................................50 
12.3 
Randomization Scheme ...............................................................................................50 
12.4 
Blind Review Resolutions............................................................................................50 
12.5 
Statistical Figures and Tables Supplementary to the Main Text .................................50 
12.6 
Data Issue File Note .....................................................................................................50 
12.7 
Detailed Description of Amendments to Text .............................................................50 
 
LIST OF IN-TEXT TABLES 
Table 5.a 
Visit Window .........................................................................................................19 
Table 6.a 
Overall Disposition of Subjects .............................................................................28 
Table 7.a 
Percentage of Days Without Heartburn During Treatment (Full Analysis Set) ....33 
Table 7.b 
Subgroup Analyses of Percentage of Days With Neither Daytime Nor 
Nighttime Heartburn Over 4 Weeks (Full Analysis Set) .......................................34 
Table 8.a 
Overview of Treatment-Emergent AEs (Safety Analysis Set) ..............................38 
Table 8.b 
Most Frequent Treatment-Emergent Adverse Events by Preferred Term - PT 
Occurring in ≥5% of Subjects in Either Treatment Group (Safety Analysis 
Set) .........................................................................................................................39 
Table 8.c 
Summary of Gastrin Results (Safety Analysis Set) ...............................................41 
 
LIST OF IN-TEXT FIGURES 
Figure 2.a 
Schematic of Study Design ....................................................................................15 
Figure 6.a 
Flow Chart of Subject Disposition .........................................................................29 
 
LIST OF APPENDICES 
Appendix A 
Criteria for Identification of Markedly Abnormal Laboratory Values ..................46 
Appendix B 
Criteria for Markedly Abnormal Values for Vital Signs .......................................47 


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Appendix C 
Criteria for Markedly Abnormal Values for Electrocardiograms ..........................48 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CMH 
Cochran-Mantel-Haenszel 
CPK 
creatine phosphokinase 
ECG 
electrocardiogram 
FAS 
full analysis set 
GERD 
gastroesophageal reflux disease 
GGT 
γ - glutamyl transferase 
HLT 
high level term 
ICF 
informed consent form 
IWRS 
interactive web response system 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MAV 
markedly abnormal values 
PT 
preferred term 
QD 
once daily 
RBC 
RBC red blood cells 
SAE 
serious adverse event 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TRAE 
treatment-related adverse event 
ULN 
upper limit of normal 
WBC 
white blood cells 
WHODrug 
World Health Organization Drug Dictionary 
 


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1.0 
STUDY OBJECTIVES 
1.1 
Primary Objective 
The primary objective was to compare the efficacy of dexlansoprazole capsule (30 mg QD) and 
placebo in relief of daytime and nighttime heartburn over 4 weeks in Chinese subjects with 
symptomatic nonerosive GERD as assessed by daily electronic diary (eDiary). 
1.2 
Secondary Objectives 
To compare the efficacy of dexlansoprazole capsules (30 mg QD) and placebo in relief of 
nighttime heartburn over 4 weeks in Chinese subjects with symptomatic nonerosive GERD as 
assessed by daily eDiary. 


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2.0 
STUDY DESIGN 
This was a phase 3, randomized, double-blind, multicenter, placebo-controlled, 2-arm study with 
a 4-week treatment period. This study compared the efficacy of dexlansoprazole capsule (30 mg 
QD) with that of placebo when administered orally as a single daily dose in the morning, without 
regard to food. The study was designed to evaluate heartburn relief in approximately 200 
subjects with symptomatic nonerosive GERD. The study consisted of 2 periods: a Screening 
Period, which lasted a maximum of 21 days, and a Treatment Period, which lasted 4 weeks.  
After signing an informed consent form (ICF), subjects underwent a Screening Period. Subjects 
were instructed that lifestyle or behavioral modifications designed to treat their symptoms of 
GERD should not be altered throughout the study.  
During the Screening Period, subjects underwent various procedures to determine eligibility for 
the Treatment Period. Screening evaluations included the following: demographics, medical and 
social history, physical examination including vital signs, height and weight, ECG, endoscopy, 
clinical laboratory evaluations including hepatitis panel, urine and serum pregnancy test (all 
women subjects of childbearing potential), and concomitant medication assessment. The 
screening clinical laboratory tests, hepatitis panel, and endoscopy were to be performed within 
14 days prior to randomization. Subjects were given rescue medication and eDiary on the first 
day of the Screening Period. Throughout the Screening Period, subjects recorded their usage of 
rescue medication (which was supplied throughout the screening period) and documented the 
presence and maximum severity of daytime and nighttime heartburn symptoms each day in their 
eDiary. Endoscopy data were collected to exclude subjects with EE. 
Subjects who satisfied the screening evaluation and selection criteria (as described in Protocol 
Section 7.1 and 7.2) were entered into the study.  
All subjects returned to the investigative site on Day -1, which was deemed as the Baseline. 
Subjects who had completed all of the Screening procedures and met all eligibility requirements 
and none of the exclusion criteria had routine fasting laboratory evaluations including fasting 
serum gastrin, a urine pregnancy test (all women subjects of childbearing potential), a physical 
examination and vital signs measurements to assure continued eligibility. In addition, subjects 
were assessed by the investigator for GERD symptoms such as heartburn, acid regurgitation, 
dysphagia, belching, and epigastric pain.  
Subjects were dispensed study drug on Day -1 according to an Interactive Web Response System 
(IWRS) and began taking study drug on the following day (Day 1). Rescue medication continued 
to be supplied during the Treatment Period. 
Subjects were randomized in a 1:1 ratio to one of the following 2 treatment groups during the 4-
week Treatment Period: 
Group I:  
dexlansoprazole capsules (30 mg QD) 
 
Group II:  
placebo (QD) 
During this 4-week Treatment Period, study drug was self-administered, orally, once a day, in 
the morning, without regard to food. Subjects continued to document the presence and maximum 


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severity of daytime and nighttime heartburn symptoms and record usage of rescue medication 
using an eDiary. Subject visits were conducted at Weeks 2 and 4 of the Treatment Period to 
collect and/or dispense study drug, assess GERD symptoms, review concomitant medication use, 
assess adverse events, and perform a physical examination including vital signs. In addition, at 
the Week 4/ Final Visit, all subjects underwent laboratory evaluations, ECG, fasting serum 
gastrin and urine pregnancy test (all women of childbearing potential). Subjects who prematurely 
discontinued after randomization underwent Week 4/Final Visit procedures no later than 5 days 
after the last dose of study drug. 
A schematic of the study design is included as Figure 2.a. 
Figure 2.a 
Schematic of Study Design 
 
dexlansoprazole (30 mg QD) 
 
 
Screening Period  
OR 
(up to 21 days) 
 
 
placebo (QD)  
 
 
 
 
Treatment Period 
 
Day -1 
Day 1 
Week 2 
Week 4/Final Visit 
 
Randomize 
1st Dose 
 
 
 
 


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3.0 
ENDPOINTS 
3.1 
Primary Endpoint 
The primary endpoint was the percentage of days with neither daytime nor nighttime heartburn 
over 4 weeks as assessed by daily eDiary. 
3.2 
Secondary Endpoints 
The secondary endpoint was the percentage of days without nighttime heartburn over 4 weeks as 
assessed by daily eDiary.  
3.3 
Additional Endpoints 
 The severity of GERD symptoms at Weeks 2 and 4 as assessed by the investigator. 
 The percentage of days without rescue medication over 4 weeks as assessed by daily eDiary. 
3.4 
 Safety Assessments 
Safety was assessed by adverse events (AEs), clinical laboratory evaluations (including gastrin), 
vital signs, physical examination, and electrocardiograms (ECGs). 


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4.0 
SAMPLE SIZE CALCULATIONS 
A total of 200 subjects were planned to be enrolled into this study to ensure 160 subjects with 
symptomatic nonerosive GERD would complete the study (assuming a 20% dropout rate). The 
sample size of 80 subjects per treatment group would provide at least 95% power at the 
0.05 two-sided significance level to detect a difference of 25% in the mean percentage of days 
without daytime or nighttime heartburn over 4 weeks between dexlansoprazole capsules (50%) 
and placebo (25%). The dexlansoprazole and placebo rates were estimated from prior 
dexlansoprazole study T-GD05-137. The common standard deviation was assumed to be 35%. 


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5.0 
STATISTICAL METHODS 
5.1 
Data Analysis Methods 
5.1.1 General Considerations 
Statistical analysis was performed using SAS software (SAS Institute, Inc., Cary, North 
Carolina) Version 9.2. 
All study-related raw data for enrolled subjects, including derived data, were presented in data 
listings. Continuous data were summarized using number of subjects, mean, standard deviation, 
median, minimum, and maximum. Categorical data were summarized using the number and 
percentage of subjects for each category where appropriate. 
All tabulations of analysis results including summaries were displayed for the following 
treatment groups: dexlansoprazole 30 mg QD and placebo QD.  
5.2 
Data Handling Conventions 
5.2.1 Premature Withdrawal 
The investigator may have discontinued a subject’s study participation at any time during the 
study when the subject met the study termination criteria. In addition, a subject may have 
discontinued his or her participation without giving a reason at any time during the study. Should 
a subject’s participation have been discontinued, the primary criterion for termination was 
recorded. Discontinued or withdrawn subjects were not replaced after enrollment. All available 
data from subjects who were withdrawn from the study were listed and all available planned data 
were included in summary. 
5.2.2 Handling of Missing Data 
With the exception of missing or partial dates (Section 5.2.3), no imputed values were used for 
missing data. 
5.2.3 Handling of Missing/Partial Date 
Completely missing start or end dates remained missing, with no imputation applied. 
Partial dates were imputed using the below conventions: 
 If the partial date was a start date and: 
– If only missing day, then impute as the first day of the month. 
– If missing both month and day then, impute as the first day of the year. 
 If the partial date was an end date and: 
– If only missing day, then impute as the last day of the month. 
– If missing both month and day, impute as the last day of the year. 


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 If the partial date was in the same month (only missing day) or same year (missing both 
month and day) as the study treatment, and the imputed start date of an adverse event (not 
pretreatment event) was prior to the start of study treatment, then the start date of study 
treatment was assumed to be the start date. The AE would then be considered as start on 
treatment (worst case scenario). 
 If the imputed end date was after the subject’s last visit date (or last contact date), then the 
last visit date (or last contact date), was considered as the end date. 
The recorded partial date was displayed in the listings.  
5.2.4 Definition of Baseline and Change from Baseline 
Baseline was defined as the last non-missing measurement prior to or on the date of the first dose 
of study drug (Study Day 1).  
The change from baseline was calculated by subtracting the baseline values from the individual 
post-baseline values. If either the baseline or post-baseline value was missing, the change from 
baseline was set to missing as well. 
5.2.5 Definition of Study Days and Visit Window 
Study day was calculated relative to the date of the first dose of study drug in the study. The 
study day prior to the first dose of study drug was calculated as:  
Date of assessment/event – date of first dose of study drug  
The study day on or after the first dose of study drug was calculated as:  
Date of assessment/event – date of first dose of study drug + 1. 
The visit windows for the post baseline visits were defined in Table 5.a. If a subject had more 
than 1 measurement in the same visit window, the measurement closest to the scheduled visit 
was used. If 2 measurements in the same window were of equal distance to the scheduled visit, 
the measurement that occurred after the scheduled visit was used. If 2 or more measurements 
occurred on the same day, the last value obtained was used. 
Table 5.a 
Visit Window 
Visit 
Scheduled Day 
Safety Labs & 
Serum Gastrin 
Vital Signs 
ECG 
GERD Symptoms 
Investigator 
Assessment 
Baseline 
Day -1 
1 
1 
1 
1 
Week 2 
Day 14 
2-21 
2-21 
NA 
2-21 
Week 4 
Day 28 
22-35 
22-35 
2-35 
22-35 
Note: Safety labs (including gastrin), vital signs, and ECG data obtained more than 7 days after the last day of study 
drug and efficacy data obtained more than 7 days after the last day of study drug weren’t included in the analyses. 
Diary entries were assigned to study days according to the beginning of the recall period. 
Specifically, entries completed in the evening (reporting heartburn during the day) were assigned 


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to the same day; entries completed in the morning (reporting heartburn during the night) were 
assigned to the previous day.  
For the purpose of diary compliance calculation and derivation of diary-based endpoints, the last 
day of study drug wasn’t included since the subject was not expected to have completed the diary 
entries for that day by the Week 4/Final Visit. Therefore, summaries for the 4 weeks of treatment 
included Study Day 1 through Study Day 35 or the day before the last dose of study drug, 
whichever occurred first. 
For efficacy variables summarized by visit, the value closest to the last day of study drug was 
summarized for each subject, including those within 7 days of the last day of study drug. If 
2 measurements were of equal distance to the last day of study drug, the later measurement was 
used. 
AEs that started more than 30 days after the last dose of study drug were listed, but excluded 
from the summaries and analyses.  
5.3 
Analysis Sets 
All efficacy analyses were performed on the full analysis set (FAS), which was defined as all 
randomized subjects who receive at least 1 dose of study drug and had post-baseline (post 
Day -1) data for the appropriate efficacy variable. The safety analysis set included all 
randomized subjects who received at least one dose of study drug. 
5.4 
Disposition of Subjects 
A subject disposition summary was provided. Subjects’ study completion data, including reasons 
for premature termination, were provided in listings and also summarized. 
A summary of screening failures was also provided. 
5.5 
Significant Protocol Deviations 
A summary of the number and percentage of subjects with a significant protocol deviation by 
type of deviation was provided using the safety analysis set. Individual subject listings of 
significant protocol deviations were provided. 
5.6 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics variables were summarized using the safety analysis 
set. 
For continuous variables (age, weight, height, and body mass index [BMI]), summary statistics 
were generated. 
For categorical variables, the number and percentage of subjects in each category was presented. 


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The following baseline characteristics were summarized.  
 Number of days with daytime or nighttime heartburn between Study Days -8 and -2, 
inclusive. 
 Number of days with nighttime heartburn between Study Days -8 and -2, inclusive. 
 Number of days with daytime heartburn between Study Days -8 and -2, inclusive. 
 Mean severity of daytime and nighttime heartburn between Study Days -8 and -2, inclusive. 
 Mean severity of nighttime heartburn between Study Days -8 and -2, inclusive. 
 Mean severity of daytime heartburn between Study Days -8 and -2, inclusive. 
 Baseline severity of GERD symptoms as assessed by the investigator. 
 Baseline number of days with daytime/nighttime rescue medication use.  
5.7 
Medical History and Concurrent Medical Conditions 
Medical history and concurrent medical conditions were presented in a data listing and were 
summarized, count and percent, using the safety analysis set. 
5.8 
Medication History and Concomitant Medications 
All medication history and concomitant medications were coded by therapeutic classification, 
sub classification, and medication using the World Health Organization Drug Dictionary (WHO 
Drug). A concomitant medication was defined as a medication that was ongoing as of Study Day 
1, ends on or after Study Day 1, or starts on or after Study Day 1 and no more than 1 day after 
the last dose of study drug. 
The number and percentage of subjects taking each concomitant medication was summarized for 
the safety analysis set. A subject with 1 or more concomitant medications within the same level 
of the WHODrug classification was counted only once in that level. WHODrug preferred term 
and therapeutic classification was used for summary: 
 Medication history that the study subjects stopped taking within 90 days prior to the 
screening visit. 
 Concomitant medications that started and stopped prior to baseline. 
 Concomitant medications that started prior to and were ongoing at baseline. 
 Concomitant medications that started after baseline. 
 Concomitant medications that were ongoing at baseline and those that started after baseline. 
5.9 
Study Drug Exposure and Overdose 
Overall study drug compliance (%) was determined as (total count of capsules taken / total 
number of days on study drug) ×100%. The total number of days on study drug (exposure) was 


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calculated as date of last dose of study drug - date of first dose of study drug + 1, assuming no 
gaps in the dosing interval. Any gaps in dosing interval was ignored in the calculation of the 
total. If last dose date was missing, then 35 days were imputed as treatment period. Summary 
statistics for the total number of days on study drug and overall compliance were generated for 
the safety analysis set.  
The number and percentage of subjects with overall study drug compliance of <80%, 80-<90%, 
and ≥90% was also summarized for the safety analysis set. Subjects with unreturned study drug 
were assumed to have taken 1 capsule of study drug for each day of exposure for the calculation 
of overall compliance. Subjects with overall compliance ≥100% were set to 100% in the 
analysis. 
In addition, diary compliance was determined as the percentage of days during treatment with 
two diary entries: 
Diary Compliance =  
(Number of days with two diary entries collected during treatment period)/(Number of 
days with two diary entries expected during treatment period) × 100% 
5.10 
Efficacy Analysis 
The FAS was used for the summary of the efficacy endpoints.  
5.10.1 Primary Efficacy Endpoint 
The percentage of days with neither daytime nor nighttime heartburn over the 4 weeks of 
treatment was summarized descriptively. Comparisons between dexlansoprazole capsules and 
placebo was made using a Wilcoxon rank-sum test. The two-sided p-value was presented for the 
difference between dexlansoprazole capsules and placebo; the difference was considered 
statistically significant if the p-value was less than 0.05.  
The percentage of days with neither daytime nor nighttime heartburn was calculated for each 
subject who has at least 1 daytime or nighttime heartburn result (presence or absence of 
heartburn) during the 4 weeks of treatment (up to last dose day or Day 35 whichever is first) by 
calculating: 
Percentage of days with neither daytime nor nighttime heartburn = (the days that were 
heartburn-free during Treatment Period)/ (Total number of days for which either a 
daytime or nighttime result was marked during Treatment Period)  100%; 
all entries on a day must be heartburn-free in order for the day to be counted as a day with 
neither daytime nor nighttime heartburn. 
The days with missing diary results for both daytime and nighttime were excluded from the 
numerator and denominator. If a subject prematurely terminated, the Treatment Period was 
defined as from first dose date to last dose date + 1 day. If last dose date was missing, then 35 
days was imputed as treatment period. 


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Subgroup Analyses: 
Similar descriptive statistics and Wilcoxon rank-sum tests were repeated on the primary endpoint 
to evaluate the treatment effect within the different baseline subpopulation levels as follows: 
 Age (<45, ≥45 to <65, ≥65 years). 
 Gender (male, female). 
 BMI (<25, 25-<30, ≥30 kg/m2). 
 H pylori status (positive, negative). 
 Overall study drug compliance (<80%, 80-<90%, ≥90%). 
Ad Hoc Sensitivity Analysis 
Similar descriptive statistics and two sample T-test were repeated on the primary endpoint to 
evaluate the treatment effect. 
5.10.2 Secondary Efficacy Endpoints 
Descriptive statistics (mean, median, standard deviation, minimum and maximum) were 
presented similarly to the primary endpoint. Comparisons between dexlansoprazole capsules and 
placebo was made using a Wilcoxon rank-sum test. The p-value was presented for the difference 
between dexlansoprazole capsules and placebo; the difference was considered significant if the 
two-sided p-value was less than 0.05. The ad hoc sensitivity analysis described for the primary 
endpoint was also performed on the secondary endpoint. 
5.10.3 Additional Efficacy Endpoints 
The severity of GERD symptoms at Weeks 2 and 4 was analyzed using a Cochran-Mantel-
Haenszel (CMH) test for ordered responses with baseline severity as the stratum. The p value 
was presented for the difference between dexlansoprazole capsules and placebo; the difference 
was considered significant if the p-value was less than 0.05.  
The percentage of days without rescue medication over 4 weeks as assessed by daily eDiary was 
analyzed using the Wilcoxon rank-sum test. 
In addition, descriptive statistics were presented for the endpoints below: 
 The percentage of days without daytime heartburn over the 4 weeks of treatment as assessed 
by daily eDiary. 
 The severity of daytime and nighttime heartburn hurt over the 4 weeks of treatment as 
assessed by daily eDiary. 
 The severity of nighttime heartburn hurt over the 4 weeks of treatment as assessed by daily 
eDiary.  
 The severity of daytime heartburn hurt over the 4 weeks of treatment as assessed by daily 
eDiary. 


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5.11 
Pharmacokinetic/Pharmacodynamic Analysis 
Not applicable. 
5.12 
Other Outcomes 
Not applicable. 
5.13 
Safety Analysis 
All safety analyses were performed using the safety analysis set.  
5.13.1 Adverse Events 
All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
A treatment-emergent adverse event (TEAE) was defined as an AE that started or worsened on 
or after Study Day 1 (defined as day first dosed), and no more than 30 days after the last dose of 
study drug. All TEAEs were listed by subject number and MedDRA coding. A listing of all 
unique coded terms was also provided. 
The number and percentage of subjects with treatment-emergent AEs was summarized in several 
different tables: 
 All AEs by system organ class (SOC), high level term (HLT), and preferred term (PT). 
 Treatment-related AEs by SOC, HLT, and PT. 
 Most frequent AEs by SOC and PT (sorted by total frequency of PT occurring in 5% of 
subjects in any treatment group).  
 Most frequent treatment-related AEs (TRAEs) by HLT and PT (sorted by total frequency of 
HLT occurring in 2% of subjects in any treatment group). If no events met the 2% criteria, 
the most frequent TRAEs were defined as those events occurring in 2 or more subjects. 
 Severity of all AEs by SOC and PT (mild, moderate, or severe). 
 Severity of TRAEs by SOC and PT (mild, moderate, or severe). 
 Relationship to study drug for all AEs by SOC and PT (not related, related). 
A subject with 2 or more AEs within the same level of the MedDRA term was counted only once 
in that level using the most extreme incident (most severe for the severity tables and related for 
the relationship to study drug tables).  
Additionally, treatment-emergent serious adverse events, deaths, and TEAEs resulting in 
premature discontinuation from study drug were listed and summarized by SOC, HLT and PT. 
The most frequent treatment-emergent non-serious AEs were also summarized by SOC, HLT 
and PT. 
A pretreatment event was defined as an AE that ends prior to Study Day 1 (defined as day first 
dosed), or ends but not worsens on or after Study Day 1 (defined as day first dosed). A list of 


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pretreatment AEs by subject number and MedDRA coding was presented separately. 
Pretreatment AEs were summarized by SOC and PT. 
5.13.2 Clinical Laboratory Evaluations 
Clinical laboratory variables (including serum fasting gastrin) were summarized using 
descriptive statistics for baseline, post baseline, and change from baseline to post baseline values. 
Individual results for clinical hematology and chemistry laboratory tests that were within the 
predefined laboratory markedly abnormal value (MAV) criteria (Appendix A) were summarized 
in tables. All clinical laboratory data were presented in data listings. 
The percentages of subjects with elevated gastrin values ≥200 pg/mL and ≥400 pg/mL were 
summarized. 
The number and percentages of patients with the following elevations in hepatic laboratory tests 
were summarized: 
 ALT or AST >8×ULN. 
 ALT or AST >5×ULN. 
 ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN. 
Summaries and listings of laboratory data were presented. MAV tables and listings were 
presented in the unit specified in the MAV criteria. 
5.13.3 Vital Signs 
Vital signs were summarized using descriptive statistics for Baseline, post baseline, and change 
from Baseline to post baseline values.  
All individual vital signs that met predefined criteria for MAVs (Appendix B) were summarized 
in tables. All vital sign data were presented in data listings. 
5.13.4 12-Lead ECGs 
ECG results were interpreted using 1 of the following categories: within normal limits, abnormal 
but not clinically significant, or abnormal and clinically significant. Week 4 ECG assessments 
were cross-tabulated against the baseline assessment.  
All individual quantitative ECG values that met predefined criteria for MAVs (Appendix C) 
were listed. All ECG data were presented in a data listing. 
5.13.5 Other Observations Related to Safety 
Physical examination results were presented in a data listing and weren’t summarized. 
5.14 
Interim Analysis 
Not applicable.  


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5.15 
Changes in the Statistical Analysis Plan 
After the unblinded results for the primary and secondary endpoints were available an ad hoc 
sensitivity analysis was performed. This was done since the placebo response was higher than 
expected and since the p-value for the primary analysis of the primary endpoint was greater than 
the level of significance by a small amount. The sensitivity analysis doesn't replace the primary 
analysis but to see if the conclusion was replicated with a different testing method. Additionally, 
the most frequent AEs were displayed by SOC and PT instead of HLT and PT. 


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6.0 
STUDY RESULTS 
6.1 
Disposition of Subjects 
A total of 325 subjects were screened. Of the subjects screened, 108 (33.2%) were ineligible for 
entrance into the treatment period. The primary reasons for screen failure were subject did not 
meet entrance criteria (80.6%), withdrawal by subject (13.9%), and other reasons (5.6%). 
Of the subjects screened, 217 (66.8%) entered the treatment period at 20 sites in China: 108 
subjects were randomized to the dexlansoprazole capsules group and 109 subjects were 
randomized to the placebo group. Of note, one subject in each group never received any study 
drug.   
A total of 10 subjects prematurely discontinued study drug, and 205 subjects completed all the 
study drug and planned study visits. 
Overall subject disposition is presented in Table 6.a, and a flow chart is presented Figure 6.a. By-
subject listings of screen failures and subject disposition are provided in Appendix 16.2.1.2 and 
16.2.1.3. 
 


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Table 6.a 
Overall Disposition of Subjects 
 
Placebo 
QD 
N (%) 
Dexlansoprazole 
30 mg QD 
N (%) 
Total 
N (%) 
Subject Screened 
 
 
325 
Subjects Eligible for Entrance Into Treatment Period (a) 
 
 
217 (66.8) 
Randomized But Not Treated (b) 
1 (<1) 
1 (<1) 
2 (<1) 
Completed Study Drug (b) 
102 (93.6) 
103 (95.4) 
205 (94.5) 
Prematurely Discontinued Study Drug (b) 
6 (5.5) 
4 (3.7) 
10 (4.6) 
Completed All Planned Study Visits (b) 
102 (93.6) 
103 (95.4) 
205 (94.5) 
Did Not Complete All Planned Study Visits (b) 
7 (6.4) 
5 (4.6) 
12 (5.5) 
Subjects Not Eligible for Entrance Into Treatment Period (a) 
 
 
108 (33.2) 
 Primary Reason Subject not Eligible for Treatment Period (c) 
 
 
 
Adverse Event 
 
 
0 
Significant Protocol Deviation 
 
 
0 
Lost to Follow-up 
 
 
0 
Withdrawal by Subject 
 
 
15 (13.9) 
Study Termination by Sponsor 
 
 
0 
Pregnancy 
 
 
0 
Did not Meet Inclusion Criteria or Did Meet Exclusion Criteria 
 
 
87 (80.6) 
Other 
 
 
6 (5.6) 
Source: Table 15.1.3 and Table 15.1.5. 
(a) Denominator of the percentage is the number of subjects screened. 
(b) Denominator of the percentage is the total number of subjects who are eligible for entrance into treatment period. 
(c) Denominator of the percentage is the total number of subjects who aren’t eligible for entrance into treatment 
period. 


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1. One subject (20016-001) had technical difficulties with the eDiary during screening, so the 
data for that subject were captured on paper for 2 days and are not included in the database. 
This was not expected to affect the analysis since the subject met the screening heartburn 
criteria. 
2. After the database was locked, site quality control revealed that one subject (20015-007) had 
heartburn symptoms for fewer than 4 days during the 7 days prior to Day -1. The subject did 
not meet the inclusion criterion for number of days with heartburn symptoms, but was 
enrolled in error and completed dosing with placebo for the entire study.  
None of the reported deviations were considered to have affected subject safety or the overall 
conclusions of the study. 
6.3 
Analysis Sets 
A total of 217 subjects were randomized and included in the randomized set: 109 subjects in 
placebo group and 108 subjects in the dexlansoprazole capsules group. Two subjects were 
excluded from the safety analysis set and full analysis set because they did not receive study drug 
(Table 15.1.7).The remaining 215 subjects were included in the safety analysis set and full 
analysis set: 108 subjects in placebo group and 107 subjects in dexlansoprazole capsules group.  
6.4 
Demographics and Other Baseline Characteristics 
The mean age of the subjects was 44.3 years. More than half of subjects were female. For the 
number of days with heartburn at baseline, the mean values were similar between treatment 
groups. And for the mean severity of heartburn at baseline, the mean values were also similar 
between treatment groups. Detailed demographic and baseline characteristics data are 
summarized in Table 15.1.8.  
6.5 
Medical History and Concurrent Medical Conditions 
Similar percentages of subjects reported a medical history item across the treatment groups. The 
most common were Caesarean section (2.3%), hysterectomy (2.3%) and chronic gastritis (2.3%). 
The incidence for all other medical history items was low (<2%). Details of medical history 
information are provided in Table 15.1.9 and Appendix 16.2.4.2. 
The incidence of concurrent medical conditions was also similar across the treatment groups. 
The most common concurrent medical condition was chronic gastritis (48.4%) and Helicobacter 
test positive (16.3%). The details of the concurrent medial conditions information are listed in 
Table 15.1.10 and Appendix 16.2.4.3. 
6.6 
Medication History and Concomitant Medications 
6.6.1 Medication History 
The incidence of medication history was similar across the treatment groups. The most common 
of these medications were propofol (48.8%) and dyclonine hydrochloride (34.9%). The details of 
medication history information are listed in Table 15.1.11 and Appendix 16.2.4.4. 


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6.6.2 Concomitant Medications 
Concomitant medications included any medication taken which was ongoing as of Study Day 1, 
ended on or after Study Day 1 or started on or after Study Day 1 and no more than 1 day after the 
last dose of study drug. 
For the concomitant medications that started and stopped prior to baseline, the incidence was 
similar across the treatment groups, and the most common concomitant medications were 
propofol: dexlansoprazole capsules group (54.2%) and placebo group (54.6%); dyclonine 
hydrochloride: dexlansoprazole capsules group (43.0%) and placebo group (34.3%); and 
hydrotalcite: dexlansoprazole capsules group (29.0%) and placebo group (38.0%). 
For the concomitant medications that started prior to and were ongoing at baseline, the incidence 
in dexlansoprazole capsules group (15.9%) was less than that in placebo group (27.8%), and the 
most common concomitant medications was hydrotalcite: dexlansoprazole capsules group 
(3.7%) and placebo group (8.3%). 
For the concomitant medications that started after baseline, the incidence in dexlansoprazole 
capsules group (34.6%) was less than that in placebo group (45.4%), and the most common 
concomitant medications was hydrotalcite: dexlansoprazole capsules group (15.9%) and placebo 
group (23.1%). 
For the concomitant medications that were ongoing at baseline and those that started after 
baseline, the incidence in dexlansoprazole capsules group (39.3%) was less than that in placebo 
group (53.7%), and the most common concomitant medications was hydrotalcite: 
dexlansoprazole capsules group (16.8%) and placebo group (25.9%). 
The details of the concomitant medications information are summarized in Table 15.1.12.1, 
15.1.12.2, 15.1.12.3, and 15.1.12.4, and by-subject listing are presented in Appendix 16.2.4.5. 
The glossary of medication history and concurrent medications by preferred medication name is 
provided in Table 15.1.13. 
6.7 
Study Drug Exposure and Overdose 
The mean duration of study drug exposure was the same in each treatment group (26.8 days). 
Mean study drug compliance was high in both groups, with values over 99%. Diary compliance 
was high in both treatment groups, with 95.74% compliance in the placebo group and 93.84% in 
the dexlansoprazole group. 
The details of study drug exposure and compliance information are summarized in Table 15.1.14 
and listed in Appendix 16.2.5.1 and 16.2.5.2. 


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7.0 
EFFICACY EVALUATION 
The FAS was used for the summary of the efficacy endpoints. All the efficacy data are presented 
in Appendix 16.2.6.2 and 16.2.6.3. 
7.1 
Primary and Secondary Efficacy Endpoint 
The median percentage of days with neither daytime nor nighttime heartburn for subjects in the 
dexlansoprazole capsules group (51.72%) was greater than for subjects in the placebo group 
(32.67%) with the difference of 19.05%. The difference between treatment groups was not 
statistically significant (P=0.057) (Table 7.a.). 
Subgroup analyses were performed on the primary endpoint, and these results are presented in 
Table 7.b. For subjects with positive H pylori results, the median percentage of days with neither 
daytime nor nighttime heartburn for subjects in the dexlansoprazole capsules group (68.62%) 
was greater than for those in the placebo group (34.62%), and the difference (34.00%) was 
statistically significant with p-value = 0.032. For subjects with the highest overall study drug 
compliance (≥90%), the median in the dexlansoprazole capsules group (51.72%) was also greater 
than for those in the placebo group (30.29%), and the difference (21.43%) was statistically 
significant with p-value = 0.037. 
For the secondary endpoint of percentage of days without nighttime heartburn over 4 weeks, the 
median value of dexlansoprazole capsules group (67.86%) was greater compared with placebo 
group (54.67%). The difference (13.19%) between treatment groups was not statistically 
significant (P=0.268) (Table 7.a). 
For the percentage of days without daytime heartburn over 4 weeks, the median value of 
dexlansoprazole capsules group (62.96%) was greater compared with placebo group (46.55%) 
(Table 7.a). 
An ad hoc sensitivity analysis was performed on the primary and secondary efficacy endpoints.. 
For primary efficacy endpoint, the difference between treatment groups was statistically 
significant (P=0.029) (Table 15.2.6). For the secondary efficacy endpoint, the difference between 
the treatment groups was not statistically significant (P=0.365) (Table 15.2.7). 
 
 


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Table 7.a 
Percentage of Days Without Heartburn During Treatment (Full Analysis 
Set) 
 
Placebo 
QD 
N = 108 
Dexlansoprazole 
30 mg QD 
N = 107 
Primary endpoint: percentage of days with neither daytime nor nighttime heartburn during treatment a 
N 
108 
107 
Mean (SD) 
36.98 (31.999) 
47.21 (35.995) 
Median  
32.67 
51.72 
P-value b 
 
0.057 
Secondary endpoint: percentage of days without nighttime heartburn during treatment 
N 
108 
107 
Mean (SD) 
50.38 (34.309) 
54.83 (37.449) 
Median 
54.67 
67.86 
P-value b 
 
0.268 
Additional endpoint: percentage of days without daytime heartburn during treatment 
N 
108 
107 
Median 
46.55 
62.96 
Source: Table 15.2.1. 
QD: once daily. 
a Percentage of days with neither daytime nor nighttime heartburn = (the days that are heartburn-free during 
treatment period) / (total number of days for which either a daytime or nighttime result is marked during treatment 
period) × 100%.  
b The 2-sided p-value was obtained using the Wilcoxon rank-sum test. 
 


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Table 7.b 
Subgroup Analyses of Percentage of Days With Neither Daytime Nor 
Nighttime Heartburn Over 4 Weeks (Full Analysis Set) 
 
Placebo 
QD 
N=108 
Dexlansoprazole 
30 mg QD 
N=107 
Age (<45 years) 
N 
46 
50 
Mean (SD) 
39.40 (34.297) 
53.09 (34.458) 
P-value 
 
0.068 
Age (≥45 to 65 years) 
 
 
N 
57 
53 
Mean (SD) 
35.02 (29.633) 
41.79 (36.018) 
P-value 
 
0.472 
Age (≥65 years) 
 
 
N 
5 
4 
Mean (SD) 
37.17 (41.722) 
45.37 (52.932) 
P-value 
 
0.898 
Gender (Male) 
 
 
N 
43 
47 
Mean (SD) 
34.40 (33.307) 
49.51 (37.033) 
P-value 
 
0.063 
Gender (Female) 
 
 
N 
65 
60 
Mean (SD) 
38.70 (31.248) 
45.40 (35.370) 
P-value 
 
0.381 
BMI (<25 kg/m^2) 
 
 
N 
69 
72 
Mean (SD) 
37.94 (31.249) 
45.50 (36.638) 
p-value 
 
0.298 
BMI (≥25 to 30 kg/m^2) 
 
 
N 
34 
28 
Mean (SD) 
34.93 (33.229) 
51.55 (36.338) 
p-value 
 
0.104 
BMI (≥30 kg/m^2) 
 
 
N 
5 
7 
Mean (SD) 
37.78 (40.352) 
47.39 (30.665) 
p-value 
 
0.744 


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Placebo 
QD 
N=108 
Dexlansoprazole 
30 mg QD 
N=107 
H pylori status (positive) 
 
 
N 
41 
40 
Mean (SD) 
39.87 (30.941) 
55.95 (35.893) 
p-value 
 
0.032 
H pylori status (negative) 
 
 
N 
67 
67 
Mean (SD) 
35.22 (32.733) 
41.99 (35.294) 
p-value 
 
0.403 
Overall study drug compliance (<80%) 
 
 
N 
0 
1 
Mean (SD) 
 
0.00 (NA) 
p-value 
 
NA 
Overall study drug compliance (80-<90%) 
 
 
N 
1 
3 
Mean (SD) 
83.33 (NA) 
64.74 (37.701) 
p-value 
 
>0.999 
Overall study drug compliance (≥90%) 
 
 
N 
106 
103 
Mean (SD) 
35.95 (31.370) 
47.15 (35.884) 
p-value 
 
0.037 
Source: Table 15.2.2. 
Note 1: Percentage of days with neither daytime nor nighttime heartburn = (the days that are heartburn-free during 
Treatment Period)/(Total number of days for which either a daytime or nighttime result is marked during Treatment 
Period) * 100%.  
Note 2: The p-value was obtained using the Wilcoxon rank-sum test. 
7.2 
Additional Efficacy Endpoints 
7.2.1 Symptom Severity 
7.2.1.1 Investigator-Assessed Symptom Severity 
Investigator assessment of GERD symptoms included heartburn, acid regurgitation, dysphagia, 
belching, and epigastric pain. For each symptom, the investigator gave an assessment of none, 
mild, moderate, severe, and very severe, which were numerically scored as 0,1,2,3,4, 
respectively. Assessments were performed at baseline and at weeks 2 and 4, results are presented 
in Table 15.2.3. For each symptom the severity scores decreased from baseline at weeks 2 and 4 
for both placebo and dexlansoprazole groups. Reductions in severity for heartburn were 
significantly greater in the dexlansoprazole group than placebo for both Week 2 (p=0.009) and 
Week 4 (p=0.005). Reductions in severity for acid regurgitation and belching were statistically 


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significantly greater in the dexlansoprazole group than placebo at Week 4 (p=0.008 and 
p=0.042). There were no significant difference for dysphagia or epigastric pain. 
Some data issues about investigator-assessed GERD symptoms were discovered after database 
lock, therefore are not reflected in the above description: There were 3 subjects whose heartburn 
assessment at Week 4/Final Visit was entered into the database as “None,” but should have been 
“Mild.” The related subjects were 20002-003 (dexlansoprazole group), 20002-004 
(dexlansoprazole group ), and 20002-001 (placebo group). Subject 20002-001 (placebo group) 
also had acid regurgitation assessment at Week 4/Final Visit that was entered into the database 
as “Mild,” but should have been “None.” This was not expected to affect the analysis. More 
detailed information is listed in TAK 390MR_302_File_Note.zip.  
7.2.1.2 Subject-Reported Heartburn Severity 
For all the endpoints listed below, the mean value of dexlansoprazole capsules group was less 
than placebo group but the difference wasn’t statistically significant (Table 15.2.5).  
 The severity of daytime and nighttime heartburn over the 4 weeks of treatment as assessed by 
daily eDiary. 
 The severity of nighttime heartburn over the 4 weeks of treatment as assessed by daily 
eDiary.  
 The severity of daytime heartburn over the 4 weeks of treatment as assessed by daily eDiary. 
7.2.2 Rescue Medication Use 
For the percentage of days without rescue medication over 4 weeks, the mean value of 
dexlansoprazole capsules group (97.81%) was greater compared with placebo group (94.40%) 
and for the value reached 100%, the number of subjects in dexlansoprazole capsules group (84) 
was greater compared with placebo group (69). The distribution of the percentage of days 
without rescue medication use was statistically significant (P=0.009) (Table 15.2.4) different for 
the dexlansoprazole 30 mg QD and placebo. 
7.3 
Efficacy Conclusions 
In this 4-week study comparing treatment with dexlansoprazole 30 mg QD or placebo in Chinese 
subjects with symptomatic nonerosive GERD, subjects treated with dexlansoprazole had a 
greater percentage of days with neither daytime nor nighttime heartburn and without nighttime 
heartburn than subjects taking placebo, but these differences were not statistically significant 
according to the pre-planned analysis.  
Subjects in the dexlansoprazole treatment group with positive H pylori results or who were 
≥90% compliant with study drug did have a statistically significantly greater percentage of days 
without daytime and nighttime heartburn than those in the placebo group. Subjects in the 
dexlansoprazole treatment group also had statistically significantly greater reduction in severity 
of heartburn, acid regurgitation, and belching according to investigator assessment of symptoms 
after 4 weeks of treatment. In addition, subjects taking dexlansoprazole had a statistically 


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significantly greater percentage of days without rescue medication use over 4 weeks of 
treatment. 


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8.0 
SAFETY EVALUATION 
All the safety data were summarized in the safety analysis set.  
8.1 
Adverse Events 
Similar percentages of subjects experienced at least 1 TEAE in the placebo and dexlansoprazole 
groups (32.4% and 36.4%, respectively) (Table 8.a). The majority of TEAEs in both groups were 
mild in severity and were not related to study drug. 
No subjects died during the study (Appendix 16.2.7.4). One subject in the dexlansoprazole group 
experienced an SAE; the event was not related to study drug and did not lead to premature 
discontinuation (Appendix 16.2.7.3). Two subjects in each treatment group prematurely 
discontinued the study due to adverse events, the majority of which recovered and resolved 
(Appendix 16.2.7.2). 
Table 8.a 
Overview of Treatment-Emergent AEs (Safety Analysis Set) 
Category 
Placebo 
QD 
N=108 
Dexlansoprazole 
30 mg QD 
N=107 
Events 
Subjects n (%) 
Events 
Subjects n (%) 
Treatment-Emergent adverse event (TEAE) 
70 
35 (32.4) 
63 
39 (36.4) 
Mild 
61 
27 (25.0) 
47 
26 (24.3) 
Moderate 
7 
6 (5.6) 
13 
10 (9.3) 
Severe 
2 
2 (1.9) 
3 
3 (2.8) 
Related 
21 
13 (12.0) 
24 
15 (14.0) 
Not Related 
49 
22 (20.4) 
39 
24 (22.4) 
Leading to Study Drug Discontinuation 
3 
2 (1.9) 
5 
2 (1.9) 
Serious adverse event (SAE) 
0 
0 
1 
1 (<1) 
Related 
0 
0 
0 
0 
Not Related 
0 
0 
1 
1 (<1) 
Leading to Study Drug Discontinuation 
0 
0 
0 
0 
Deaths 
0 
0 
0 
0 
Source: Table 15.3.1.1. 
8.1.1 Display of Adverse Events 
All TEAEs are listed by subject in Appendix 16.2.7.1. Overall, the most frequently reported 
TEAEs occurring in ≥5% of subjects in either treatment group (by MedDRA PT) were upper 
respiratory tract infection and nasopharyngitis (Table 8.b). All of these were non-serious adverse 
events that were not considered by the investigator to be related to study drug, and none led to 
study drug discontinuation.  


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Table 8.b 
Most Frequent Treatment-Emergent Adverse Events by Preferred Term - 
PT Occurring in ≥5% of Subjects in Either Treatment Group (Safety 
Analysis Set) 
PT 
No. of Subjects (%) 
Placebo 
QD 
N=108 
Dexlansoprazole 
30 mg QD 
N=107 
Subjects with any TEAEs 
35 (32.4) 
39 (36.4) 
Upper respiratory tract infection 
8 (7.4) 
5 (4.7) 
Nasopharyngitis 
7 (6.5) 
4 (3.7) 
Source: Table 15.3.1.7.1. 
8.1.2 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
8.1.2.1 Deaths 
No death was reported. 
8.1.2.2 Other Serious Adverse Events 
One subject experienced a single serious adverse event during the study. This subject was in the 
dexlansoprazole group and experienced an event of “cat claw scratch” on Day 1. The event 
resolved on Day 50. It was not considered related to study drug and did not lead to 
discontinuation of study drug (Appendix 16.2.7.3). 
8.1.2.3 Other Significant Adverse Events 
A total of 4 subjects (2 from each group) experienced 8 TEAEs leading to study drug 
discontinuation (Appendix 16.2.7.2). All of these TEAEs were considered by the investigator to 
be related to study drug. In the placebo group, one subject discontinued from study drug due to 
dizziness (mild) and hypertension (moderate); the other subject discontinued from study drug 
due to sleep disorder (severe). In the dexlansoprazole group, one subject discontinued from study 
drug due to fall (mild), joint injury (mild), dizziness (mild), and syncope (moderate); the other 
subject discontinued from study drug due to dyspepsia (moderate). 
8.2 
Clinical Laboratory Evaluation 
8.2.1 Hematology 
By-subject hematology parameters result are presented in Appendix 16.2.8.1.1 and the out-of- 
normal-range results are presented in Appendix 16.2.8.1.5. 
Descriptive statistics for baseline, post baseline, and change from baseline to post baseline values 
for relevant hematology parameters are summarized in Table 15.3.4.1.3. Mean changes from 
baseline in hematology parameters in both groups were small and were not clinically concerning. 


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Some shifts from baseline to week 4 in hematology values were observed in both treatment 
groups and are summarized in Table 15.3.4.1.5. These shifts occurred in few subjects overall, 
and none were clinically concerning.  
Hematology MAVs are summarized in Table 15.3.4.1.7.1 and listed in Appendix 16.2.8.1.8. No 
subjects in the dexlansoprazole group had hematology MAVs during treatment. Two subjects in 
the placebo group had hematology MAVs at week 4. One subject had markedly abnormally low 
hemoglobin (<88g/L). The second subject had markedly abnormally low platelets (<75× 
103/µL). The hematology MAVs were not reported as AEs. 
No subject had abnormalities in hematology parameters that were classified as SAEs. 
8.2.2 Serum Chemistry 
By-subject serum chemistry parameters results are presented in Appendix 16.2.8.1.2 and the out-
of-normal-range result was presented in Appendix 16.2.8.1.6. 
Descriptive statistics for baseline, post baseline, and change from baseline to post baseline values 
for relevant serum chemistry parameters are summarized in Table 15.3.4.1.4. Mean changes 
from baseline in chemistry parameters in both groups were small and were not clinically 
concerning. 
Some shifts from baseline to week 4 in chemistry values were observed in both treatment groups 
and are summarized in Table 15.3.4.1.6. These shifts occurred in few subjects overall, and none 
were clinically concerning.  
Chemistry MAVs are summarized in Table 15.3.4.1.7.1 and listed in Appendix 16.2.8.1.8. Two 
subjects (1 in each group) had a chemistry MAV during treatment. None of the MAVs were 
reported as an AE and none were clinically concerning. 
8.2.3 Urinalysis 
By-subject urinalysis results are presented in Appendix 16.2.8.1.3 and the out-of-normal range 
results are presented in Appendix 16.2.8.1.7. None of the urinalysis results were clinically 
concerning. 
8.2.4 Serum Gastrin 
The percentages of subjects with elevated gastrin values ≥200 pg/mL and ≥400 pg/mL are 
presented in Table 8.c. The number and the percentage of subjects with elevated gastrin values 
was greater in the dexlansoprazole capsules group than in the placebo group at week 4. 
Descriptive statistics for baseline, post baseline, and change from baseline to post baseline values 
for gastrin are summarized in Table 15.3.4.1.10. The mean change value in the dexlansoprazole 
capsules group (73.9 pg/mL) were greater than those in the placebo group (-3.8 pg/mL) at week 
4. 


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Table 8.c 
Summary of Gastrin Results (Safety Analysis Set) 
Elevated Gastrin Values 
No. of Subjects (%) 
Placebo 
QD 
N=108 
Dexlansoprazole 
30 mg QD 
N=107 
No. of Subjects at Visit 4 (Week 4) 
102 
103 
≥200 pg/mL 
6 (5.9) 
15 (14.6) 
≥400 pg/mL 
3 (2.9) 
4 (3.9) 
Source: Table 15.3.4.1.8. 
8.3 
Vital Signs 
By-subject vital signs data are presented in Appendix 16.2.8.2.1. Details of vital signs MAVs are 
summarized in Table 15.3.4.2.3.2 and listed in Appendix 16.2.8.2.2. 
The descriptive statistics for baseline, post baseline, and change from baseline to post baseline 
values for vital signs are summarized in Table 15.3.4.2.2. The mean changes from baseline to 
week 4 in each group were small and not clinically concerning. 
None of the vital signs MAVs were reported as an AE and none were clinically concerning. 
8.4 
12-Lead ECGs 
By-subject ECG results are presented in Appendix 16.2.8.3.1. The descriptive statistics for 
baseline, post baseline, and change from baseline to post baseline ECG results are summarized in 
Table 15.3.4.3.2. 
ECG MAVs are summarized in Table 15.3.4.3.3 and are listed by subject in Appendix 
16.2.8.3.2. None of the ECG MAVs were reported as an AE and none were clinically 
concerning. 
Shifts in ECG interpretation results are summarized in Table 15.3.4.3.4 and none were clinically 
concerning. 
8.5 
Other Observations Related to Safety 
Physical examination results are presented in Appendix 16.2.8.4. 
8.6 
Safety Conclusions 
In this 4-week study in Chinese subjects with symptomatic non-erosive GERD, treatment with 
dexlansoprazole 30 mg QD was generally well tolerated. The incidence of TEAEs was similar 
between subjects taking placebo or dexlansoprazole; most events were mild in intensity and were 
considered unrelated to treatment. The most frequently reported TEAEs were consistent with the 
known safety profile of dexlansoprazole. Few subjects experienced an AE that led to premature 
discontinuation. No study drug-related SAE was reported. There were no remarkable findings in 
the safety clinical laboratory, vital signs, or ECG data. Overall, no safety concerns were 
identified in this study. 


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9.0 
DISCUSSION AND OVERALL CONCLUSIONS 
9.1 
Discussion 
Phase 3 studies performed in the United States have demonstrated positive results using 
dexlansoprazole capsules for heartburn relief in subjects with symptomatic nonerosive GERD. 
This study was the first to examine the efficacy and safety of dexlansoprazole capsules in 
Chinese subjects with symptomatic nonerosive GERD. 
The main objective of this phase 3, double-blind, randomized study was to compare the efficacy 
of dexlansoprazole capsule (30 mg QD) and placebo in relief of daytime and nighttime heartburn 
over 4 weeks in Chinese subjects with symptomatic nonerosive GERD as assessed by daily 
electronic diary (eDiary). 
No major differences in subject disposition were observed across treatment groups. Subject 
discontinuation rates in dexlansoprazole capsules groups (3.7%) were generally lower than 
placebo group (5.5%). Treatment compliance was high in all groups, with ≥97% of the total 
215 subjects maintaining greater than 90% compliance with the dosing schedule. Similarly, no 
major differences were observed across treatment groups in subject demographics. More females 
(58.1%) were enrolled in the study (consistent across treatment groups); however, this gender 
difference did not have an impact on the analysis of efficacy results. Approximately 51% of 
subjects were aged from 45 to 65 years. A small proportion of subjects were aged 65 years or 
older (4.2%); therefore, any interpretation of efficacy results in these subjects is limited. 
The results of Study TAK-390MR_302 showed that, although subjects in the dexlansoprazole 
group had a greater percentage of days with neither daytime nor nighttime heartburn than those 
taking placebo, the results of the primary endpoint (percentage of days and nights without 
heartburn) did not reach statistical significance based on the original planned analysis (p=0.057). 
Statistical significance was missed by a small margin. As an indication of how close the results 
were to reaching significance, when analyzed in subjects with the highest treatment compliance 
(≥90%), the difference was statistically significant; these results indicate that dexlansoprazole 
treatment was more effective than placebo for treating Chinese subjects with symptomatic 
nonerosive GERD when the medication was taken consistently. Subjects who took 
dexlansoprazole also had a greater percentage of nights without heartburn than those who took 
placebo, but the difference was not statistically significant. Subjects in the dexlansoprazole group 
had statistically significantly greater reductions in investigator-assessed symptoms of heartburn, 
acid regurgitation, and belching after 4 weeks of treatment, and also used statistically 
significantly less rescue medication than subjects in the placebo group. 
After the unblinded results for the primary and secondary endpoints were available, an ad hoc 
sensitivity analysis (two sample t-test) was performed to explore the influence of the higher than 
expected placebo response in light of the fact that the p-value for the primary analysis of the 
primary endpoint was insignificant by only a small amount. The sensitivity analysis results in a 
statistically significant difference between the group means for the primary endpoint (percentage 
of days with neither daytime nor nighttime heartburn, p=0.029). The difference between groups 


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for the secondary endpoint (percentage of days without nighttime heartburn) was not statistically 
significant based on the sensitivity analysis (p=0.365). 
The results of Study TAK-390MR_302 were similar to Study T-GD05-137 (on which the 
assumptions for study power were based) for measuring the dexlansoprazole treatment effect, but 
were not consistent for measuring the placebo effect. Because this was a well-controlled clinical 
trial, a few of the reasons that might explain this outcome are discussed herein.  
One possible reason for the outcome of this study is random chance. With a type 1 error rate of 
5%, this study had a 1 in 20 chance of showing non-significant results when a true treatment 
difference existed. It is interesting to recall that in the dexlansoprazole pivotal trials, a stronger 
level of significance (α=0.0025) was used and satisfied.  
Another possible reason for the outcome may be that the placebo effect is higher among the 
population sampled in this study than the population sampled in previous dexlansoprazole 
studies. In this case, the situation is not that the active treatment is disproven as effective, but is 
that the study wasn’t adequately powered to measure the treatment differences. The assumptions 
for which this study was powered (ie, sample size determination) were based on Study T-GD05-
137, in which the mean percentage of days without daytime or nighttime heartburn for subjects 
taking placebo was 25%; this placebo response rate was similar in the other dexlansoprazole 
studies that included a placebo arm (Studies T-GD04-082 and T-GD07-170). High placebo 
response rates have been observed in other studies of symptomatic GERD [1-3]. Chinese 
subjects who took placebo in Study TAK-390MR_302, however, had a higher placebo response 
rate (mean percentage of days without daytime or nighttime heartburn was 37%).  
A final reason for the outcome of Study TAK-390MR_302 may be that the disease burden of 
those sampled was not exactly comparable to that of the patients who participated in the US 
pivotal and supportive studies, which resulted in the higher than expected placebo response.  
For at least two of the three possible reasons described here, the lack of statistical significance 
shown for the primary endpoint in Study TAK-390MR_302 is not because of a lack of treatment 
effect, but because the study was not adequately powered to detect the treatment differences. The 
result of the ad hoc sensitivity analysis supports this conclusion. The t-test used in the sensitivity 
analyses is a more statistically powerful test than the Wilcoxon rank sum test, when certain 
assumptions are met. In the case of a large sample size (eg. 200 subjects), the t-test is robust. 
Although the placebo response rate observed in this study of Chinese subjects was unexpected 
based on previous dexlansoprazole data, it is not inconsistent with the results of a similar study 
in another Asian population. Specifically, Hongo, et al, studied the efficacy of famotidine (an 
H2RA) in Japanese patients with nonerosive reflux disease in a double-blind, placebo-controlled, 
parallel-group, multicenter study [4]. The percentage of days without heartburn over 8 weeks for 
subjects on active treatment in this study ranged between 59% and 62% depending on dose, 
while subjects who took placebo had a response rate of 55%. The authors who reported the 
results of this study concluded that “the efficacy of placebo is considerably higher in Japanese 
nonerosive GERD patients than in Western nonerosive GERD patients.”  


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There may be several physiological reasons for the higher-than-expected placebo response rate 
observed in Chinese patients with symptomatic nonerosive GERD in Study TAK-390MR_302. 
Asian patients have lower gastric acid output than white patients [5], as well as lower rates of 
TLESR [6]; thus, Asian patients may experience fewer acid-related GERD symptoms than their 
western counterparts. It has also been suggested that factors other than acid may be important in 
the pathophysiology of nonerosive GERD in Chinese patients, such as esophageal 
hypersensitivity, weakly acid or weakly alkaline reflux, or psychosocial factors [7]. This 
hypothesis was based on the results of an esomeprazole study in Chinese patients with 
symptomatic nonerosive GERD, in which esomeprazole was effective in relieving symptoms, 
but a lower complete symptom response rate was observed than in studies of PPIs in Western 
patients with nonerosive GERD. It is important to keep in mind, however, that it is not possible 
to draw definitive conclusions about placebo response rates in Asian patients compared to their 
western counterparts based only on data from 2 relatively small studies in Chinese patients. 
For the additional analyses, a statistically significant improvement in the days without rescue 
medication over 4 weeks was observed for dexlansoprazole capsules compared with placebo. For 
each GERD symptom, the mean severity scores decreased from baseline at weeks 2 and 4 for 
both placebo and dexlansoprazole groups. Reductions in severity for heartburn were significantly 
greater in the dexlansoprazole group than placebo for both Week 2 (p=0.009) and Week 4 
(p=0.005). Reductions in severity for acid regurgitation and belching were significantly greater 
in the dexlansoprazole group than placebo at Week 4 (p=0.008 and p=0.042). There were no 
significant difference for dysphagia or epigastric pain. 
The proportion of subjects with any TEAE was similar in the placebo and dexlansoprazole 
groups (32.4% and 36.4%, respectively).The proportion of subjects with a TEAE that led to 
study discontinuation was low, supporting that dexlansoprazole capsules were well tolerated by 
Chinese subjects. Only one SAE was observed, but it was not considered to be related to study 
drug. No deaths were reported during this study. There were no abnormalities that were 
classified as SAEs with respect to vital signs, ECG results, or laboratory parameters. 
9.2 
Conclusion 
In this 4-week study of dexlansoprazole 30 mg or placebo in Chinese subjects with symptomatic 
nonerosive GERD, dexlansoprazole was safe and well tolerated. Subjects taking dexlansoprazole 
had a greater percentage of days without daytime or nighttime heartburn (difference of 19 
percentage points) and without nighttime heartburn alone (difference of 13 percentage points) 
than subjects taking placebo, but the differences between the treatment groups were not 
statistically significant. Statistically significant improvements were observed, however, in 
several investigator-assessed GERD symptoms after 4 weeks of treatment with dexlansoprazole 
(an additional endpoint). In addition, subjects taking dexlansoprazole used statistically 
significantly less rescue medication than those taking placebo. 


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10.0 
REFERENCES 
1. 
Aciphex (rabeprazole sodium) Delayed-Release Tablets. Full Prescribing Information. 
Woodcliff Lake, NJ: Eisai Inc., Revised June 2018. 
2. 
Nexium (esomeprazole magnesium) Delayed-Release Capsules, Delayed-Release Oral 
Suspension. Full Prescribing Information. Wilmington, DE: AstraZeneca 
Pharmaceuticals LP, Revised December 2014. 
3. 
DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of 
gastroesophageal reflux disease. Am J Gastroenterol 2005;100(1):190-200. 
4. 
Hongo M, Kinoshita Y, Haruma K. A randomized, double-blind, placebo-controlled 
clinical study of the histamine H2-receptor antagonist famotidine in Japanese patients 
with nonerosive reflux disease. J Gastroenterol 2008;43(6):448-56. 
5. 
Sharma P, Wani S, Romero Y, Johnson D, Hamilton F. Racial and geographic issues in 
gastroesophageal reflux disease. Am J Gastroenterol 2008;103(11):2669-80. 
6. 
Wu JC. Gastroesophageal reflux disease: an Asian perspective. J Gastroenterol Hepatol 
2008;23(12):1785-93. 
7. 
Tan VP, Wong WM, Cheung TK, Lai KC, Hung IF, Chan P, et al. Treatment of non-
erosive reflux disease with a proton pump inhibitor in Chinese patients: a randomized 
controlled trial. J Gastroenterol 2011;46(7):906-12. 
 
 


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Appendix A Criteria for Identification of Markedly Abnormal Laboratory Values 
Hematology—Criteria for Markedly Abnormal Values 
Parameter 
Low Abnormal 
High Abnormal 
Hemoglobin 
<0.8 × LLN, 
>1.2 × ULN 
Hematocrit 
<0.8 × LLN, 
>1.2 × ULN  
RBC count  
<0.8 × LLN,  
>1.2 × ULN 
WBC count  
<0.5 × LLN 
>1.5 × ULN 
Platelet count 
<75 x 103/L 
>600 x 103/L 
RBC=red blood cell, WBC=white blood cell. LLN=lower limit of normal, ULN=upper limit of normal 
Chemistry—Criteria for Markedly Abnormal Values 
Parameter 
Low Abnormal 
High Abnormal 
ALT 
-- 
>3x ULN 
AST 
-- 
>3x ULN 
GGT 
-- 
>3x ULN 
Alkaline phosphatase 
-- 
>3x ULN 
Total bilirubin 
-- 
>2.0 mg/dL 
Albumin 
<2.5 g/dL 
-- 
Total protein 
<0.8x LLN 
>1.2x ULN 
Creatinine 
-- 
>2.0 mg/dL 
Blood Urea Nitrogen 
-- 
>30 mg/dl 
Sodium 
<130 mEq/L 
>150 mEq/L 
Potassium 
<3.0 mEq/L 
>6.0 mEq/L 
CPK 
-- 
>5 x ULN 
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, CPK=creatine 
phosphokinase, LLN=lower limit of normal, ULN=upper limit of normal. 
 


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Appendix B Criteria for Markedly Abnormal Values for Vital Signs 
Parameter 
Unit 
Lower Criteria  
Upper Criteria 
Pulse 
bpm 
<50  
>120 
Systolic blood pressure 
mm Hg 
<85  
>180  
Diastolic blood pressure 
mm Hg 
<50  
>110 
Body temperature 
oC 
<35.6 
>37.7 
 


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Appendix C Criteria for Markedly Abnormal Values for Electrocardiograms 
Parameter 
Unit 
Lower Criteria  
Upper Criteria 
Heart Rate 
bpm 
<50 
>120 
QT Interval 
msec 
≤50 
≥460 
QTcB Interval 
msec 
≤50 
≥500  
OR  
≥30 change from baseline and ≥450 
QTcF Interval 
msec 
≤50 
≥500  
OR  
≥30 change from baseline and ≥450 
 


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11.0 
DATA ISSUE NARRATIVES 
There are some data issues after site quality control, but they didn’t make a difference to the 
overall conclusion. For the data issues about protocol deviations and GERD symptoms, they 
were noted in section 6.2 and 7.2, respectively. For the other data issues, they were all listed in 
TAK 390MR_302_File_Note.zip. 


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12.0 
APPENDIX 
12.1 
Source Database, Analytic Database and Corresponding Variable Specification 
Document 
The content was stored in the ZIP file "TAK-390MR_302-Statistical-Analysis-Report- 
Appendix.zip" as the appendix of the document. 
12.2 
Flow Chart of Subject Disposition 
Please refer to Figure 6.a Disposition of Subjects. 
12.3 
Randomization Scheme 
The content was stored in the ZIP file "TAK-390MR_302-Statistical-Analysis-Report- 
Appendix.zip" as the appendix of the document. 
12.4 
Blind Review Resolutions 
The content was stored in the ZIP file "TAK-390MR_302-Statistical-Analysis-Report- 
Appendix.zip" as the appendix of the document. 
12.5 
Statistical Figures and Tables Supplementary to the Main Text 
The content was stored in the ZIP file " TAK-390MR_302-Statistical-Analysis-Report- 
Appendix.zip" as the appendix of the document. 
12.6 
Data Issue File Note 
The content was stored in the ZIP file " TAK-390MR_302-Statistical-Analysis-Report- 
Appendix.zip" as the appendix of the document. 
12.7 
Detailed Description of Amendments to Text 
Change 1: Correct the incidence of TEAEs that were mild in intensity and recovered/resolved. 
The change occurs in Synopsis: 
Initial wording: All TEAEs were mild in intensity and all recovered and resolved. 
Amended wording: All Most TEAEs were mild in intensity and all recovered and resolved. 
Rationale for Change: Correct wording. 
 
Change 2: Correct the cross-references for some data presented and correct the description of 
how many adverse events that led to premature discontinuation had recovered or resolved. 
The change occurs in Section 8.1 Adverse Events: 


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Initial wording: No subjects died during the study (Appendix16.2.7.3). One subject in the 
dexlansoprazole group experienced an SAE; the event was not related to study drug and did not 
lead to premature discontinuation (Appendix 16.2.7.4). Two subjects in each treatment group 
prematurely discontinued the study due to adverse events that all recovered and resolved 
(Appendix16.2.7.2). 
Amended wording: No subjects died during the study (Appendix 16.2.7. 34). One subject in the 
dexlansoprazole group experienced an SAE; the event was not related to study drug and did not 
lead to premature discontinuation (Appendix 16.2.7.43). Two subjects in each treatment group 
prematurely discontinued the study due to adverse events that all, the majority of which 
recovered and resolved (Appendix 16.2.7.2). 
Rationale for Change: Correct wording and source data. 
 
Change 3: Add the information about adverse events that led to study discontinuation as “other 
significant adverse events.” 
The change occurs in Section 8.1.2.3 Other Significant Adverse Events: 
Initial wording: No other significant adverse event was reported. 
Amended wording: No other significant adverse event was reported. A total of 4 subjects (2 
from each group) experienced 8 TEAEs leading to study drug discontinuation (Appendix 
16.2.7.2). All of these TEAEs were considered by the investigator to be related to study 
drug. In the placebo group, one subject discontinued from study drug due to dizziness 
(mild) and hypertension (moderate); the other subject discontinued from study drug due to 
sleep disorder (severe). In the dexlansoprazole group, one subject discontinued from study 
drug due to fall (mild), joint injury (mild), dizziness (mild), and syncope (moderate); the 
other subject discontinued from study drug due to dyspepsia (moderate). 
Rationale for Change: Add the information that was inadvertently left out of the original SAR. 
 
Change 4: Clarify the type of markedly abnormal hematology values observed during the study. 
The change occurs in Section 8.2.1 Hematology : 
Initial wording: Hematology MAVs are summarized in Table 15.3.4.1.7.1 and listed in Appendix 
16.2.8.1.8. No subjects in the dexlansoprazole group had hematology MAVs during treatment. 
Two subjects in the placebo group had hematology MAVs at week 4. One subject had decreased 
hemoglobin (<88g/L). The second subject had decreased platelets (<75× 103/µL). The 
hematology MAVs were not reported as AEs. 
Amended wording: Hematology MAVs are summarized in Table 15.3.4.1.7.1 and listed in 
Appendix 16.2.8.1.8. No subjects in the dexlansoprazole group had hematology MAVs during 
treatment. Two subjects in the placebo group had hematology MAVs at week 4. One subject had 
decreased markedly abnormally low hemoglobin (<88g/L). The second subject had decreased 


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markedly abnormally low platelets (<75× 103/µL). The hematology MAVs were not reported 
as AEs. 
Rationale for Change: Clarify wording. 
 
Change 5: Correct the cross-references for some data presented and add the number of observed 
records of visit 4 (week 4) and clarity the format of table for the summary of gastrin results. 
The change occurs in Section 8.2.4 Serum Gastrin: 
Initial text and table: Descriptive statistics for baseline, post baseline, and change from baseline 
to post baseline values for gastrin are summarized in Table 15.3.4.1.8.a. The mean change value 
in the dexlansoprazole capsules group (73.9 pg/mL) were greater than those in the placebo group 
(-3.8 pg/mL) at week 4. 
Table 8.c 
Summary of Gastrin Results (Safety Analysis Set) 
Elevated Gastrin Values 
No. of Subjects (%) 
Placebo 
QD 
N=108 
Dexlansoprazole 
30 mg QD 
N=107 
During Treatment (a) 
 
 
≥200 pg/mL 
6 (5.7) 
15 (14.3) 
≥400 pg/mL 
3 (2.8) 
4 (3.8) 
 
 
 
By Visit 
 
 
Visit 4 (Week 4) 
 
 
≥200 pg/mL 
6 (5.9) 
15 (14.6) 
≥400 pg/mL 
3 (2.9) 
4 (3.9) 
Note: (a) At least one markedly abnormal result During treatment.   
Source: Table 15.3.4.1.8. 
Amended text and table: Descriptive statistics for baseline, post baseline, and change from 
baseline to post baseline values for gastrin are summarized in Table 15.3.4.1.8.a10. The mean 
change value in the dexlansoprazole capsules group (73.9 pg/mL) were greater than those in the 
placebo group (-3.8 pg/mL) at week 4. 


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Table 8.c 
Summary of Gastrin Results (Safety Analysis Set) 
Elevated Gastrin Values 
No. of Subjects (%) 
Placebo 
QD 
N=108 
Dexlansoprazole 
30 mg QD 
N=107 
During Treatment (a) 
 
 
≥200 pg/mL 
6 (5.7) 
15 (14.3) 
≥400 pg/mL 
3 (2.8) 
4 (3.8) 
 
 
 
By Visit 
 
 
No. of Subjects at  Visit 4 (Week 4) 
102 
103 
≥200 pg/mL 
6 (5.9) 
15 (14.6) 
≥400 pg/mL 
3 (2.9) 
4 (3.9) 
Note: (a) At least one markedly abnormal result During treatment.   
Source: Table 15.3.4.1.8. 
Rationale for Change: Add the information that was inadvertently left out of the original SAR. 
 
Change 6: Modify the language in the safety conclusion regarding the SAE or AE that led to 
premature discontinuation for consistency with the clinical study report (Section 8.6). 
The change occurs in Section 8.6 Safety Conclusions: 
Initial wording: In this 4-week study in Chinese subjects with symptomatic non-erosive GERD, 
treatment with dexlansoprazole 30 mg QD was generally well tolerated. The incidence of TEAEs 
was similar between subjects taking placebo or dexlansoprazole; most events were mild in 
intensity and were considered unrelated to treatment. The most frequently reported TEAEs were 
consistent with the known safety profile of dexlansoprazole. Few subjects experienced an SAE 
or an AE that led to premature discontinuation. There were no remarkable findings in the safety 
clinical laboratory, vital signs, or ECG data. Overall, no safety concerns were identified in this 
study. 
Amended wording: In this 4-week study in Chinese subjects with symptomatic non-erosive 
GERD, treatment with dexlansoprazole 30 mg QD was generally well tolerated. The incidence of 
TEAEs was similar between subjects taking placebo or dexlansoprazole; most events were mild 
in intensity and were considered unrelated to treatment. The most frequently reported TEAEs 
were consistent with the known safety profile of dexlansoprazole. Few subjects experienced an 
SAE or  an AE that led to premature discontinuation. No study drug-related SAE was 
reported. There were no remarkable findings in the safety clinical laboratory, vital signs, or 
ECG data. Overall, no safety concerns were identified in this study. 
Rationale for Change: Clarify wording and for consistency with clinical study report. 
 


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Change 7: Replace the table of efficacy results with one that does not include the ad hoc 
analyses. Update references in text accordingly. 
The change occurs in Section 7.1 Primary and Secondary Efficacy Endpoint: 
Initial wording: An ad hoc sensitivity analysis was performed on the primary and secondary 
efficacy endpoints, and these results are also presented in Table 7.a. For primary efficacy 
endpoint, the difference between treatment groups was statistically significant (P=0.029). For the 
secondary efficacy endpoint, the difference between the treatment groups was not statistically 
significant (P=0.365). 
[Table 7.a including ad hoc analyses] 
Amended wording: An ad hoc sensitivity analysis was performed on the primary and secondary 
efficacy endpoints, and these results are also presented in Table 7.a. For primary efficacy 
endpoint, the difference between treatment groups was statistically significant (P=0.029) (Table 
15.2.6). For the secondary efficacy endpoint, the difference between the treatment groups was 
not statistically significant (P=0.365) (Table 15.2.7). 
[Table 7.a without ad hoc analyses and matching clinical study report] 
Rationale for Change: Consistency with clinical study report, in which ad hoc analyses are not 
included in the in-text efficacy table in order to clarify which analysis was pre-planned.